"support the hypothesis that early life gut microbiota are associated with neurodevelopmental outcomes in childhood"

Question: "Is the gut microbiome in infancy associated with neurodevelopment in children at preschool age?" Answer: "findings appear to support the hypothesis that early life gut microbiota are associated with neurodevelopmental outcomes in childhood."

That was the about the sum of the findings reported by Joanne Sordillo and colleagues [1] and their analyses of "Ages and Stages Questionnaire, third edition (ASQ-3)" data and "microbiome analysis using 16S rRNA gene sequencing" of stool samples from over 300 infants who were taking part in something called the "Vitamin D Antenatal Asthma Reduction Trial (VDAART)."

The Sordillo paper is open-access so doesn't require any rehashing from me. A few details do however stick out. So: "findings suggest that the infant gut microbiome may be associated with subsequent development of communication, personal and social, and fine motor skills in typical developing 3-year-old children and with odds of possible developmental delays." The authors were specifically drawn to "Clostridiales (Lachnospiraceae genera and other, unclassified Clostridiales taxa)" as being important when it came to their stool analyses. Said bacteria seemed to be *associated* with various ASQ-3 data covering "poorer ASQ-3 communication... and personal and social... scores and with increased odds of potential delay for communication... and personal and social skills."

The word 'autism' is also mentioned in the Sordillo paper, alongside the idea that (1) "poor performance of children on the ASQ-3 (particularly on communication skills) at 16 to 30 months of age has been shown to be sensitive (but not specific) for diagnosis of ASDs [autism spectrum disorders]", and (2) "A number of cross-sectional studies comparing the gut microbiome of neurotypical children with that in children with ASDs have reported increased levels of Clostridiales in the gut microbiome of individuals with ASDs, including higher levels of Clostridium,... Clostridium histolyticum,... and Ruminococcus." Indeed, there's also mention of the Luna study [2] covered on this blog previously (see here).

Obviously there are caveats to the Sordillo findings; not least that this all about looking at two variables (ASQ-3 scores and stool bacterial content) and marrying them together at some quite specific time points. I'd for example, be interested to see whether further follow-up studies saw a continuation of the trends described in this paper perhaps covering examination of multiple stool samples taken over different testing occasions. Also going back to the 'autism' suggestion, the authors note that they "did not have data on clinical diagnoses of ASDs for our analysis" so one has to be a little bit careful with any suggestions there too.

Still, such work is important and further contributes to the idea that the brain probably isn't the only place to look when considering things like cognitive and behavioural development (see here). Indeed, as mentioned previously on this blog (see here), a possible role for inflammation 'impairing' social cognitive processes might not be a million miles away from the Sordillo findings on the basis that the new triad - gut bacteria, intestinal permeability, gut immune function - might be really quite important for lots of processes. And then there is another question to consider: if one is able to 'alter' the gut bacterial make-up at an early age, can one potentially affect behavioural and/or developmental outcomes? I say that in the context that something similar has been talked about before (see here).

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[1] Sordillo JE. et al. Association of the Infant Gut Microbiome With Early Childhood Neurodevelopmental Outcomes. JAMA Netw Open. 2019; 2: e190905.

[2] Luna RA. et al. Distinct Microbiome-Neuroimmune Signatures Correlate With Functional Abdominal Pain in Children With Autism Spectrum Disorder. Cellular and Molecular Gastroenterology and Hepatology. 2017; 3: 218-230.

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Treating ADHD: better school results, less risk of crime and better sleep?

I

I had already written and scheduled in this blog post before an important - very important - headline appeared on the BBC News website: "ADHD [attention-deficit hyperactivity disorder] testing after 'impulsive crime' arrests should be mandatory, MPs say." The news piece covered, amongst other things, some of the peer-reviewed research findings suggesting that a diagnosis of ADHD appears to place someone at various enhanced risk for adverse life outcomes. And that potentially includes offending behaviour and prison time.

So...

Today's post is a bit of a mash-up insofar as bringing together three pieces of independent peer-reviewed research pertinent to the important idea of managing or 'treating' ADHD when it arises. I appreciate that not many people would want their nearest-and-dearest 'medicated' for example in the long-term. But when it comes to something like ADHD the case is indeed growing strong for how pharmacological intervention in particular, could literally be a life-saver for some (see here)...

The papers: first there are the findings reported by Andreas Jangmo and colleagues [1] who "analyzed school performance in students with ADHD compared to students without ADHD, and the association between pharmacological treatment of ADHD and school performance." This continues a research theme (see here). The second paper is that from Christina Mohr-Jensen and colleagues [2] which looked at "the risk of long-term conviction and incarceration associated with childhood attention-deficit/hyperactivity disorder (ADHD), and to identify risk and protective factors including associations with active treatment with ADHD medication." Again, this is a topic that has previously received quite a bit of study before (see here). Finally, I'd like to bring the paper by Stephen Becker and colleagues [3] to the blogging table, investigating whether "sleep duration is causally linked to sleepiness, inattention, and behavioral functioning in adolescents with ADHD." The answer: yes, yes it was, in line with other independent research (see here). And that potentially opens the door to intervention (see here).

Minus any sweeping generalisations from me or anyone else, the net result of these studies suggest that intervention for ADHD - primarily pharmacotherapy along the lines of what is currently indicated for ADHD - seems to have an important positive effect for many people diagnosed with ADHD. Some examples of this in action:

• School performance and ADHD: "ADHD was associated with substantially lower school performance independent of socioeconomic background factors." But the good news: "Treatment with ADHD medication for 3 months was positively associated with all primary outcomes" including higher grades and improving access to education. Such data was derived from a total sample size in the hundreds of thousands.
• Crime and ADHD: "Out of n=4,231 individuals with ADHD, n=1,355 (32.0%) had received at least one conviction compared to n=3,059 (15.6%) of the n=19,595 participants without ADHD." But... "The crime rates increased with the number of associated risks but were reduced during periods of taking ADHD medication."
• Sleep and ADHD: "Compared to the extended sleep week, parents reported more inattentive and oppositional symptoms during the restricted sleep week." The Becker study did not specifically talk about the use of intervention for sleep issues in the context of ADHD but it wouldn't be a giant leap to look at 'options' for improving sleep parameters in that context (and what knock-on effects this might have for behaviour).

Caveats? Well, correlation is not the same as causation, so even despite the 'strong' connections noted across these various studies mentioning ADHD, one cannot rule out other confounding variables playing a role. There's also the issue of balancing efficacy and safety to consider as and when any form of pharmacotherapy is introduced, something that is still being looked at with for example, methylphenidate and ADHD (paediatric ADHD) in mind [4]. I'm also minded to suggest that more fundamental work on the basis for ADHD should continue, alongside examination of the hows-and-whys of certain medicines *working* in the context of the biology of ADHD too. That, and an acceptance that medication might be but one tool in the arsenal (see here and see here and see here) to help prevent ADHD from negatively affecting a person's life and/or life chances.

