Saturday, 25 March 2017

Including the "full intellectual range" in autism vision research

The paper by Alyse Brown and colleagues [1] (open-access available here) is probably not going to gain any significant media headlines (unlike other recent studies - see here and see here) but does cover a rather important question regarding the autism research landscape: how representative is autism research?

Specifically looking at the collected research on visual processing (distinct from physical issues with the eyes that still require greater awareness) with autism in mind, the authors surveyed the research literature to determine "what extent the ASD with-ID [intellectual disabilitypopulation has been excluded from visual research." Intellectual or learning disability is one of the more frequently over-represented comorbidities that can accompany a diagnosis of autism or autism spectrum disorder (ASD). Their answer: "our searches indicate that 80% of the vision research associated with ASD is representative of less than 60% of the appropriate population, i.e., those with ASD without ID while the ASD with ID group who we argue currently represent 42% of the ASD population, have not been adequately considered."

You may well quibble with the "recalculation of ASD prevalence figures, using the criteria of DSM-5" as a means of calculating that '~40% of those with autism have ID too' figure. For me however, the message is quite stark: autism research - specifically related to visual processing issues - is not yet representative of  'all autism'.

"Reluctance to test individuals who are below 80 in IQ is presumably a practical stance as the data collected from these individuals are often hard to obtain, and often close to floor level performance." The authors note however that the presence of ID alongside autism in the area of visual processing is not something that cannot be 'overcome' by researchers with some creative thinking and a few modification(s) to their experimental designs. Indeed, visual processing research lends itself well to quite a few alterations to methods [2]...

How applicable might these results be to other areas of autism research? Well, we just don't know. I daresay that quite a lot of the 'psychology' based autism research in particular might show a bias towards autism without intellectual disability for just those reasons listed above. The problem then of grand, over-arching generalisations to 'all autism' on the basis of results from the more 'cognitively-able' becomes apparent. Of course, in these days of the plural 'autisms' (see here) and the realisation that 'heterogeneity means heterogeneity' when it comes to autism (see here) one could argue that even characterisations based on the presence of ID or not when it comes to autism are equally 'simplistic' and equally 'useless'. How many autisms might well have an ID element to them? Is ID a comorbidity or something rather more central to some of the autisms? These questions and related others are ones that autism research as a whole will eventually have to start looking at and taking into account.

And going back to the issue of eye disorders being potentially over-represented and under-diagnosed in relation to autism, the paper by Mouridsen and colleagues [3] reiterates that intellectual ability when accompanying autism needs more health equality: "The rate of eye disorder was particularly high (24.5%) in those with a co-occurring profound or severe learning disability (IQ < 50)."

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[1] Brown AC. et al. Vision Research Literature May Not Represent the Full Intellectual Range of Autism Spectrum Disorder. Front Hum Neurosci. 2017 Feb 14;11:57.

[2] Boot FH. et al. Delayed visual orienting responses in children with developmental and/or intellectual disabilities. J Intellect Disabil Res. 2013 Dec;57(12):1093-103.

[3] Mouridsen SE. et al. Eye Disorders among Adult People Diagnosed with Infantile Autism in Childhood: A Longitudinal Case Control Study. Ophthalmic Epidemiol. 2017 Mar 15:1-4.

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ResearchBlogging.org Brown AC, Chouinard PA, & Crewther SG (2017). Vision Research Literature May Not Represent the Full Intellectual Range of Autism Spectrum Disorder. Frontiers in human neuroscience, 11 PMID: 28261072

Friday, 24 March 2017

Autism and anxiety disorder: zooming in on the details

Although it is not necessarily new news that (a) autism rarely exists in some sort of diagnostic vacuum, and (b) that some of the comorbidity 'over-represented' when it comes to autism can actually be more disabling than autism itself, there are still more investigations to be done.

