The autism numbers game: now 1 in 45 (estimated)

I want to (briefly) draw your attention to the findings reported by Benjamin Zablotsky and colleagues [1] (open-access) recently on the topic of the (estimated) autism prevalence rate. Specifically the figure that seems to be making some media headlines: "The estimated ASD [autism spectrum disorder] prevalence was 2.24% (1 in 45) in 2014."

Based on data derived from the 2014 US National Health Interview Survey (NHIS) designed with the purpose "to monitor the health of the United States population through the collection and analysis of data on a broad range of health topics" researchers turned their eyes towards the question of "the lifetime prevalence of ASD, intellectual disability (ID), and any other developmental delay (other DD)." The added interest in this latest version of the NHIS was the inclusion of a "standalone question" to respondents about autism/ASD along the lines of "Did a doctor or health professional ever tell you that [child's name] had autism, Asperger's disorder, pervasive developmental disorder, or autism spectrum disorder?" In previous times, the survey only included autism/ASD among a list of various other health-related conditions including Down syndrome and cerebral palsy.

Taking into account the change in format to the current (2014) survey bringing autism/ASD to the forefront, Zablotsky et al report something of a considerable shift in the number of people reporting a positive response to that question. So based on the estimated prevalence of 2.2% this time around, researchers noted that this was "a significant increase" compared with previous versions of the NHIS (2011-2013) where the figure was 1.25% or an estimated 1 in 80 children (aged 3-17 years old) with autism/ASD. At the same times as an increase in reports of autism/ASD/Asperger syndrome/PDD, there was a significant decrease in the number of reports of 'other developmental delay' (this question being standalone in both the 2011-2013 and 2014 surveys). Reports on the frequency of intellectual (learning) disability were not significantly different between the 2011-2013 and 2014 data (1.2% vs. 1.1% respectively). More discussion about the study can be read here.

The authors (and some of the media) have made quite a bit of the change in questioning format as being a primary variable to account for the estimated prevalence. I would tend to agree that how one asks the question and specifically the prominence of the question, is likely to impact on what responses one gets from these kinds of surveys, also bearing in mind that this was not a 'go out there and objectively screen' kind of autism prevalence study. That being said, I am open to the idea that part of the percentage increase in reports of autism/ASD may also reflect other factors not limited to just something like diagnostic substitution for example.

Whilst the 1 in 45 figure might be a shock to some/many people, I personally am not that surprised. Only this year (2015) I've talked about a figure of 1 in 46 coming out of Canada (see here) making the previous 1 in 68 estimate from the CDC look a little conservative in the context of the North American experience taking into account differences in ascertainment (see here). Irrespective of the discussions around what factors might be contributory to reported autism rates (estimated and actual), such findings suggest that quite a bit more planning and resources may need to be put into catering for the needs of this ever-growing population both in childhood and indeed, beyond.

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[1] Zablotsky B. et al. Estimated Prevalence of Autism and Other Developmental Disabilities Following Questionnaire Changes in the 2014 National Health Interview Survey. National Health Statistics Reports. 2015; 87. Nov 13.

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Benjamin Zablotsky, Lindsey I. Black, Matthew J. Maenner, Laura A. Schieve, & Stephen J. Blumberg (2015). Estimated Prevalence of Autism and Other Developmental Disabilities Following Questionnaire Changes in the 2014 National Health Interview Survey National Health Statistics Reports

CFS/ME associated with pandemic influenza infection

"Pandemic influenza A (H1N1) infection was associated with a more than two-fold increased risk of CFS/ME [Chronic fatigue syndrome/myalgic encephalomyelitis]."

That was the headline finding from the study by Per Magnus and colleagues [1] looking at whether large population data might provide some clues about 'associated' variables when it comes to the various debilitating conditions headed under the terms CFS/ME.

I'm blogging at a slight disadvantage with regards to the Magnus study because I don't yet have the full-text paper. Looking at the source data - "Using the unique personal identification number assigned to everybody who is registered as resident in Norway" - and observing some notable names on the authorship list, I'm inclined to suspect that this study might have some MoBa undertones (see here) bearing in mind the focus on the "complete Norwegian population" not just pregnant women and their offspring. Indeed, other research from this authorship group provides some further clues about data derivation [2].

