CDC and the autism numbers game

Static @ Paul Whiteley

The waiting is over. The speculating is done. They're here...

Three years after the last update in 2009*, the US Centers for Disease Control and Prevention (CDC) have revealed their latest estimate for US childhood autism prevalence.

The 2009 estimate, based on surveillance in 2006, suggested that 1 in 110 US children (roughly equating to 1%) aged 8 years old - so born in 1998 - has an autism spectrum disorder. The caveat to that data was that the estimates fluctuated to some degree across the 11 States included in the analysis ranging from 12.1 per 1000 in the States of Arizona and Missouri to 4.2 per 1000 in the sunshine State of Florida. The overall figures nevertheless represented a 57% increase in the numbers of diagnosed cases compared with data from 2002** which previously estimated a rate of about 1 in 150 US children.

The paper trail of recent autism prevalence studies by the CDC using the same DSM-IV - DSM-IV TR criteria makes for some nice standardised methods for screening and case ascertainment which are not to be sniffed at.

So what is the latest estimate?

1 in 88.
[Update: the full report can be found here***]


Childhood autism in the United States has officially broken through the 1% prevalence threshold.

Are these latest figures a great surprise? Probably not to anyone who has followed the numbers over the years. Some people will remember the South Korea (SK) study from last year (2011) which suggested that 1 in 38 children (2.64% cumulative) may present with an autism spectrum condition. The data from Utah, USA, however, and their suggestion of 1 in 77 children with autism, seemed not to have received the same level of media interest despite being closer to the recent CDC mark. Utah also having the benefit of a good history on estimating autism prevalence down the years.

So, where next?

Based on the new estimate, I assume a familiar story will be put out to account for the change (better awareness, diagnostic substitution, more willingness to diagnose, widening of diagnostic criteria, etc) which whilst perfectly acceptable explanations still might not provide the full picture; not at least according to the Nature article from last year (2011). I have to say that I am always struck by how sure some people are that they know what is driving the increase in cases of autism as per one of the commentators on this recent newspaper article on autism going up here in the UK.

Autism on the rise as a consequence of better awareness? Well we do have World Autism Awareness Day on April 2nd and every year it seems to get bigger and bigger in terms of events and participation. Personally I'd like to think that the over the years of the DSM-IV and ICD-10, most professionals, whether teachers, health visitors, psychologists / psychiatrists, SALTs, know what to look for when it comes to autism in the early years. I think also that we should perhaps not underestimate parents and their observations in the early days of autism manifesting itself as important to this process. I could perhaps argue therefore that the awareness issue is probably to some extent covered in terms of the expertise and the various screening programmes in operation around the globe for autism. I'm not saying that awareness might not be contributory to the increasing prevalence but find it very difficult to say this is the sole 'cause' of the increase.

Diagnostic substitution? Widening of the criteria? Again, possible reasons, although probably more important reasons about 10-15 years ago following the replacement of DSM-III for example. Nowadays I'm not as sure that they still carry the same sort of weight.

So what are we left with? I've talked quite a bit on this blog about the rise and rise of epigenetics with autism in mind; that is genes and environment interacting together. Environment covers a lot of ground and I don't really want to start speculating on what facets of environment may or may not be linked. I do however think that we need to start shifting research attention away from the purely 'autism is genetic' model which has persisted for quite a few years. Autism may well have genetic underpinnings, which variably act on different people to different extents, but I don't seriously think that anyone would entertain all autism as being solely genetic. Indeed, epigenetics is beginning to turn quite a few areas on their research head and, in coming years, I am sure we will hear much more about it.

One final point to make: if the changes being suggested to DSM-5 (and I assume ICD-11 for that matter) for autism are actually implemented, we could be looking at a totally new way of coding for autism in subsequent CDC and other reports which will break those years of standardised measure based on DSM-IV. Will these changes affect the numbers of cases, and if so, in what direction? Mmm, a tough one.

* Prevalence of autism spectrum disorders - Autism and Developmental Disabilities Monitoring Network, United States, 2006. Autism and Developmental Disabilities Monitoring Network
MMWR Surveill Summ. 2009; 58: 1-20.