The paper by Vicki Bitsika & Christopher Sharpley [1] represents an example of how autism science is starting to go past the whole 'is there a connection between...' bit when it comes to autism and various comorbidity, specifically focused on the issue of anxiety. Looking at parental responses on "the Social Responsiveness Scale (SRS) and the GAD subscale of the Child and Adolescent Symptom Inventory (CASI-4 GAD) about their sons" researchers reported some rather interesting trends when it came to the two based on a cohort of young males diagnosed with autism. The authors used the term 'high-functioning' to describe the particular 'type' of autism being looked at in their study but I'm rather less sure this is an appropriate description ('high- and low-functioning' tend to be very generalised terms).

I should back-track slightly and point out that the reasoning behind this research was to "assist in treatment or avoidance of GAD [generalised anxiety disorder] by identifying ASD [autism spectrum disorder]-related behaviours as 'targets' for intervention with anxious children as well as for preventative treatments that could be implemented into daily routines before children become anxious." Of all the debates past and present in relation to autism, specifically on the topic of 'treatment' (or even 'cure'), I don't think anyone would be opposed to the idea that anxiety (whether symptoms or disorder) should be treated and potentially 'cured' in this context. Anxiety can be absolutely disabling including when tied into autism.

Results: bearing in mind their focus on only two parameters (SRS scores and GAD scores) in this study, there are some interesting trends in need of further investigation. So: "For pre-adolescents, high levels of tension in social situations were associated with 3.5-times greater likelihood of having GAD; for adolescents, experiencing difficulty in changes in routine was associated with a 10-fold increase in risk of GAD." The pre-adolescents and adolescents bit in that sentence was due to the division of their cohort on the basis of age. The results suggest therefore that anxiety (or at least GAD) might express itself for various different reasons potentially linked to the age/maturity of the person.

I know some people might be shrugging their shoulders at such a finding and saying 'we already knew that'. Well, I'm not one of them. Take for example the 'change in routines' as being a possible factor in the expression of GAD in adolescents. The recent work by Joyce and colleagues [2] looking at another important term relevant to this issue - intolerance of uncertainty - adds an additional layer to the Bitsika/Sharpley findings as per their conclusion that: "replicated previous findings based on parent report showing a significant positive relationship between RRB [restricted and repetitive behaviours] and anxiety." RRBs can, amongst other things, include responses to routine (and changes to said routines).

As to the question of what such findings might mean in the context of intervention, the authors talk about how intervening in the symptoms of GAD (a kind of reactionary approach) might also benefit from also trying to focus intervention on certain autistic symptoms too. Outside of the [careful] use of some of the talking/behavioural therapies and perhaps the whiff of some effect from certain pharmacological interventions when it comes to RRBs and autism, there isn't a great deal on offer at the moment in autism science and practice in this area. Indeed, if the relationship between RRBs and anxiety is further confirmed (and I mean confirmed [3]), I'd perhaps suggest that moves to target RRBs in the context of autism could/should be a research priority if only to potentially reduce the effects of anxiety.

And the inquiry continues [4]...

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[1] Bitsika V. & Sharpley CF. The association between parents' ratings of ASD symptoms and anxiety in a sample of high-functioning boys and adolescents with Autism Spectrum Disorder. Res Dev Disabil. 2017 Mar 1;63:38-45.

[2] Joyce C. et al. Anxiety, Intolerance of Uncertainty and Restricted and Repetitive Behaviour: Insights Directly from Young People with ASD. J Autism Dev Disord. 2017 Feb 25.

[3] Wang S. et al. Sex Differences in Diagnosis and Clinical Phenotypes of Chinese Children with Autism Spectrum Disorder. Neurosci Bull. 2017 Feb 25.

[4] South M. et al. Symptom overlap on the srs-2 adult self-report between adults with asd and adults with high anxiety. Autism Res. 2017. March 7.