Focusing on those specifically diagnosed with CFS/ME - "diagnostic code G93.3 in the International Classification of Diseases, Version 10" researchers calculated hazard ratios (HRs) for CFS/ME "after influenza infection and/or vaccination." A few details emerged including:

• "The incidence rate of CFS/ME was 2.08 per 100,000 person-months at risk." At this point I might direct you towards some details on the difference between incidence and prevalence.
• Influenza infection seemed to confer something of an enhanced risk for CFS/ME as per the finding of an adjusted HR of 2.04 (95% CI: 1.78-2.33). 
• That being said, the authors report "no indication of increased risk of CFS/ME after [pandemic] vaccination." This has potentially important public health implications (see here).
• They conclude by suggesting that such natural infection = increased risk of CFS/ME vs. antigenic stimulation (vaccination) = no increased risk of CFS/ME might indicate "a model whereby symptomatic infection, rather than antigenic stimulation may trigger CFS/ME."

The first thing that struck me about these findings was the 'overlap' noted with a familiar concept to this blog: maternal immune stimulation and offspring outcomes. This is the idea that immune 'stimulation' during critical periods of pregnancy might have the propensity to affect offspring developmental outcomes in a behavioural fashion (see here for example). Two of the big names in this area (Alan Brown and the late Paul Patterson) wrote rather a good review of this area focused on how some of the tools of public health such as vaccination might already be affecting the risk of development/onset of schizophrenia in relation to the maternal immune activation (MIA) model [3] with viruses such as influenza in mind. More detailed work is of course indicated.

Without trying to equate CFS/ME with schizophrenia or any other related label, I do find it interesting that infection and the associated biological response associated with it, might show some 'connection' to CFS/ME in the same/similar way that such biology might also be involved in priming a person for later-life schizophrenia. If we've learned anything about CFS/ME this year aside from it being 'a real illness' (see here if you really needed telling) it is that in amongst the multitude of findings on the condition, there is some really interesting 'immune-related' features coming through (see here). I know the term 'immune-related features' covers a lot of ground but alongside the already tantalising idea that infection is linked to CFS/ME onset (see here) (why else would it be also referred to as post-viral fatigue syndrome), I'm talking about how infection and response to infection might so severely impact on a person and what could be done to potentially prevent it.

Further work is indicated on the basis of the Magnus findings including a focus not just on influenza and CFS/ME but other biological agents such as the really, really interesting prospect of a connection between cases of CFS/ME and acute enterovirus infection [4] for example. Assuming that genetic make-up probably plays an important role in the handling of such viruses in relation to labels like CFS/ME, I'd like to think that research is heading in the right direction to offer viable prevention / treatment options for such devastating disorders bearing in mind the heterogeneity present [5]...

Music: Therapy? - Nowhere.

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[1] Magnus P. et al. Chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) is associated with pandemic influenza infection, but not with an adjuvanted pandemic influenza vaccine. Vaccine. 2015 Oct 13. pii: S0264-410X(15)01433-4.

[2] Bakken IJ. et al. Two age peaks in the incidence of chronic fatigue syndrome/myalgic encephalomyelitis: a population-based registry study from Norway 2008-2012. BMC Med. 2014 Oct 1;12:167.

[3] Brown AS. & Patterson PH. Maternal Infection and Schizophrenia: Implications for Prevention. Schizophrenia Bulletin. 2011;37(2):284-290.

[4] Chia J. et al. Acute enterovirus infection followed by myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and viral persistence. J Clin Pathol. 2010 Feb;63(2):165-8.

[5] Zdunek M. et al. A Cross Cultural Comparison of Disability and Symptomatology Associated with CFS. Int J Psychol Behav Sci. 2015;5(2):98-107.