But still the combined results are important. And they may well be important to those who don't quite reach all the thresholds for ADHD as a diagnosis [5] too... 

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[1] Jangmo A. et al. Attention-Deficit/Hyperactivity Disorder, School Performance, and Effect of Medication. J Am Acad Child Adolesc Psychiatry. 2019 Feb 1. pii: S0890-8567(19)30059-0.

[2] Mohr-Jensen C. et al. Attention-Deficit/Hyperactivity Disorder in Childhood and Adolescence and the Risk of Crime in Young Adulthood in a Danish Nationwide Study. J Am Acad Child Adolesc Psychiatry. 2019 Feb 11. pii: S0890-8567(19)30105-4.

[3] Becker SP. et al. Shortened Sleep Duration Causes Sleepiness, Inattention, and Oppositionality in Adolescents With ADHD: Findings From a Crossover Sleep Restriction/Extension Study. J Am Acad Child Adolesc Psychiatry. 2018 Nov 1. pii: S0890-8567(18)31914-2.

[4] Inglis SK. et al. Prospective observational study protocol to investigate long-term adverse effects of methylphenidate in children and adolescents with ADHD: the Attention Deficit Hyperactivity Disorder Drugs Use Chronic Effects (ADDUCE) study. BMJ Open. 2016;6(4):e010433.

[5] Kirova AM. et al. Are subsyndromal manifestations of attention deficit hyperactivity disorder morbid in children? A systematic qualitative review of the literature with meta-analysis. Psychiatry Res. 2019 Feb 3;274:75-90.

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Regression and autism: "The regression group was significantly more functionally impaired..."

The quote forming part of the title of today's post - "The regression group was significantly more functionally impaired..." - comes from the findings reported by Lucy Thompson and colleagues [1] (open-access available here). It continues something of an important theme in autism research circles whereby regression, as in a regression of previously acquired skills, is being seen as important not just for a few but for many (see here).

There were a few aims to the Thompson study such as establishing "the relative prevalence of regression in autism" and "possible predictors, mediators and moderators of regression in autism, including pre- and perinatal factors." The data for the study were derived from "two community-based cohorts" in Sweden totalling just over 300 participants (children) diagnosed with an autism spectrum disorder (ASD) who were observed over two different time points (T1 and T2 2 years later). Another important detail is mentioned by Thompson et al: "Given the lack of previous systematic representative studies in the field, our study sets out to be descriptive rather than hypothesis-driven." Figures and details on regression in the cohort(s) were obtained via specific questioning on this topic "defined as loss of expressive language skills (loss of 5 or more words that had been used communicatively) in connection with the onset of autism." This data was also combined with other medical records information to determine 'consistency'.

Results: "Just over 20% (62/303) of the combined sample of children had regressive autism." That's 1 in 5 children with autism experiencing some kind of regression in relation to language skills. When looking at those who regressed (n=62) compared with those with no regression (n=241), a few details emerged: "Those with regressive autism had a younger age when they first walked... had a more severe language impairment at T1... and more often intellectual disability... [and] lower mean VAB [Vineland Adaptive Behaviour Scales-II] scores." Also: "Severity of autism was higher in the regressive group, with a higher proportion of children with autism... (as opposed to autistic-like condition)."

This is important data. It kinda tallies with other studies of regression accompanying autism suggesting that those who regress tend to have a more 'severe' form of autism with accompanying learning (intellectual) disability. The diagnostic issues - as in more likely to be diagnosed with Kanner's autism rather than other diagnoses - similarly ties in with other findings.

Caveats? Well, a few: "We have chosen to focus on language regression specifically (rather than social, play or motor regression) as communication is by far the most common skill to be lost or diminished in regressive autism." That being said, regression accompanying autism seems to take many, many forms and does not always just mean a loss or partial loss of vocal communication (see here).

Also: "There was also a similar level of maternal disease in pregnancy in the regressive and non-regressive groups, suggesting that prenatal exposure via maternal disease does not seem to be a key feature in the development of regressive autism." I have to question why the authors stuck to looking at just pre- and perinatal factors as possibly being *linked* to regression when regression is likely to occur quite some time after such a developmental window. Surely it would have made more sense to ask a few further questions about the timing of regression - "The average age at regression was 20.13 months... with 54 children (88.5%) showing regression by the age of 24 months" - and whether one or more event might have proceeded such regression in a similar time frame. Y'know whether infection might be a feature (see here and see here for examples) or whether other events might require further investigation (see here). I know this might take such research down some uncomfortable paths, but temporality is surely an important factor for some regression in some cases of autism? Or am I being too unreasonable?

I might also advance the idea that the time to start asking questions about the biology of regression accompanying autism is fast approaching. We've already had some clues in the recent (at the time of writing) peer-reviewed research literature (see here) but lots more needs to be done in this area. Are there important genetic and/or epigenetic variables to consider? Do mitochondrial issues play a role in some regressive autism (see here)? We just don't know enough yet. And yes, this does mean also asking about whether regression in behaviour or cognitive skills was also accompanied by any changes to somatic variables too (see here).

And then there is another question to ask/answer: does regression mean that certain 'therapeutic' options might be particularly useful? I'm thinking back to some research a few years back talking about corticosterioid therapy *potentially* being indicated for some cases of regressive autism (see here). No, I'm not making any medical or clinical claims or giving any advice on such an issue. Merely mentioning that regressive autism needs to be more of a research priority than it currently is. To quote Thompson and colleagues again: "Children with a regressive developmental trajectory, with or without autism, always need a careful neuropediatric work-up to investigate possible neurological disorders that may lead to developmental regression, taking into account possible treatable conditions." Who would argue with that?

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[1] Thompson L. et al. Autism With and Without Regression: A Two-Year Prospective Longitudinal Study in Two Population-Derived Swedish Cohorts. J Autism Dev Disord. 2019 Feb 4.

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Breastfeeding and ADHD meta-analysed

Readers are asked to consider this post discussing the findings from Ping-Tao Tseng and colleagues [1] concerning breastfeeding and offspring attention-deficit hyperactivity disorder (ADHD) risk, an extension of other blogging chatter on the topic of breastfeeding and other offspring developmental outcomes (see here). The connections? Well, yes, both posts emphasise a possible *association* between breastfeeding and offspring development, but perhaps just as important, both posts will also emphasise how correlation is not necessarily the same as causation and how one has to be careful about making sweeping assumptions when it comes to breastfeeding *choice*...

Same as on the previous paper by Tseng and colleagues [2] I'll mention having a minor part to play in authoring the latest Tseng paper, and how such participation will in no way interfere with my hopefully critical musings on this latest publication.