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ResearchBlogging.org Bitsika, V., & Sharpley, C. (2017). The association between parents’ ratings of ASD symptoms and anxiety in a sample of high-functioning boys and adolescents with Autism Spectrum Disorder Research in Developmental Disabilities, 63, 38-45 DOI: 10.1016/j.ridd.2017.02.010

Thursday, 23 March 2017

Congenital cytomegalovirus (CMV) infection and autism continued

I wanted to briefly talk about the paper by Francesca Garofoli and colleagues [1] on congenital cytomegalovirus (CMV) infection and autism not because it contains any novel data (see here), but because it reminds us that the potential 'pathways' to a diagnosis of autism are multiple and not necessarily 'pre-programmed' as per the 'it's all genetic' arguments that frequently figure in various domains.

Congenital CMV infection refers to the transmission of CMV - "a common virus that belongs to the herpes family of viruses" - from mother to foetus during pregnancy. The details are still under investigation as to how and why CMV affects a foetus (bearing in mind this is quite a common virus) but autism as a consequence of [some] congenital CMV infection has growing evidence-based support [2].

Garofoli et al included 70 'proven' cases of CMV "congenitally-infected infants" in their study; specifically looking "to correlate congenital cytomegalovirus (CMV) infection with autism spectrum disorder (ASD) and to define its prevalence." They determined that 2 of their 70 strong cohort met criteria for an ASD at the age of 3 years. Two of 70 translated as 2.8% of their cohort and contrasts with [estimated] autism prevalence "in general Italian population (0.66-1.36%)." The figure of 2.8% is also not a million miles away from other estimates of autism suggested via congenital CMV infection [3].

Although 2.8% of the cohort (2/70) might not sound like a lot I'm inclined to suggest that it does prompt quite a lot more additional investigation. Not least is the question: 'why was autism/ASD not diagnosed in the other 68 children?' and onward whether other factors (genetics(!), biology, infection timing, immunologic responseetc) might come into play [4] in relation to the congenital CMV infection - autism association? Taking also into account the estimated prevalence of ASD in Italy, these figures (estimates) do seem to be a little lower than that described in other geographical locations (see here and see here for examples). Indeed, bearing in mind the research evidence already looking at estimated ASD prevalence in Italy [5] it's not unfair to say that 'under-estimation' might be a familiar theme...

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[1] Garofoli F. et al. An Italian Prospective Experience on the Association Between Congenital Cytomegalovirus Infection and Autistic Spectrum Disorder. J Autism Dev Disord. 2017 Mar 3.

[2] Ornoy A. et al. Prenatal factors associated with autism spectrum disorder (ASD). Reprod Toxicol. 2015 Aug 15;56:155-69.

[3] Engman ML. et al. Prenatal acquired cytomegalovirus infection should be considered in children with autism. Acta Paediatr. 2015 Aug;104(8):792-5.

[4] Lombardo MV. et al. Maternal immune activation dysregulation of the fetal brain transcriptome and relevance to the pathophysiology of autism spectrum disorder. Mol. Psychiatr. 2017. March 21.

[5] Ferrante M. et al. Prevalence and age at diagnosis of Autism Spectrum Disorder in south Italy, 2004–2014. Eur J Public Health. 2015; 25 (suppl_3).

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ResearchBlogging.org Garofoli F, Lombardi G, Orcesi S, Pisoni C, Mazzucchelli I, Angelini M, Balottin U, & Stronati M (2017). An Italian Prospective Experience on the Association Between Congenital Cytomegalovirus Infection and Autistic Spectrum Disorder. Journal of autism and developmental disorders PMID: 28258350

Wednesday, 22 March 2017

On genotype and environmental exposure patterns

I was rather interested to read the paper by Michela Traglia and colleagues [1] (open-access available here) concluding that: "maternal and fetal genetic make-up are important determinants of mid-gestational maternal circulating levels of some environmental organohalogens." Interested because, in these days of gene-environment interactions being applied to just about everything, the detail that is missing - which genes might potentially be linked to which environmental factors - has not yet been suitably addressed in the peer-reviewed science literature.