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Magnus P, Gunnes N, Tveito K, Bakken IJ, Ghaderi S, Stoltenberg C, Hornig M, Lipkin WI, Trogstad L, & Håberg SE (2015). Chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) is associated with pandemic influenza infection, but not with an adjuvanted pandemic influenza vaccine. Vaccine PMID: 26475444

Recurrent antibiotic exposure and risk of depression and/or anxiety?

Accepting the notions that (i) correlation is not necessarily the same as causation and that (ii) case-control observational studies in particular are not the best way to ascertain whether A causes B, I was rather interested in the findings reported by Ido Lurie and colleagues [1] and that: "Recurrent antibiotic exposure is associated with increased risk for depression and anxiety but not for psychosis."

Starting from the idea that: "Changes in the microbiota (dysbiosis) were suggested to increase the risk of several psychiatric conditions through neurologic, metabolic, and immunologic pathways", y'know, the old microbiota-gut-brain axis that everyone seems to be talking about these days (see here), researchers set about looking at how one particular set of agents - antibiotics - known to affect the balance of the trillions of wee beasties that call out gut home, might play a role in said relationship. Analysing "3 nested case-control studies during the years 1995–2013 using a large population-based medical record database from the United Kingdom" Lurie et al pulled in several thousand participants ("202,974 patients with depression, 14,570 with anxiety, and 2,690 with psychosis and 803,961, 57,862, and 10,644 matched controls"). Receipt of antibiotic therapy - 1 of 7 antibiotic classes - more than 1 year before an index date was the "primary exposure of interest" taking into account various other potential confounding variables.

The results: "Treatment with a single antibiotic course was associated with higher risk for depression with all antibiotic groups." The risk, or rather odds ratios, wasn't massively increased but given the participant numbers was deemed significant enough to report. Further, the risk stats increased when multiple antibiotic exposures figured, potentially indicating something of a dose-dependent relationship. Authors also noted that further attention to the use of anti-fungal medicines might also figure in any further research in this area.

Going back and reiterating the caveats with which I started this post, these are interesting results. The idea that the various bacteria, fungi and viruses that inhabit our gut might be doing much more than we ever truly realised is gaining some significant research traction these days (see here for example). Yes, we have to beware of the hype and inevitable sweeping generalisations that accompany the whole 'gut bugs doing more than digesting food' mantra but data are data and this recent data strengthens the calls for more research inspection in this area including on the longer-term effects of 'swallowing a grenade'. I might add that facets of the gut bacteria and depression have been talked about before in the research literature (see here).

Although perhaps not looking at precisely the same aspect of the gut bacteria - behaviour link, it is timely that the Lurie paper coincides at the time of writing with some new reports coming out of this years Society for Neuroscience (SfN) conference. The headline ran with: "Probiotic bacteria may aid against anxiety and memory problems" highlighting some interesting results on the use of a daily capsule containing Bifidobacterium longum 1714 on aspects of mild anxiety and other parameters. What this and other research suggests is that when it comes to mental health and wellbeing, it may be advisable to pay due consideration to the idea of a 'gut feeling' alongside the idea that supplementing with probiotics or even eating certain foods (see here) might actually be heading to a psychiatrist near you...

Music: Saint Etienne - Nothing Can Stop Us.

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[1] Lurie I. et al. Antibiotic Exposure and the Risk for Depression, Anxiety, or Psychosis: A Nested Case-Control Study. J Clin Psychiatry. 2015. October 15.

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Lurie, I., Yang, Y., Haynes, K., Mamtani, R., & Boursi, B. (2015). Antibiotic Exposure and the Risk for Depression, Anxiety, or Psychosis The Journal of Clinical Psychiatry DOI: 10.4088/JCP.15m09961

Schizophrenia and the constant (immune) gardeners

"Immune clue to preventing schizophrenia" went the BBC headline, as the paper by Peter Bloomfield and colleagues [1] garnered some significant media interest recently specifically tied into their findings suggesting that: "neuroinflammation is linked to the risk of psychosis and related disorders, as well as the expression of subclinical symptoms."