The name of the research game this time around was to 'meta-analyse' the currently available collected peer-reviewed research literature into some sort of coherent 'where we're at' statement on the topic of breastfeeding practices and offspring ADHD risk. This wasn't about 'making' any new data; just synthesising what is already there on some specific topics: "(1) the difference in the duration of maternal breastfeeding between children with and without ADHD, and (2) the association between maternal breastfeeding and ADHD in children." A total of 11 articles pertinent to those research questions were identified and information was 'boiled down'.

Results: "an association was found between non-breastfeeding and ADHD children (adjusted OR = 3.71, 95% CI = 1.94 to 7.11, p < 0.001)." At first glance this looks like a pretty impressive *relationship* between 'non-breastfeeding' and the presence of a diagnosis of ADHD in offspring. It is, but it might not necessarily mean what you first think. Authors do mention how the early presentation of certain ADHD or possibly related traits might not have been conducive to successful breastfeeding behaviour to the point where a lack of 'cooperation' could have led to less breastfeeding. I'm not saying this is THE reason for the results we reported; merely that it is one possibility to entertain. There may also be other factors to take into consideration too (see here for example) minus any sweeping generalisations.

Whilst I am cautious about making too much of the Tseng findings - subsequent individual studies have reported no link [3] - other, more recent meta-analyses have arrived at similar conclusions to Tseng [4]. Yes, the Zeng paper [4] looked specifically at breastfeeding duration, and yes it was a meta-analysis that overlapped with material used in the Tseng study. But the conclusion - "maternal breastfeeding may reduce the risk of ADHD in children" - is similar, and again suggests closer inspection of any possible relationship specifically focused on the hows-and-whys.

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[1] Tseng PT. et al. Maternal breastfeeding and attention-deficit/hyperactivity disorder in children: a meta-analysis. Eur Child Adolesc Psychiatry. 2018 Jun 15.

[2] Tseng PT. et al. Maternal breastfeeding and autism spectrum disorder in children: A systematic review and meta-analysis. Nutr Neurosci. 2017 Oct 18:1-9.

[3] Schwenke E. et al. Predicting attention deficit hyperactivity disorder using pregnancy and birth characteristics. Arch Gynecol Obstet. 2018 Nov;298(5):889-895.

[4] Zeng Y. et al. Association between the different duration of breastfeeding and attention deficit/hyperactivity disorder in children: a systematic review and meta-analysis. Nutr Neurosci. 2018 Dec 21:1-13.

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"the incidence of ADHD, ASD, and DD significantly increased after TBI events in early childhood"

TBI mentioned in the title of this post refers to traumatic brain injury, and represents the 'target variable' examined by Hsuan-Kan Chang and colleagues [1] in the context of rates of "attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorder (ASD), and developmental delay (DD)."

Consistent with various other research published by this authorship group, the fantastic but sadly now defunct National Health Insurance Research Database (NHIRD) in Taiwan was the resource used by Chang et al in pursuit of their research goal. And the participant numbers under study reflected the use of the NHIRD: "A total of 7,801 and 31,204 children were enrolled in the TBI and control cohorts, respectively."

As well as instances of TBI being listed in the NHIRD "from 1998-2008", researchers also had access to "the incidence of subsequent ADHD, ASD, or DD (according to ICD-9 criteria)." They observed that: "The TBI cohort exhibited a higher incidence of subsequent ADHD, ASD, or DD than the controls" and that said developmental diagnoses tended to be made "at a younger age compared with the controls" (non-TBI controls). They concluded that TBI seemed to increase the risk of each developmental diagnosis and that "severe TBI, repeated TBI events, and TBI at a younger age" were all (variably) potentially important factors for the labels.

This is interesting and thought-provoking research. It does require some 'treading carefully' sentiments; not least with the idea that within the huge heterogeneity and variability of labels such as ADHD and autism (ASD), TBI *might* be a route or part of a possible route towards a diagnosis. Whilst not discounting the idea that sub-clinical signs and symptoms of developmental disorders could actually put someone at greater risk for TBI (see here for example), the possibility that TBI 'might lead to' a developmental diagnosis should not be shied away from. Indeed, other independent findings might also be important (see here). I say that mentioning that TBI is a general term that says nothing about the reason for the injury, the type of injury or what specific part of the brain may be affected. If one however takes autism as an example, it's not beyond the realms of possibility that certain TBIs could 'mimic' effects seen in other examples of 'acquired autism' where brain injury is part-and-parcel of the clinical picture (see here and see here). Indeed, similar sentiments have been expressed in relation to ADHD too (see here).

Whatever the relationship and mechanisms involved, the Chang findings imply that further investigations are needed in this area. Also, far greater efforts need to go into first preventing and then managing TBI...

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[1] Chang HK. et al. Traumatic Brain Injury in Early Childhood and Risk of Attention-Deficit/Hyperactivity Disorder and Autism Spectrum Disorder: A Nationwide Longitudinal Study. J Clin Psychiatry. 2018 Oct 16;79(6). pii: 17m11857.

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"greater autism severity predicted greater pain response"

Among the many pressing topics that require [significant] research funds and attention when it comes to autism, I can think of only a few (one actually) that top the observation that pain *might* be something particularly important when it comes to autism (see here). It is with this in mind that I briefly bring the findings reported by Domingo Garcia-Villamisar and colleagues [1] to the blogging table, and their conclusion that: "greater autism severity predicted greater pain response" that "was partially mediated by anxiety and depression."

Authors describe how they 'observed' over 40 adults diagnosed with autism and "intellectual delay" whilst they were undergoing either vaccination or dental cleaning. We are told that "their pain behaviours [were] coded and measures of autism symptom severity, anxiety, depression and obsessivity taken." When the data was gathered and analysed, authors observed that *association* between the intensity/severity of autistic signs and symptoms and the expression of pain. They concluded also that: "Mood must therefore be considered in future research on pain in ASD [autism spectrum disorder] as well as clinical pain management."

Accepting that 'pain coding' is something that requires a little more research, particularly in the context of autism, I'm willing to accept the authors' findings as a road-map to further investigations in this area. Given that conditions/states/symptoms like depression and anxiety are no strangers to autism (see here) it's perhaps implied that they may have quite a large bearing on pain expression in the context of autism.

And if something like anxiety and depression might be 'mediators' of the pain response, shouldn't we doing everything we can to alleviate such issues in the context of autism? Even if that means targeting core symptoms (see here and see here)?

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[1] Garcia-Villamisar D. et al. Internalizing Symptoms Mediate the Relation Between Acute Pain and Autism in Adults. J Autism Dev Disord. 2018 Sep 27.

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Do childhood sleep issues "have a causal role" in 'chronic disabling fatigue' in adolescence?

There's those words again: 'chronic disabling fatigue' or CDF, being used as a proxy for chronic fatigue syndrome (CFS, also known as 'ME') as per the findings reported by Simon Collin and colleagues [1].