So, based on data - "serum levels of a set of 21 organohalogens in a subset of 790 genotyped women and 764 children" - derived from participants included in the Early Markers for Autism (EMA) Project, researchers set about assessing how genetics might impact on environmental pollutant exposure profiles. Maternal blood samples were collected at around 15-20 weeks pregnancy. Children provided blood samples via the fabulous resource that is the newborn screening program, where: "Newborn blood spots were collected on filter paper 1-2 days after birth." Maternal samples were analysed for various environmental pollutants and both sets of samples were analysed for the genetic material they contained pertinent to whether "circulating mid-gestational levels of organohalogens would be driven by common maternal genetic determinants, and that these results could shed light on the observed associations between the organohalogens and ASD [autism spectrum disorder]."

Results: yes, the authors "found evidence that a large proportion of maternal circulating levels of BB-153, BDE-47, -100, -153 [polybrominated congenersand their sum was significantly controlled by common genetic factors." Those 'common genetic factors' typically referred to the presence of point mutations (SNPs) that litter everyone's genome and on occasion, can affect the function/production of specific biological processes. So: "Genome-wide association analyses identified significant maternal loci for p,p'-DDE... in the CYP2B6 gene and for BDE-28... near the SH3GL2 gene, both involved in xenobiotic and lipid metabolism." In other words, although the environmental pollutants measured are not great products in the first place (in terms of safety), a person's genetic make-up can influence how such products are eventually dealt with by the body and potentially onwards, what subsequent effects they might have.

Additionally: "results suggest that the maternal circulating levels of some compounds were more highly influenced by fetal genetic factors than maternal genetics." This leads into another aspect of the current study whereby foetal genetic factors might also play a part in "controlling the toxicant disposition between mother and fetus." Specifically, authors noted that aspects of the individual genetics of a foetus (distinct from its mother) "contributed to the levels of BDE-100... and PCB187... near the potential metabolic genes LOXHD1 and PTPRD, previously implicated in neurodevelopment."

And finally: "We confirmed that the serum levels of BDE-100, -153 and the total sum of PBDEs were significantly lower in mothers of ASD-affected children compared to mothers of control children." This is interesting in light of other discussions about PBDEs and autism in particular (see here). The authors do discuss various scenarios to account for their results not least that "transplacental transfer of organohalogens during pregnancy may be driven by the fetal genome expressed in placenta." Further analyses of the 'placentome' might therefore be indicated.

To reiterate, this is interesting research. It tells us that many [adverse] environmental exposures, whilst typically to be avoided, don't act on the body in a uniform way as a function of differing genomes and differences in the ways that the body 'handles' such exposures. With autism in mind, this is not necessarily new news (remember paraoxonase gene variants and organophosphate metabolism [2] and air pollution and offspring autism?) but is a useful reminder. Such work also provides a template for looking at the myriad of other environmental factors put forward to influence autism risk and whether individual product safety is necessarily the only or most important factor when it comes to assessing relative risk profiles.

I might finally also draw your attention to a recent interesting meta-analysis of the various environmental risk factors potentially linked to autism [3] (open-access) and another article talking about similar things [4] (open-access) (thanks Annabelle). Genes and environment, genes and environment...

Music: Petula Clark sings the Beatles? Personally, I think it's better than the original...

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[1] Traglia M. et al. Independent Maternal and Fetal Genetic Effects on Mid-gestational Circulating Levels of Environmental Pollutants. G3 (Bethesda). 2017 Feb 24. pii: g3.117.039784.

[2] D'Amelio M. et al. Paraoxonase gene variants are associated with autism in North America, but not in Italy: possible regional specificity in gene-environment interactions. Mol Psychiatry. 2005 Nov;10(11):1006-16.

[3] Modabbernia A. et al. Environmental risk factors for autism: an evidence-based review of systematic reviews and meta-analyses. Molecular Autism. 2017; 8: 13.

[4] Parker W. et al. The role of oxidative stress, inflammation and acetaminophen exposure from birth to early childhood in the induction of autism. Journal of International Medical Research. 2017. Jan 20.