** Prevalence of autism spectrum disorders - Autism and Developmental Disabilities Monitoring Network, 14 sites, United States, 2002. Autism and Developmental Disabilities Monitoring Network
MMWR Surveill Summ. 2009; 58: 1-20.

*** Prevalence of autism spectrum disorders - Autism and Developmental Disabilities Monitoring Network, 14 sites, United States 2008. Autism and Developmental Disabilities Monitoring Network
MMWR Surveill Summ. 2012; 61: 1-19

Labels and lumping: is autism common in schizophrenia?

As a species, we love our labels. I'm not talking about your fashion labels or anything like that but rather our love of compartmentalising things; to divide them up into groups or categories, put them in a box and with the giant social marker pen of the time give them a descriptor.

Labels have had an absolutely vital relationship to autism and how it has been viewed down the years. Indeed the proposed changes to the way DSM labels autism (DSM-5) have been fodder for discussion after discussion in many an online and print forum. I might just throw this paper by McPartland and colleagues* into the mix given the column inches that some of the authorship team have created with certain soundbites.

It is with labels in mind that I would like to discuss this paper** by Unenge Hallerbäck and colleagues who asked: is autism spectrum disorder common in schizophrenia? Before going to work on the paper and its very interesting and possibly contentious findings, I did find the thesis of Dr Unenge Hallerbäck online (see here) which, if you have the time, is certainly worth a read.

A summary of the research:

• The aim of the study was to look at the rates of autism spectrum conditions in a cohort of people diagnosed with schizophrenia and whether the presence of autism is more or less common in any sub-type of schizophrenia and vice-versa. I suppose to be accurate I should be using the term schizophrenia spectrum disorder (SSD) as per the realisation that health is not necessarily all about absolutes but rather degrees and spectrums.
• A participant group of 46 young adults with a diagnosed SSD were included in the study. Their initial diagnosis was evaluated using the SCID. The parents of 32 participants agreed to complete the DISCO-11, a semi-structured interview covering a 'spectrum' of clinical domains with autism as a focus. Participants also completed the Autism Quotient (AQ) for a more personal view.
• The results: most participants' diagnoses (and their variants) were corroborated by the SCID. Of the 32 parental reports via the DISCO-11, 41% of these participants had "an algorithm diagnosis of ASD". With specific regards to the confirmed diagnosis via the SCID and where parental data was available (n=23), 52% fulfilled the DISCO-11 diagnosis of ASD. Indeed the authors note that within the SCID diagnosis of paranoid schizophrenia, 60% of participants had an algorithm diagnosis of ASD too. Based on the Gillberg criteria for Asperger syndrome, five participants (all male) from the participant group could be diagnosed with Asperger syndrome (AS).

Agreeing with the authors, over 40% of their participants with schizophrenia also presenting with symptoms concordant to a diagnosis of autism spectrum disorder, is quite a high prevalence. Obviously the numbers of participants for whom complete data was available were relatively low. That combined with the use of retrospective interview introducing confounders like recall bias, means some caution needs to be applied to the current findings.

The first thought passing through my mind is the exclusionary criteria normally applied to the great label-givers like DSM-IV when it comes to autism and AS; as in, if schizophrenia is present, don't bother trying to diagnose an autism spectrum condition unless something like AS was clearly apparent before the onset of schizophrenia symptoms. Both Fitzgerald and Corvin*** (full-text) and Dr Tom Berney**** (full-text) provide quite good overviews of how this rule might apply in clinical practice alongside some of the potential pitfalls of mistaking AS for say, psychosis.

My second thought is not so much a scientific analysis but rather some cultural questions: how would people feel about autism being quite intricately linked to schizophrenia and vice-versa? Are we indeed seeing the diagnostic merry-go-round potentially reverting back to the 'olden days' and autism as childhood schizophrenia and beyond? What would happen to the rates of autism if the exclusionary clause on schizophrenia were no longer present in diagnostic manuals? I pass no opinion by the way, but will refer you to this paper by King and Lord***** as a possible clue to the future direction of the great psychiatric labeling machine.