Elements of this authorship group seem to be using CDF quite a bit (see here and see here) in their various research studies, and I have to say it's starting to get a little confusing (see here). I'll come back to my thoughts on the term CDF in a moment...

On this research occasion, Collin et al set out to explore whether "sleep might be a causal risk factor for CFS/ME" (or should that just be CDF) on the basis that sleep issues have been reported in that context previously [2]. Once again, "data from the Avon Longitudinal Study of Parents and Children (ALSPAC) birth cohort" was the research source material, and researchers were specifically looking at: "sleep patterns of children aged 6 months to 11 years, who were subsequently classified as having (or not having) 'chronic disabling fatigue'... between the ages 13 and 18 years." Sleep duration was quite a big element to this study.

So yeah, shorter night-time sleep duration from 6 months to 11 years of age did seem to show some connection to CDF. To quote: "The odds of CDF at age 13 years were 39% lower... for each additional hour of night-time sleep at age nine years, and the odds of CDF at age 16 years were 51% lower... for each additional hour of night-time sleep at age 11 years." This and a few other observations led authors to conclude that sleep abnormalities might have a role to play in relation to CFS/ME (sorry, CDF).

I have to say however, that I'm not particularly impressed with these findings. I say that on the basis that one set of variables (sleep) are being *correlated* with another later variable (CDF) and well, correlation does not necessarily equal causation. As per other work from this authorship group [2], they've also previously suggested that level of physical activity *might* also correlate with CFS/ME (sorry CDF) albeit with a reduced timescale between the variables. This dual research based on the same cohort I assume, kinda disqualifies any one variable from being related to CDF. Assuming that is, that sleep and physical activity are not somehow connected...

And then there's the issue of how sleep duration was measured in the latest Collin paper: "The sleep durations in our study were obtained from parents’ (mostly mothers’) answers to questions about the child’s usual bedtime and waking time, rather than from data collected in a sleep/wake diary or by actigraphy." So, they basically asked what time children went to bed and what time they woke up. There's nothing wrong with asking such questions but likewise there is little to confirm that children actually closed their eyes and nodded off the minute they went to bed and/or woke up the minute of parental report on waking. Anyone who has children knows that this is 'optimistic' at best (and indeed, takes no account of things like duration of night waking or quality of sleep for examples). The lack of use of actigraphy - that fabulous wearable tech that allows us to objectively chart sleep and activity cycles - is a real problem for elements of CFS/ME research (see here), and is something that is getting harder and harder to overlook. This includes the lack of use in this particular research study too.

Then, back to CDF. CDF basically comes about because we are told that "children in [the] study were not examined by a physician" when it comes to CFS/ME. Further: "CDF at ages 13 and 16 years was defined as fatigue (feeling tired or lacking in energy) of >6 months’ duration that was associated with absence from full-time school or that had prevented the child from taking part in activities ‘quite a lot’ or ‘a great deal’, excluding fatigue possibly associated with sport, snoring, and other illnesses." So fatigue is a primary symptom. But how can you exclude fatigue associated 'other illnesses'? Did the authors for example, screen for something like fatigue due to mitochondrial issues or disorders (see here)? No, they didn't appear to. Similarly there is no mention as far as I can see of another primary symptom of CFS/ME: post-exertional malaise (PEM). Important too was another quote from the authors: "Our definition of CDF did not exclude children with comorbid depressive symptoms." I'll say little more on this topic.

So, again, unfortunately I have to say that I'm left unimpressed by these latest findings from Collin and colleagues. And once again, I have to point out that CDF whilst described as "a proxy for chronic fatigue syndrome/ME" is not necessarily CFS or ME (and indeed, neither it seems, could it be both).

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[1] Collin SM. et al. Childhood sleep and adolescent chronic fatigue syndrome (CFS/ME): evidence of associations in a UK birth cohort. Sleep Med. 2018 Jun;46:26-36.

[2] Collin SM. et al. Physical activity at age 11 years and chronic disabling fatigue at ages 13 and 16 years in a UK birth cohort. Arch Dis Child. 2018 Jun;103(6):586-591.

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ALSPAC says... "Social communication impairments had the strongest association with a depression diagnosis at age 18 years"

ALSPAC mentioned in the title of this post refers to The Avon Longitudinal Study of Parents and Children, one of the premier research initiatives here in Blighty, that has provided all-manner of interesting and important research associations. With autism in mind, ALSPAC has opined on various different research questions (see here and see here for examples) including the issue of a possible 'real' increase in the numbers of children presenting with autistic traits (see here).

On this particular research occasion, ALSPAC was the source data for the findings reported by Dheeraj Rai and colleagues [1] who set out to "compare trajectories of depressive symptoms from ages 10 to 18 years for children with or without ASD [autism spectrum disorder] and autistic traits, to assess associations between ASD and autistic traits and an International Statistical Classification of Diseases, 10th Revision (ICD-10) depression diagnosis at age 18 years, and to explore the importance of genetic confounding and bullying." I might add that some of this authorship group are making some real research waves when it comes to investigations using population registries with autism in mind (see here).

The starting point this time around was the notion that a diagnosis of autism is in no way protective when it comes to a diagnosis of depression and/or the expression of depressive signs and symptoms. Again, it's a topic that has cropped up before on this blog (see here) and is perhaps one of the longer term associations that have been made down the years. The idea that depression or depressive symptoms *might* be something much more than just 'comorbid' in the context of at least 'some' autism is something else that has been banded around the peer-reviewed research literature before (see here) but the evidence base is not particularly big or strong in this area at the moment.

There were a few different research questions asked by Rai et al, including looking at children "with or without ASD or high scores on autistic trait measures" and any relationship(s) with depression and depressive traits. They report findings for over 6000 children ("maximum sample with complete data") where questionnaire items on bullying were also included ("Relational and overt bullying was assessed as separate yes or no items at ages 8, 10, and 13 years using the modified Bullying and Friendship Interview Schedule") alongside various other potentially confounding variables.

Results: "children with ASD and those with higher scores on all autistic trait measures had more depressive symptoms at age 10 years than the general population, and these remained elevated in an upward trajectory until age 18 years." I don't think there's anything too novel in such findings, aside from the observation that depression / depressive symptoms may start quite early on in childhood. I can remember when I started out in autism research a couple of decades ago hearing about depression being typically linked to the onset of adulthood in the context of autism. This current data suggests otherwise.