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ResearchBlogging.org Traglia M, Croen LA, Lyall K, Windham GC, Kharrazi M, DeLorenze GN, Torres AR, & Weiss LA (2017). Independent Maternal and Fetal Genetic Effects on Mid-gestational Circulating Levels of Environmental Pollutants. G3 (Bethesda, Md.) PMID: 28235828

Tuesday, 21 March 2017

PACE trial recovery data and chronic fatigue syndrome - a reply

I'd encourage readers interested in the background to the response paper by Michael Sharpe and colleagues [1] to have a look at a previous blogging occasion when the topic of the PACE trial, chronic fatigue syndrome (CFS) and 'recovery' were discussed (see here).

Suffice to say that this latest paper is a reply to one published by Carolyn Wilshire and colleagues [2] who concluded that: "The claim that patients [with CFS] can recover as a result of CBT [cognitive behaviour therapy] and GET [graded exercise therapy] is not justified by the data, and is highly misleading to clinicians and patients considering these treatments." Said discussions linking back to some quite extensive debates on how one should (and shouldn't) treat/manage conditions like CFS (see here).

I wanted to highlight the latest Sharpe paper because (a) I anticipated a reply from these authors following the Wilshire paper criticism of their recovery paper [3], and (b) although the debates in this area have been quite extensive already, the use of the scientific peer-reviewed medium to discuss and even argue is an important avenue. The authors have a right to scientific reply.

So how did Sharpe et al respond? Well the words 'recovery', 'threshold' and ''no generally agreed measure of recovery" when it comes to CFS form the crux of the response to the Wilshire paper. They address the issue of recovery thresholds that have been a real source of discussion in relation to the PACE trial secondary analysis concluding that: "No participant met our full criteria for recovery at baseline." They point out that whilst "13% of participants met the recovery criterion of being within the normal range... for physical functioning when entering the trial" physical functioning was but one measure they used to determine recovery.

They also approach the topic of 'changing thresholds' when it came to the definition of recovery in the PACE trial. To quote: "We changed these thresholds for our detailed analysis plan because after careful consideration and consultation, we concluded that they were simply too stringent to capture clinically meaningful recovery." They also report that elements of their assessment - the PACE walking test - are "not comparable with data collected in other studies" as a function of their reliance on personal motivation/ability over and above the use of encouragement as in other studies.

Finally, authors also talk about 'what other studies have found regarding recovery' when it comes to CFS. They note that their findings in relation to the use of standard medical care (SMC) for CFS in the PACE trial were similar to other reports [4]. They also point to research suggesting that the use of CBT in independent study for CFS show similar rates of recovery [5] to theirs originally reported. In other words, they make a case for their findings fitting in with some of the other literature on this topic.

A quick trawl of PubMed with the terms 'chronic fatigue syndrome' and 'recovery' reveals that there is indeed quite a bit more to do in this area of science. To quote from one paper (a critical review) [4]: "Estimates of recovery ranged from 0 to 66 % in intervention studies and 2.6 to 62 % in naturalistic studies." What this tells us is that (a) how recovery is reported in relation to CFS is still in need of some clarification [6] and perhaps more importantly, agreed uniformity is still required in its assessment; (b) some of the measures used to form judgements of recovery when it comes to CFS are not necessarily fit for purpose [7] (bearing in mind not everyone agrees with this); and (c) further efforts need to go into looking at many more aspects of CFS recovery outside of just a reliance on the fatigue parameter (see here and see here for examples). In short, science does not really know what recovery looks like in relation to CFS [8] despite it seemingly happening for all manner of reasons...