Based on the use of "second-generation radioligand [11C]PBR28 and PET to image microglial activity in the brains of participants at ultra high risk for psychosis", researchers reported on 56 participants looking to record their microglial activity. Microglia, as I've talked about before, are something like the constant gardeners of our immune defences in their role as macrophages (big eaters of the immune system) of the brain and spinal cord. Bloomfield et al reported that some of the highest levels of microglia activity were seen in those participants diagnosed with schizophrenia. There also appeared to be something of a potentially important dose related relationship between microglial activity and those at ultra-high risk of psychosis too. Ergo: "Microglial activity is elevated in patients with schizophrenia and in persons with subclinical symptoms who are at ultra high risk of psychosis and is related to at-risk symptom severity." Quite a nice write-up of the study can be read here.

It's not necessarily new news that immune activation and inflammatory processes may be part and parcel of at least some schizophrenia. I've covered the topic quite a few times on this blog (see here and see here for example). The novelty in the Bloomfield results is that researchers actually looked at neuroinflammation as being part of the process linked to excess immune activation in their cohort including people on the schizophrenia-psychosis spectrum.

Where next with this work? Well, replication - independent replication - is a must-have for this area and might also include some analysis of other more general circulating markers of inflammation such as C-reactive protein (CRP) and other pentraxins for example. That also the orchestra of immune-related chemicals that fall under the banner of cytokines (see here) might also be included in further work would also be a valuable scientific addition bearing in mind that not all schizophrenia/psychosis might be immune related: remember the schizophrenias (plural). I might also forward the idea that we might already have some clues as to the possible agents involved in such immune stimulation as per the interesting work looking at Toxoplasma gondii and some schizophrenia (see here).

With regards to the BBC and other media talking about possible treatments focused on some 'anti-inflammatory' action, this again is not new news as per reports such as the one by Friedrich [2]. With other psychiatric labels in mind also talking about inflammation as being part and parcel of pathology (see here) there may be a variety of anti-inflammatory strategies requiring scientific analysis within the context of schizophrenia and/or psychosis. Indeed, such work might overlap across various different labels (see here) and even point to some rather unorthodox intervention ideas (see here and see here).

The times are a changin' for psychiatry methinks.

Music: All I Wanna Do Is Have Some Fun...

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[1] Bloomfield PS. et al. Microglial Activity in People at Ultra High Risk of Psychosis and in Schizophrenia: An [11C]PBR28 PET Brain Imaging Study. American Journal of Psychiatry. 2015. Oct 16.

[2] Friedrich MJ. Research on Psychiatric Disorders Targets Inflammation. JAMA. 2014; 312: 474-476.

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Bloomfield, P., Selvaraj, S., Veronese, M., Rizzo, G., Bertoldo, A., Owen, D., Bloomfield, M., Bonoldi, I., Kalk, N., Turkheimer, F., McGuire, P., de Paola, V., & Howes, O. (2015). Microglial Activity in People at Ultra High Risk of Psychosis and in Schizophrenia: An [ C]PBR28 PET Brain Imaging Study American Journal of Psychiatry DOI: 10.1176/appi.ajp.2015.14101358

Going long: examining psychiatric comorbidity in PDD-NOS

"Psychiatric comorbidities in children with autism spectrum disorder (ASD) are rather a rule than an exception."

That was the opening sentence to the paper by Verheij and colleagues [1] (open-access available here) who charted the stability of such comorbidity in a "7-year follow-up of 74 6-12 year old children with Pervasive Developmental Disorder-Not Otherwise Specified [PDD-NOS]."

Continuing a theme from this research group [2] looking longitudinally at what happened to individuals who "were initially referred for diagnostic evaluation to the Department of Child and Adolescent Psychiatry/Psychology of the Erasmus Medical Center—Sophia Children’s Hospital between July 2002 and September 2004", researchers examined various comorbid psychiatric disorders such as anxiety and mood disorder(s) via the use of the Diagnostic Interview Schedule for Children IV Parent Version (DISC-IV-P) over the course of two testing waves (aged 6-12 years and aged 12-20 years).