Next: "Social communication impairments had the strongest association with a depression diagnosis at age 18 years. Findings were robust to adjustment for a range of confounders, including maternal depression and anxiety and the child’s polygenic risk for autism." This is important. What it suggests is that there may something 'more than just comorbid' about depression or depressive symptoms appearing alongside autism or at least in connection to certain autistic traits. I know some people have already taken exception to this possibility alongside the use of the word 'impairment' by the authors. But much like other research on an important bedfellow to depression - anxiety - one may have to entertain the possibility that there may be some enhanced 'predisposition' to something like depression alongside the presentation of autistic traits (see here and see here) perhaps mediated by factors such as rumination and perseveration for example [2]. This doesn't mean that depression is solely a product of autistic traits; merely that certain traits may potentially form an important vulnerability factor. I'm similarly minded to bring in other work from the ALSPAC initiative [3] (including Rai and colleagues as authors) where related findings were mentioned: "Social communication impairments are an important autistic trait in relation to suicidality." This on the basis that depression and suicidality show an important association.

Also: "We found evidence of a substantial role of bullying in contributing to and explaining a higher risk of depression in individuals with ASD and autistic symptoms." Bullying in the context of autism is another long-standing topic (see here). Bullying covers a lot of ground in terms of behaviour and also source (see here). The authors opine that: "Previous work has shown strong links between the experience of bullying and later depression... although confounding could have a role, the association is considered to be at least partially causal." It's also important to note that social-communication 'issues' were reported to be potentially predictive of being bullied according to the authors. The model that then appears hints that the appearance of depression *might* be linked to "reduced self-esteem or social isolation after the bullying" accepting that causality is not established and also not accounting for other variables: "other relevant characteristics, including comorbidities with neurodevelopmental conditions (eg, attention-deficit/hyperactivity disorder) and classroom placement could be important in this association within or outside the context of bullying." That last point is important in the context that autism rarely exists in some sort of diagnostic vacuum (see here).

There are a few caveats attached to the Rai findings that need to be kept in mind outside of any 'correlation does not necessarily equal causation' sentiments. So: "atypical presentations of depression are common in ASD, and our study has the potential for outcome measurement error because we used scales... that have not been adapted for autism." Indeed. I've previously talked about how bipolar disorder for example, might not follow a typical pattern when present in the context of autism (see here). I daresay that this could also hold for other types/forms of depression too. I'm also minded to reiterate that depression, as well as being a heterogeneous condition, also seemingly has many pathways to it. Some of those pathways will include psychological and social variables such as bullying and perhaps even more extremes of 'trauma'; where a diagnosis of PTSD is for example, no stranger to autism (see here). 'Happiness' and perceived quality of life (see here) are also likely to exert an important effect too.

Other pathways to depression seem to be more biologically defined as per depression in the context of physical ailments (see here) that may have a *link* to some autism (see here) or following the use of seemingly common medicines according to recent news reports (see here). I'll also mention that things like physical activity and exercise *seem* to show an important relationship with depression (see here). This could also be pertinent to the data suggesting that physical activity levels are typically not optimal where and when autism is diagnosed (see here). Other factors (fatigue, sleep, etc) also need to be mentioned in the context of depression. In short, there are lots and lots of potential variables to consider [4].

Outside of the important messages from the Rai findings on how depression is over-represented in relation to autism and how social factors like bullying seem to be linked  to it and thus are subsequently 'modifiable', there is another important point to consider: depression is typically treatable. Minus any medical or clinical advice being given or intended, the first step in managing/treating depression is identifying it. Perhaps the Rai findings might serve as a further call to action for preferential screening in the context of autism...

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[1] Rai D. et al. Association of Autistic Traits With Depression From Childhood to Age 18 Years. JAMA Psychiatry. 2018 Jun 13.

[2] Patel S. et al. Association between anger rumination and autism symptom severity, depression symptoms, aggression, and general dysregulation in adolescents with autism spectrum disorder. Autism. 2017 Feb;21(2):181-189.

[3] Culpin I. et al. Autistic Traits and Suicidal Thoughts, Plans, and Self-Harm in Late Adolescence: Population-Based Cohort Study. J Am Acad Child Adolesc Psychiatry. 2018 May;57(5):313-320.e6.

[4] Köhler CA. et al. Mapping risk factors for depression across the lifespan: An umbrella review of evidence from meta-analyses and Mendelian randomization studies. J Psychiatr Res. 2018 May 25;103:189-207.

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More bad news for pregnancy paracetamol use?

An article in Medical News Today titled: "Is acetaminophen really safe in pregnancy?" caught my attention recently. Highlighting various recent peer-reviewed research suggesting that pregnancy paracetamol (acetaminophen) use seems to carry some *elevated risk* for quite a few potential adverse events for offspring, the *correlation* news just seems to be getting worse for this go-to over-the-counter painkiller and fever-reducer (see here and see here).

The Medical News Today article highlights a few studies but I want to focus on one in particular, by Carl-Gustaf Bornehag and colleagues [1], which suggested that risk of language delay in female offspring *might* show some correlation with early pregnancy paracetamol use.

Based on data derived from the SELMA study (Swedish Environmental Longitudinal, Mother and child, Asthma and allergy [2]), an important initiative that has already produced quite a bit of data (see here), researchers looked at "prenatal APAP [acetyl-para-aminophenol a.k.a paracetamol] exposure in relation to language development in offspring at 30 months of age." Data from over 750 women were garnered; covering both maternal report on paracetamol usage between conception and enrolment on the study (between 8-13 weeks of pregnancy) and "APAP urinary concentration at enrollment." Yes, this study did actually test for paracetamol [metabolite] concentration(s) in urine during the early stages of pregnancy. Such data was analysed in the context of offspring language development around 30 months of age via a nurse's assessment and parental report on "the number of words the child used (<25, 25–50 and >50)."

Results: paracetamol usage during conception/early pregnancy was not uncommon (around 60% of mothers reported this). Nothing particularly shocking there. Also: "APAP was measurable in all urine samples and urinary APAP was correlated with the number of APAP taken during pregnancy (P < 0.01)." Some good news there that maternal reports of paracetamol usage seemed to correlate pretty well with the measured values of paracetamol metabolites in the urine samples analysed.

Then, although language delay - "parental report of use of fewer than 50 words, termed language delay (LD)" - was present in about 1 in 10 children with a characteristic male bias (see here), female offspring born to mothers reporting paracetamol usage more than six times during early pregnancy were approximately six times more likely to show such language delay than those reporting no paracetamol usage. In effect, the female advantage over males when it came to reported language delay disappeared when paracetamol use was put into the clinical picture. Further: "The OR [odds ratio] for LD in girls whose mothers’ urinary APAP was in the highest compared to the lowest quartile was 10.34 (95% CI 1.37–77.86)." Those girls born to mums with the highest urinary concentrations of paracetamol metabolites, compared with those born to those with some of the lowest levels, seemed also to be at greater risk of language delay.

The authors themselves note that independent replication of their results is required before any grand claims are made. Alongside more formal assessment for something like language delay, I'd also like to see how some of the other metabolites measured for [3] in the SELMA initiative (there we quite a few) might also impact on their conclusions too; particularly in the context of endocrine disrupting chemicals being noted in other studies of paracetamol - offspring development (see here). Further investigation is also required on the 'whys' of paracetamol use in the context of pregnancy: does higher use of something like paracetamol perhaps indicate that some underlying issue that is being 'treated' by such use might also/instead be correlated with offspring developmental outcomes? Pain, fever or something else?