Where do we go from here? This is a difficult question to answer. It is doubtful that the response from Sharpe and colleagues is going to change too many opinions about PACE given the strength of feeling on the topic and the various goings-on that have occurred around debate in this area (see here). Still today, other comments on the PACE trial continue to emerge in the peer-reviewed domain [9] from notable CFS researchers and there are even calls to retract the original recovery paper (see here). Yes, there are lessons to be learned from the PACE trial (e.g. stick to your "original protocol thresholds", make your data 'open-access' and think about how to do this in the planning/recruitment stages of your trial, be mindful that short-term gains don't necessarily translate into long-term ones, work with the ME/CFS community (rather than labelling elements of them 'vexatious' or worse when they ask questions or request data) but I can't see how these factors will immediately and positively affect the lives of people living with CFS/ME here and now. That recommendations on the use of CBT for CFS have already altered in some parts of the world (see here) - "The strength of evidence on global improvement is downgraded from moderate to low when considering CBT separately from other counseling and behavioral interventions" - and are potentially likely to change here in Blighty perhaps signifies that science and medicine is moving on when it comes to this topic. Science should be doubling its efforts to expand its research boundaries when it comes to managing CFS outside of just a reliance on the [outdated?] psychosomatic model and indeed, it is...

And on the topic of other CFS research avenues, I've already talked about a few interesting avenues on this blog (see here and see here and see here) mindful that when we talk about CFS/ME, we're probably not talking about just one entity (see here). Also alongside, that there seems to be an awful lot of 'over-represented' comorbidity accompanying quite a lot of CFS/ME (see here for example) to also contend with...

Music: Lush Life (even if you don't know the song title, you might recognise the tune).

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[1] Sharpe M. et al. Do more people recover from chronic fatigue syndrome with cognitive behaviour therapy or graded exercise therapy than with other treatments? Fatigue: Biomedicine, Health & Behavior. 2017. Feb 15.

[2] Wilshire C. et al. Can patients with chronic fatigue syndrome really recover after graded exercise or cognitive behavioural therapy? A critical commentary and preliminary re-analysis of the PACE trial. Fatigue: Biomedicine, Health & Behavior. 2016. Dec 14.

[3] White PD. et al. Recovery from chronic fatigue syndrome after treatments given in the PACE trial. Psychol Med. 2013 Oct;43(10):2227-35.

[4] Cairns R. & Hotopf M. A systematic review describing the prognosis of chronic fatigue syndrome. Occup Med (Lond). 2005 Jan;55(1):20-31.

[5] Flo E. & Chalder T. Prevalence and predictors of recovery from chronic fatigue syndrome in a routine clinical practice. Behav Res Ther. 2014 Dec;63:1-8.

[6] Twisk FN. A definition of recovery in myalgic encephalomyelitis and chronic fatigue syndrome should be based upon objective measures. Qual Life Res. 2014 Nov;23(9):2417-8.

[7] Matthees A. Assessment of recovery status in chronic fatigue syndrome using normative data. Qual Life Res. 2015 Apr;24(4):905-7.

[8] Brown B. et al. 'Betwixt and between'; liminality in recovery stories from people with myalgic encephalomyelitis (ME) or chronic fatigue syndrome (CFS). Sociol Health Illn. 2017 Feb 27.

[9] Jason LA. The PACE trial missteps on pacing and patient selection. Journal of Health Psychology. 2017. Feb 1.

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ResearchBlogging.org M Sharpe, T Chalder, AL Johnson, KA Goldsmith, & PD White (2017). Do more people recover from chronic fatigue syndrome with cognitive behaviour therapy or graded exercise therapy than with other treatments? Fatigue: Biomedicine, Health & Behavior, 1-5 : 10.1080/21641846.2017.1288629

Monday, 20 March 2017

ALSPAC says no to cat ownership - psychosis risk hypothesis but...

"While pregnant women should continue to avoid handling soiled cat litter, given possible T. gondii exposure, our study strongly indicates that cat ownership in pregnancy or early childhood does not confer an increased risk of later adolescent PEs [psychotic experiences]."

So said the findings reported by Francesca Solmi and colleagues [1] (open-access) who brought a smile to any reader of the title of their paper: "Curiosity killed the cat: no evidence of an association between cat ownership and psychotic symptoms at ages 13 and 18 years in a UK general population cohort." For those who might not be aware of the hypothesis, cat ownership has been previously linked to 'adverse' psychological outcomes (see here) tied into some peer-reviewed evidence on one possible environmental factor linked to psychosis and conditions manifesting psychosis: Toxoplasma gondii.