They found that: "The rate of comorbid psychiatric disorders dropped significantly from childhood (81 %) to adolescence (61 %)." Specifically, the frequency of anxiety disorders dropped from 55% in wave 1 (6-12 years) to 31% in wave 2 (12-20 years) (based on an average follow-up time between waves of nearly 7 years). The frequency of social phobia also seemed to drop between the testing waves (~11% vs. 1%) as did the frequency of specific phobias (40% vs. 25%); these differences were noted to be significant.

But it was not all good news, as we are told that: "The rates for externalizing (i.e. disruptive) disorders did not significantly change from childhood (i.e. 61 %) to adolescence (i.e. 51 %)"; this categorisation including diagnoses such as attention-deficit hyperactivity disorder (ADHD) (various types) and conduct disorder. Indeed also, when it came to issues such as major depressive disorder, the authors noted a non-significant increase in the frequency of this label examined over the course of the testing waves. Further: "Of the individuals who had no comorbid psychiatric disorder in childhood (n = 14), 50 % (n = 7) stayed free of a comorbid psychiatric disorder in adolescence, whereas 50 % (n = 7) of the individuals developed at least one comorbid psychiatric disorder in adolescence."

In terms of predicting stability across the comorbidity and non-comorbidity groups - "the “persistent presence” group (n = 38) versus the “presence to absence” group (n = 22)" - parent-reported stereotyped behaviours and reduced social interest in childhood as measured on the Children’s Social Behavior Questionnaire (CSBQ) seemed to play something of a role, albeit with the requirement for much further study.

Set within the context of PDD-NOS falling into at least some descriptions of the autism spectrum (newer diagnostic criteria don't mention this category) these are interesting results. That certain psychiatric comorbidity wax and wane as a function of issues such as maturation for example, provides something of a ray of hope that these often disabling comorbidity (yes, anxiety can be utterly disabling) may not always be set in stone. At least that is, with regards to their reaching clinical significance and diagnostic thresholds.

Following a trend in autism research suggesting that the core traits of autism are also probably more dynamic than anyone has hitherto appreciated (see here), I might also advance the idea that where issues such as anxiety wane, so to this might have an effect on the core presentation of autism in terms of things like intervention success for example (see here). I might also refer you back to the idea of optimal outcome (OO) in relation to autism and what this might also mean for the presence of psychiatric comorbidity (see here).

The suggestion that certain psychiatric elements however may not be as likely to retreat when it comes to some autism, such as certain types of ADHD and/or major depressive disorder, remains a worrying prospect. As per the Myriam De-la-Iglesia / José-Sixto Olivar discussion piece [3] (see here for my take) on depression and at least some autism, the often far-reaching effects of depression in conjunction with autism is something that really does need to be tackled, and tackled effectively. Not least because of the "high index of depression in this collective emphasises the need to detect suicidal tendencies." A sad but all too real outcome I'm afraid (see here).

I end with a few caveats to bear in mind about the Verheij data: "Results are based on parental interviews in a relatively small sample of individuals with PDD-NOS with an average to high IQ who were referred to one particular center, thus clinicians should make careful considerations regarding their own specific clients, and further research on samples with more phenotypic variation in ASD severity and cognitive ability using multiple informants is needed." That also there were gaps in important variables such as medication history and other more socially-related variables should also be noted.

Still, this kind of longitudinal research is the kinda thing that autism science really needs to do a lot more of, allied to the idea that psychiatric comorbidity is probably over-represented when it comes to the label of autism [4].

To close, the Japanese trailer for the next Star Wars instalment has some new scenes to tantalise...

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[1] Verheij C. et al. The Stability of Comorbid Psychiatric Disorders: A 7 Year Follow Up of Children with Pervasive Developmental Disorder-Not Otherwise Specified. J Autism Dev Disord. 2015 Oct 12.

[2] Louwerse A. et al. ASD Symptom Severity in Adolescence of Individuals Diagnosed with PDD-NOS in Childhood: Stability and the Relation with Psychiatric Comorbidity and Societal Participation. J Autism Dev Disord. 2015 Sep 22.