As you can see, the Bornehag study is interesting but not without flaws. Still, set within the rising tide of peer-reviewed research talking about potential issues associated with pregnancy use (excessive use?) of paracetamol and offspring outcomes [4], it's not however something that can be easily ignored...

And whilst we're on the topic of paracetamol, I also recently came across the paper by Abdulaziz Saeedan and colleagues [5] talking about testing the hypothesis that "paracetamol (PCM) can precipitate autistic like features when used to counteract vaccine-induced fever using experimental rat pups." I know (a) this takes us into a 'hot potato' area and (b) this is a study on rats, but set against work from other authors discussing a potential role for post-vaccine paracetamol use in the context of 'risk' of autism [6], such findings also perhaps offer a few further ideas for experimental study.

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[1] Bornehag C-G. et al. Prenatal exposure to acetaminophen and children's language development at 30 months. European Psychiatry. 2018. Jan 10.

[2] Bornehag C-G. et al. The SELMA study: a birth cohort study in Sweden following more than 2000 mother-child pairs. Paediatr Perinat Epidemiol. 2012 Sep;26(5):456-67.

[3] Bornehag C-G. The SELMA study, a longitudinal study following 2,000 mother-child pairs from early pregnancy over birth and up in school age. Environ Health Perspectives. 2013: 5824: S-2-35-05.

[4] Bauer AZ. et al. Prenatal paracetamol exposure and child neurodevelopment: A review. Horm Behav. 2018 Jan 13. pii: S0018-506X(17)30454-3.

[5] Saeedan AS. et al. Effect of early natal supplementation of paracetamol on attenuation of exotoxin/endotoxin induced pyrexia and precipitation of autistic like features in albino rats. Inflammopharmacol. 2018. Jan 11.

[6] 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.

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Sleep duration and ADHD: a correlation across the years?

"Longer sleep duration (>10 hours per day) was associated with a lower ADHD [attention-deficit hyperactivity disorder] symptom score" was one of the findings reported by Gabriela Peralta and colleagues [1].

They sought to examine whether a particular set of activities (sleeping, physical activity, television watching, etc) might show some *correlation* to "(1) attention-deficit/hyperactivity disorder (ADHD) symptoms and (2) behavior problems, both assessed at 7 years, in ADHD-free children at baseline."

Drawing on a not-insignificant number of children participants (N=817) who were part of a research birth cohort previously discussed on this blog (see here and see here), authors relied on parental report via the Conners' Parent Rating Scales and the Strengths and Difficulties Questionnaire to ascertain ADHD and 'behaviour problem' scores respectively. This was carried out when the child was aged around 7 years old. A few years earlier - when the child was around 4 years old - parents had previously reported on a few other variables: "the time that their children spent sleeping, watching TV, engaging in cognitively stimulating activities, and engaging in physical activity." The two sets of data were married together for analysis.

Results: it's probably not escaped your notice that (a) parental report is a mainstay of the Peralta data and (b) data for a child at 4 years old and then again at 7 years old represents quite a large time frame during which lots can (and does) happen. With those factors firmly in mind, researchers provided some frequency data on activities at 4 years old. They then added in the data taken at 7 years old where that finding on longer sleep duration (at 4 years) seemed to be linked to lower ADHD scores (at 7 years) came from. Further: "Longer time spent in cognitively stimulating activities (>1 hours per day) was associated with lower scores of both ADHD symptoms... and behavior problems" and also rather interestingly: "Time spent watching TV and engaging in physical activity were not associated with either outcomes."

The quite fuzzy picture emerging from this data - with appropriate caveats - is that sleep and 'keeping the mind active' might be important factors when it comes to the presentation of something like ADHD (symptoms) and other 'behaviour problems' in childhood. The sleep side of things is particularly topical at the moment, given some research chatter about how a sleep intervention might be something to consider for at least some (diagnosed) cases of ADHD (see here). There are also seemingly lots of benefits from ensuring a regular bedtime routine for young children; assuming that is, that poor sleeping patterns are not an early marker for possible ADHD?

The whole 'cognitively stimulating activities' bit is slightly more fluffy in terms of what constitutes such activities and any relationship with ADHD or behavioural issues. I say this on the basis that whilst reading and writing for a 4-year old is likely to be cognitively stimulating, so are lots of other activities such as exploring nature for example or even spending time on the dreaded computer/tablet devices (depending on what activities are being done). Even time spent in front of the gogglebox could be considered cognitively stimulating if they're watching Blue Planet for example, and not just a re-run of Peppa Pig (sorry Peppa). And on the topic of television viewing or at least screen time in the context of ADHD risk, other data have suggested something *correlatively* different from the Peralta findings (see here) just to complicate matters further.

To close, it's been a while but here is some music... Elvin Bishop and a track brought back to life by the Guardians...

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[1] Peralta GP. et al. Sleeping, TV, Cognitively Stimulating Activities, Physical Activity, and ADHD Symptom Incidence in Children: A Prospective Study. J Dev Behav Pediatr. 2017 Dec 18.

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MoBa does... prenatal exposure to acetaminophen and offspring ADHD risk

MoBa mentioned in the title of this post refers to the Norwegian Mother and Child Cohort Study, an initiative that has figured quite a few times on this blog (see here and see here and see here for examples).

This time around [1] scientific attention turned to a question of growing research importance: does acetaminophen - paracetamol to us here in Blighty - use during pregnancy affect the risk of offspring being diagnosed with attention-deficit hyperactivity disorder (ADHD)? The data thus far on the issue of this pain-relieving, antipyretic medicine and offspring health has been discussion-provoking to say the least (see here and see here)...

The findings reported by Eivind Ystrøm and colleagues [1] are based on observations for over 100,000 offspring "including 2246 with ADHD." Both "maternal use of acetaminophen during pregnancy and... paternal use before pregnancy" were included in the statistical mix designed to estimate "hazard ratios (HRs) for an ADHD diagnosis."

The results were not exactly unexpected given what has gone on before in this area of investigation. Acetaminophen use was pretty widespread across all pregnancies; approximately 50% of mums had used it at some point. Short-term use during pregnancy - less than 8 days - actually correlated with a decreased risk of offspring ADHD according to the Ystrøm findings. More chronic use of the medicine however - "more than 29 days of maternal acetaminophen use" - showed an opposite relationship, yielding something like a 200% increase in offspring ADHD "even after adjusting for indications of use, familial risk of ADHD, and other potential confounders."