ALSPAC - Avon Longitudinal Study of Parents and Children - brought it's quite significant scientific prowess to bear on the question of whether "cat ownership in pregnancy and childhood (ages 4 and 10 years) was associated with psychotic experiences (PEs) in early (age 13, N = 6705) and late (age 18, N = 4676) adolescence, rated from semi-structured interviews." Having a cat in the house was not the only question asked by Solmi et al as the presence of other pets were also investigated: "dogs, rabbits, rodents, birds (all waves), and tortoises and fish (from 21 months)." PEs were assessed at approximate ages of 13 and 18 years old via responses to the "psychotic-like symptoms interview (PLIKSi), a semi-structured interviewer-rated screening assessment for PEs." Various other variables were also factored into the examination of any effect or not.

Results: well, as per the opening sentence to this post, cat ownership did not seem to be related to later PEs. The potential caveat being that in some of their analyses there did seem to be a possible association - "Owning a cat at age 4 years was associated with higher odds of having PEs at age 13 years in univariable models" - but the significance of this association disappeared when adjustments for other potentially confounding variables were made. Obviously this kind of study can't control for every single potentially confounding variable but they did at least try.

Why the disparity between these results and the previous ones suggestive of a possible connection between childhood cat ownership and later adverse psychological health? Well, an important point is made by Solmi and colleagues: "Our study was based on PEs in early and late adolescence, unlike other studies which were based on a clinical diagnosis of schizophrenia." In other words. psychotic experiences might be part and parcel of schizophrenia but not necessarily all that schizophrenia encompasses and not necessarily just enough to merit a diagnosis of schizophrenia. They do also go on to highlight how the previous report on the association may also not have included the range of potentially confounding variables that were included and controlled for in the current study as another possibility for the differences reported. Having said that [2]...

Does the T. gondii - schizophrenia hypothesis fall as a result of the Solmi results? Probably not. Solmi et al hint that even though cat ownership probably isn't related to PEs, they do not totally debunk the idea that there may be a connection. They did not for example, look for the presence of contact with T. gondii in this particular study (others have) as per serological examination of participants. I say this bearing in mind that not every moggy is necessarily infected with T. gondii or anything else. Sweeping generalisations on all cats are not required.

Music to close, and containing the lyric 'Caringosity killed the Kerouac cat', a chirpy little number from a band with quite a contentious name...

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[1] Solmi F. et al. Curiosity killed the cat: no evidence of an association between cat ownership and psychotic symptoms at ages 13 and 18 years in a UK general population cohort. Psychol Med. 2017 Feb 22:1-9.

[2] Fuller Torrey E. et al. The antecedents of psychoses: a case-control study of selected risk factors. Schizophr Res. 2000 Nov 30;46(1):17-23.

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ResearchBlogging.org Solmi F, Hayes JF, Lewis G, & Kirkbride JB (2017). Curiosity killed the cat: no evidence of an association between cat ownership and psychotic symptoms at ages 13 and 18 years in a UK general population cohort. Psychological medicine, 1-9 PMID: 28222824

Saturday, 18 March 2017

HSV-2 gestational infection and offspring autism risk

"In our cohort, high levels of antibodies to herpes simplex virus 2 at midpregnancy were associated with an elevated risk of autism spectrum disorder in male offspring. These findings provide support for the hypothesis that gestational infection may contribute to the pathogenesis of autism spectrum disorder and have the potential to drive new efforts to monitor women more closely for cryptic gestational infection and to implement suppressive therapy during pregnancy."

That was the conclusion reached in the paper published by Milada Mahic and colleagues [1] including the research tag-team that is Mady Hornig and Ian 'virus hunter' Lipkin in the list of contributing authors. Having already received some media attention (see here), it doesn't need much more from me but I do want to include a few details and relevant points in this blog entry.