[3] De-la-Iglesia M. & Olivar JS. Risk Factors for Depression in Children and Adolescents with High Functioning Autism Spectrum Disorders. ScientificWorldJournal. 2015;2015:127853.

[4] Russell AJ. et al. The mental health of individuals referred for assessment of autism spectrum disorder in adulthood: A clinic report. Autism. 2015 Oct 15. pii: 1362361315604271.

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Verheij C, Louwerse A, van der Ende J, Eussen ML, Van Gool AR, Verheij F, Verhulst FC, & Greaves-Lord K (2015). The Stability of Comorbid Psychiatric Disorders: A 7 Year Follow Up of Children with Pervasive Developmental Disorder-Not Otherwise Specified. Journal of autism and developmental disorders PMID: 26456972

Head circumference and brain size in autism meta-analysed

I read with interest the paper by Roberto Sacco and colleagues [1] providing some much needed clarity on the topic of head circumference and brain size in relation to autism spectrum disorder (ASD).

Detailing the results of a systematic review and meta-analysis based on "27 studies defining percentages of macrocephalic patients and 44 structural brain imaging studies providing total brain volumes for patients and controls", researchers provided "conclusive effect sizes and prevalence rates for macrocephaly and brain overgrowth in autism."

So: "Head circumference was significantly larger in autistic compared to control individuals, with 822/5225 (15.7%) autistic individuals displaying macrocephaly." Further: "Brain overgrowth was recorded in 142/1558 (9.1%) autistic patients." Something of an interaction was also reported between age and total brain volume "resulting in larger head circumference and brain size during early childhood."

As per previous discussions on this topic, there was always a degree of confusion about the the research reporting abnormal head size to be linked to autism (see here). Previous, quite sweeping generalisations, about 'big heads' being linked to the presentation of autism turned out to be a little too sweeping despite some investigations even talking about head size and screening opportunities (see here). The recognition of specific 'types' of autism perhaps being linked to head size and brain enlargement (see here) perhaps offered a more 'real-world' perspective to this issue in-line with quite a lot of research direction in these days of more 'plural' autism (see here). The evidence for this endophenotype concept related to head size comes in a large part from the various studies of specific genetic issues being associated with autism and head size as per the example from Nebel and colleagues [2].

Being careful not to over-generalise the issue of age related to head size [3] and understanding that where one draws comparison population norm data from might be important [4], I'd like to think that there are still some research benefits to continued study of head and brain size when it comes to autism. Not least are the various studies talking about connectivity with reference to brain regions in relation to autism, and whether brain size might be an important factor. That accelerated head circumference might be part and parcel of other growth parameters [5] is also an interesting observation and begs some interesting questions about [some] autism in relation to whole body physiology...

'Everything I do' (but perhaps not the way remember).

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[1] Sacco R. et al. Head circumference and brain size in autism spectrum disorder: A systematic review and meta-analysis. Psychiatry Res. 2015 Sep 28. pii: S0925-4927(15)30057-3.

[2] Nebel RA. et al. Reciprocal Relationship between Head Size, an Autism Endophenotype, and Gene Dosage at 19p13.12 Points to AKAP8 and AKAP8L. PLoS One. 2015 Jun 15;10(6):e0129270.

[3] Cederlund M. et al. Pre-schoolchildren with autism spectrum disorders are rarely macrocephalic: a population study. Res Dev Disabil. 2014 May;35(5):992-8.

[4] Raznahan A. et al. Compared to what? Early brain overgrowth in autism and the perils of population norms. Biol Psychiatry. 2013 Oct 15;74(8):563-75.

[5] Chawarska K. et al. Early generalized overgrowth in boys with autism. Arch Gen Psychiatry. 2011 Oct;68(10):1021-31.

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Sacco R, Gabriele S, & Persico AM (2015). Head circumference and brain size in autism spectrum disorder: A systematic review and meta-analysis. Psychiatry research PMID: 26456415