Alongside the suggestion that short-term paracetamol use was associated with a decreased risk for offspring ADHD was another 'make you think' finding: "Paternal and maternal use of acetaminophen were similarly associated with ADHD." Here, a father's use of paracetamol a month or so before conception seemed also to affect the risk for offspring ADHD too. In some media interest on this paper, the authors speculate "that "it could be that fathers who use a lot of acetaminophen have a higher genetic risk for ADHD" or that long-term use of the medicine might lead to changes in sperm." I might add that given the focus on paracetamol as a pain-relieving medicine, the topic of pain and ADHD is already something present in the peer-reviewed science domain (see here). Further research is called for in an accompanying editorial on the Ystrøm paper by Mark Wolraich [2] noting the benefits of using 'big data' from initiatives such as MoBA.

Accepting that the Ystrøm results suggest correlation and not necessarily causation, not everyone has been overwhelmed by the findings. I note in that lay media piece about the research, a few critical voices have suggested that "children diagnosed with ADHD by codes in their medical records" is no substitute for the real 'diagnostic' thing. Personally, I don't see this argument as being particularly valid as anyone that reads anything about MoBA would probably realise. Scandinavian countries and their population databases have some of the best collected and kept databases in the world in terms of reliability and applicability of population health data and statistics. A quick check on PubMed regarding the amount of peer-reviewed data that has been generated from MoBA for example, illustrates that point well.

Perhaps a more pertinent issue is the question of whether longer-term use of paracetamol during pregnancy could denote a more serious underlying maternal illness/injury which might have a more powerful effect on the risk of offspring ADHD than medicine use itself. This is a similar sort of argument to that put forward in relation to pregnancy antidepressant use and various offspring outcomes detailed in the research literature (see here) and similarly, is not something that can be answered by study designs such as those used by Ystrøm.

But then other the questions arise: 'Is paracetamol use during pregnancy safe?' 'How much is safe?' and 'What are the alternatives?' At this point I'm going to stand back and say little more given my blogging caveats of no medical and/or clinical advice given or intended. I will refer you to some current opinion on this topic provided in the peer-reviewed domain [3] alongside suggesting that more large and smaller-scale investigations are required, including that on 'adjacent' diagnoses in relation to pregnancy paracetamol use too (see here)...

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[1] Ystrøm et al. Prenatal Exposure to Acetaminophen and Risk of ADHD. Pediatrics. 2017. Oct 30.

[2] Wolraich ML. An Association Between Prenatal Acetaminophen Use and ADHD: The Benefits of Large Data Sets. Pediatrics. 2017. Oct 30.

[3] Andrade C. et al. Use of acetaminophen (paracetamol) during pregnancy and the risk of attention-deficit/hyperactivity disorder in the offspring. J Clin Psychiatry. 2016 Mar;77(3):e312-4.

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Toxoplasma infection may be a risk factor for manifestation of psychotic-like symptoms

It's been a while since I last talked about Toxoplasma gondii on this blog (see here). All the initial research excitement from a few years back on how T. gondii exposure might correlate with various psychiatric symptoms/conditions seems to have been toned down in recent times. Still, I continue to be fascinated with the idea that at least for some, exposure to T. gondii might be more than just a somatic thing...

The findings reported by Lindgren and colleagues [1] illustrate how my interest in the gondii remains justified as per their conclusion: "Toxoplasma infection may be a risk factor for manifestation of psychotic-like symptoms." Based on data from Finland - "Health 2000, a large cross-sectional health survey of the Finnish general population aged 30 and above" - the authorship team included on the Lindgren paper contain some names familiar to the T. gondii research scene: namely Faith Dickerson and Robert Yolken.

So, the presence of lifetime psychotic-like symptoms via "section G of the Composite International Diagnostic Interview, Munich version (M-CIDI)" were analysed alongside seropositivity to Toxoplasma "defined as a cutoff of 50IU/ml of IgG antibodies" in nearly 6000 participants. Various other potentially interfering variables - "age, gender, education, region of residence, cat ownership, and C-reactive protein measuring inflammation" - were also thrown into the statistical mix. Cat ownership by the way, refers to the [disputed] research hypothesis that some cats might be unwitting hosts for the gondii with potential onward implications for owners (see here).

Results: "T. gondii seropositivity was significantly associated with clinically relevant psychotic-like symptoms... and with the number of psychotic-like symptoms." That being said, presenting with an immune profile suggestive of some contact with T. gondii did not show any significant connection with diagnosed conditions with a psychotic element to them such as schizophrenia. The authors however, felt confident enough to say that psychotic symptoms might not be totally unrelated to T. gondii exposure.

Accepting that there may be various reasons why someone might present with clinically-relevant psychotic-like symptoms [2] I find good reason to continue with the research agenda looking at T. gondii exposure and human behaviour on the basis of results such as those from Lindgren. The spectrum of labels - behavioural/psychiatric - potentially *associated* with T. gondii exposure is not to be sniffed at [3]. Even if only a proportion of cases are found to be *associated* with gondii exposure, there are treatments readily available (see here) to manage the infection. Whether such intervention(s) might also provide some relief of psychiatric symptoms alongside, is something too that needs more investigation...

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[1] Lindgren M. et al. The association between toxoplasma and the psychosis continuum in a general population setting. Schizophr Res. 2017 Jul 12. pii: S0920-9964(17)30391-2.

[2] Cosgrave J. et al. The interaction between subclinical psychotic experiences, insomnia and objective measures of sleep. Schizophr Res. 2017 Jul 12. pii: S0920-9964(17)30397-3.

[3] de Barros JL. et al. Is there any association between Toxoplasma gondii infection and bipolar disorder? A systematic review and meta-analysis. J Affect Disord. 2017 Feb;209:59-65.

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On vaccinated and un-vaccinated homeschooled children: the disappearing-reappearing-disappearing-reappearing studies

I originally began writing this post in the last week of November 2016 following first sight of the study abstract by Anthony Mawson and colleagues [1] and their journey into a topic that has had its fair share of discussion/argument* (*delete as appropriate) with autism in mind down the years: are vaccines or immunisation patterns potentially linked to [some] autism?

As it happened, this post was shelved for some time because (a) only an abstract appeared despite a publication date accompanying the initial open-access submission in a Frontiers journal and (b) the subsequent sudden disappearance of the abstract from the publishers website following some discussions on social media about the paper and the review process (see here and see here for more information).

The study then appeared in a different journal (April 2017) before once again disappearing.

Now it's back - for now - in the same journal, so once again it's fodder for this blog...

As I always do when it comes to any chatter specifically on this topic, I should reiterate a few things: (a) the prime directive of this blog - no clinical or medical advice is given or intended - and (b) that vaccines save lives. I know some people attribute other factors to that 'life-saving' angle when it comes to vaccines over the longer term (better health, better environment, etc), but one really only needs to look at the protective effect of the various meningitis vaccines for example, to see their results in something like real-time. I repeat again: vaccines save lives.