So, the Autism Birth Cohort was the starting point, and "442 mothers of children with ASD... and 464 frequency-matched controls" who all provided plasma samples "(903 samples acquired at midpregnancy and 878 acquired after delivery)." Said samples were analysed for IgG antibodies to ToRCH agents: "Toxoplasma gondii, rubella virus, cytomegalovirus (CMV), and herpes simplex viruses 1 (HSV-1) and 2 (HSV-2)." Some of those viruses and parasites have previously been mentioned with [some] autism in mind (see here and see here and see here).

Results: well, an important detail first: "Because rubella vaccination is part of the routine child vaccination schedule in Norway, almost all individuals had IgG antibodies to rubella virus." Indeed, other authors have speculated that rubella vaccination has actually "prevented substantial numbers" of autism as a knock-on effect of reducing the numbers of cases of congenital rubella syndrome [2]. Vaccination doing more than just saving lives eh?

Next: "Our data suggest that the presence of high levels of anti-HSV-2 antibodies at midpregnancy increases the risk of ASD [autism spectrum disorder] in boys." The authors complemented this finding by some rather neat statistical wizardry whereby odds ratios were calculated based on "four different anti-HSV-2 reference levels (60, 120, 180, and 240 arbitrary units [AU]/ml)." Having said that: "High levels of antibodies, which are typically indicative of recent infection, were found in only a small number of subjects." They also reported "no statistically significant association with risk was found with high levels of HSV-2 antibodies at delivery" and saw nothing significant when it came to the other infections examined. These important points have been picked up in the NHS Choices entry on this study (see here).

These are interesting findings and, as far as I can see, represent something quite novel to the quite vast autism research landscape (assuming you count maternal HSV-2 levels and not antibody levels in actual people diagnosed with autism). The reliance on data from an initiative like the Autism Birth Cohort ensured some rigour in terms of the diagnosis of autism [3] and with the reputations following Drs Hornig and Lipkin, one would have to be pretty brave to question their virus-hunting credentials also with autism in mind [4].

Then to the million-dollar question: how might elevated HSV-2 antibodies during pregnancy affect offspring risk of autism? There is a familiar theme offered by the authors to this question as per statements like: "ASD risk associated with high levels of antibodies to HSV-2 is not specific to HSV-2 but instead reflects the impact of immune activation and inflammation on a vulnerable developing nervous system." I know some people still have a bit of a problem with the idea that something like maternal immune activation (MIA) might up the risk for various offspring outcomes [hint: if an article contains the word 'truth' in the title, step away] but please, stop with the 'it can never happen' generalisations and instead look to the existing peer-reviewed evidence on the topic [5]. Yes, science needs to do more on the topic of MIA and autism but clues are emerging all the time...

Oh, and I'll be coming to research talking about another member of the herpesviruses in relation to autism quite soon on this blog.

To close, operation hardtack and other videos (best viewed in full-screen mode).

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[1] Mahic M. et al. Maternal Immunoreactivity to Herpes Simplex Virus 2 and Risk of Autism Spectrum Disorder in Male Offspring. mSphere. 2017. Feb 22.

[2] 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.

[3] Stoltenberg C. et al. The Autism Birth Cohort (ABC): A Paradigm For Gene-Environment-Timing Research. Molecular Psychiatry. 2010;15(7):676-680.

[4] Hornig M. et al. Lack of association between measles virus vaccine and autism with enteropathy: a case-control study. PLoS One. 2008 Sep 4;3(9):e3140.

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ResearchBlogging.org Milada Mahic, Siri Mjaaland, Hege Marie Bøvelstad, Nina Gunnes, Ezra Susser, Michaeline Bresnahan, Anne-Siri Øyen, Bruce Levin, Xiaoyu Che, Deborah Hirtz, Ted Reichborn-Kjennerud, Synnve Schjølberg, Christine Roth, Per Magnus, Camilla Stoltenberg, Pål Surén, Mady Hornig, & W. Ian Lipkin (2017). Maternal Immunoreactivity to Herpes Simplex Virus 2 and Risk of Autism Spectrum Disorder in Male Offspring. mSphere : 10.1128/mSphere.00016-17