What however does seem to be missing from at least some of the general discussion about vaccines as a whole and their very positive health effects is the fact that they are medicines. As such they are not somehow impervious to potentially producing side-effects for some people, albeit a small proportion of people who use them. The problem at the moment is, that we don't really know everything there is to know about which people might be at greater risk of side-effects than others (although some clues are emerging) and importantly, how all those side-effects may manifest. Science - metabolomic science - is however starting to tackle some aspects of these issues [2] minus too much hype at the present time.

As per the title of this post, Mawson et al set about examining whether there were differences between those children who were vaccinated and those un-vaccinated across "a broad range of health outcomes." In line with the previous history hypothesising about autism and specific vaccination, the authors focused on any 'association' between vaccination status and neurodevelopmental disorders (NDD) taking into account other potentially confounding variables.

The source data for those vaccinated / un-vaccinated children participants (N=666) was an anonymous online questionnaire completed by mothers of children who were members of various homeschooling organisations in four regions of the United States. Homeschooling refers to a situation where a child is educated at home outside of the mainstream education system choices. Homeschoolers were selected for study because, according to the authors, a "higher proportion are unvaccinated compared to public school children."

Results: around 40% of the participants were indeed described as un-vaccinated in the Mawson cohort. This is quite a bit higher than other estimates [3] specifically looking at homeschooled children. Then to some of the details: "Vaccinated children were significantly less likely than the unvaccinated to have been diagnosed with chickenpox and pertussis." If you needed more evidence that vaccines work, that last sentence kinda provides you with it, particularly in light of what diseases like pertussis can potentially do to the most vulnerable.

And then some potential controversies: vaccinated children were significantly more likely to have been diagnosed with pneumonia, otitis media, allergies and NDDs (defined as autism spectrum disorder, attention deficit hyperactivity disorder, and/or a learning disability). After some statistical adjustment for potentially confounding variables, authors reported that "vaccination, nonwhite race, and male gender were significantly associated with NDD after controlling for other factors." I might also draw your attention to the reported finding that: "preterm birth and vaccination combined was strongly associated with NDD in the final adjusted model with interaction, more than doubling the odds of NDD compared to vaccination alone." This might suggest that there are synergistic variables at work influencing any identified risk continuing a research theme [4]. Indeed, the same authors have devoted a whole other article to this finding [5] (this paper also went through the same disappearing-reappearing act too).

Wearing the objective blinkers of science, this is by no means perfect research. Not only are there potential issues related to the use of an on-line questionnaire (and anonymous at that), the focus on subjective reports over inspection of more objective medical records (even though parents were asked to obtain and use their child's vaccination record(s) when completing the questionnaire), and problems associated with recall (including possible telescoping effects), there are a whole host of other issues that one could cite in relation to such research and potential biases that could/might have influenced the results (including factors such as this one). I might also add that the Mawson study did not appear to 'name names' when it came to which individual vaccines may or may not have been involved in their findings despite asking questions about if and when specific immunisations were administered to participants. Indeed authors noted: "We did not set out to test a specific hypothesis about the association between vaccination and health." Then there is also the 'reaction' angle to papers such as this one to mention; bearing in mind that science these days does not exist in some sort of social/cultural vacuum as per other very recent and very relevant examples. Cumulatively, you can see that there are issues and factors to consider, as there are in relation to other investigations in this still contentious area (see here).

Does then the Mawson paper therefore provide definitive proof of any link between vaccination status and NDDs including autism? No it doesn't, bearing in mind that science generally deals in probabilities over and above 'proof'.

Does the Mawson paper provide any relevant information on vaccination status and the variety of health outcomes included for questioning? Well, on this point I'm gonna cautiously say maybe; at least with the requirement for further scientific investigation. Bearing in mind the caveats discussed previously, it is interesting that the authors' analysis of those fully vaccinated, partially vaccinated and not-vaccinated for example, suggested something when it comes to risk of things like allergic rhinitis, ADHD, eczema, a learning disability, and NDD in a sort of dose-related pattern. This of course, could be due to chance, but without further study we don't or won't know. Yes, I know that the 'too many, too soon' question has already been discussed in the peer-reviewed domain and hasn't stood up well to scrutiny (see here) but perhaps further studies are indicated to confirm/refute such dose-related findings and if necessary, identify any potentially relevant mechanism that might be at work? I say all that with the realisation that something like allergy and atopic disease already has a potentially interesting relationship to the presentation of ADHD (see here) and/or [some] autism (see here).

Within the context of quite a lot of research indicating that, at a population level, vaccinations are pretty safe medicines and probably not linked to autism (possibly even protective when delivered under certain circumstances [6]) one has to be careful not to inflate the Mawson findings above what they currently represent on the hierarchy of scientific evidence. This was, by no means, perfect research. The fact however that this topic continues to be discussed in various parts of society (including the peer-reviewed domain) suggests that science might still have an important role to play in this area particularly in the context of the pluralised autisms (and other labels) and taking into account some chatter a while back about various 'kingdoms of autism'. But such investigations need to be done with care and without grand, sweeping statements being made that could undermine the vital service that immunisation provides to the population as a whole. The associated use of seemingly under-vaccinated populations such as homeschoolers for example, might also represent something of an 'under-used' natural research cohort to further enable more rigorous science to be conducted into such 'hot potato' research areas...

To close, and without too much chatter, Roald Dahl and his experience of measles. Not to scare, not to name-call, not to stigmatise, just to remember a time when measles was rife and for some, measles was deadly.

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[1] Mawson AR. et al. Pilot comparative study on the health of vaccinated and unvaccinated 6- to 12-year-old U.S. children. J Transl Sci 2017. 3.

[2] McClenathan BM. et al. Metabolites as biomarkers of adverse reactions following vaccination: A pilot study using nuclear magnetic resonance metabolomics. Vaccine. 2017; 35: 1238–1245.

[3] Thorpe EL. et al. Homeschooling parents’ practices and beliefs about childhood immunizations. Vaccine. 2012; 30:  1149–1153.

[4] Wang C. et al. Prenatal, perinatal, and postnatal factors associated with autism: A meta-analysis. Medicine (Baltimore). 2017 May;96(18):e6696.

[5] Mawson AR. et al. Preterm birth, vaccination and neurodevelopmental disorders: a cross-sectional study of 6- to 12-year-old vaccinated and unvaccinated children. J Transl Sci. 2017; 3.

[6] Berger BE. et al. Congenital rubella syndrome and autism spectrum disorder prevented by rubella vaccination - United States, 2001-2010. BMC Public Health. 2011; 11: 340.

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Anthony R Mawson, Brian D Ray, Azad R Bhuiyan, & Binu Jacob (2017). Pilot comparative study on the health of vaccinated and unvaccinated 6- to 12-year-old U.S. children Journal of Translational Science : 10.15761/JTS.1000186