As much as the current paper is interesting it is not the first time in recent research history that autism and schizophrenia have been 'overlapped' particularly as maturation kicks in and children progress through infancy into adolescence and adulthood and their behavioural presentation changes. Indeed outside of diagnosis, there is quite a bit of evidence to suggest that the overlap extends well beyond just diagnostic circles into areas such as genes and biochemistry. Do I even mention one of my real areas of interest on gluten- and casein-free dietary intervention for autism sprouting from the earlier work of the late Curt Dohan in schizophrenia?

We have to be careful when looking at any similarities and differences between labels like autism and schizophrenia. I've pretty much exhausted the times that I've said that autism is not seemingly protective of any other condition, which should surely also include schizophrenia with the current diagnostic caveats taken into consideration. If there is a positive side to any attempt to 'lump' the two conditions into some kind of 'spectrum' it would probably be the wealth of research undertaken on both conditions and how each could potentially inform the other. Staying out of the pharmacotherapy side of things (e.g. neuroleptic use), I'm thinking about the five serum (and one urinary) biomarkers study published not so long ago on schizophrenia and whether the diagnostic (and pathological) implications of that work might further inform at least some cases of autism?

To finish, Led Zeppelin ("who were they Daddy?") and a question: how long has it been since you've rock n' roll-ed? If the answer is too long, then clear a space and let Jimmy and the boys help with that 3 minute workout.

* McPartland JC. et al. Sensitivity and Specificity of Proposed DSM-5 Diagnostic Criteria for Autism Spectrum Disorder. Journal of the American Academy of Child & Adolescent Psychiatry. March 2012.
DOI: 10.1016/j.jaac.2012.01.007

** Unenge Hallerbäck M. et al. Is autism spectrum disorder common in schizophrenia? Psychiatry Research. March 2012

*** Fitzgerald M. & Corvin A. Diagnosis and differential diagnosis of Asperger syndrome. Advances in Psychiatric Treatment. 2001; 7: 310-318
DOI: 10.1192/apt.7.4.310

**** Berney T. Asperger syndrome from childhood into adulthood. Advances in Psychiatric Treatment. 2004; 10: 341-351
DOI: 10.1192/apt.10.5.341

***** King BH. & Lord C. Is schizophrenia on the autism spectrum? Brain Research. 2011; 1380: 34-41

Allergy-related autism, communication and NAET

For quite a while now I have been catching the odd mention of something called NAET with regards to lots of different conditions. NAET stands for the Nambudripad Allergy Elimination Technique coincidentally named after its discoverer Dr Devi S. Nambudripad.

Looking more closely at the description of NAET, my brow becomes slightly furrowed as words like 'selective energy balancing' are used to describe part of a process to desensitise a person from their allergies. I don't want to seem unfair or exclusionary to such concepts, and please no hate comments from any NAET supporters, but in my ignorance I do find it slightly difficult to picture such energy and how or what relationship it might have to the body. Certainly it is not something that my doctor ever shared with me about my childhood cat allergy and I would have probably had a hard time bringing it into any consultation with them. Having said that I can't [normally] see magnetism or gravity either but don't give them such a hard time; assuming that is, that they don't start to claim to affect things like allergy or autism without the appropriate research evidence as back up.

I would therefore not normally be paying too much attention to NAET. When however the results of a randomised-controlled trial are published, I tend to become a little more attentive. So it is that thanks to Research Autism, I stumbled upon this paper by Teitelbaum and colleagues* (full-text) looking at the use of NAET with a group of children with autism. The study was also registered with the NIH ClinicalTrials.gov site (here) although no raw results have been posted following the last review in June 2008.

So what did this paper say?

• Sixty children with a diagnosis of autism and a history 'suggestive' of food sensitivity (bowel, skin and/or other issues) were randomly allocated to a treatment (n=30) or control group (n=30). The randomisation method was an interesting one in that a 5-year old child picked names on papers from a bowl. What a great introduction to the scientific method for him!
• Treatment consisted of acupressure along the spine, hands and feet while the participant was holding particular allergens followed by something called neuromuscular sensitivity testing (NST), a procedure described as being similar to muscle response testing to assess effectiveness of treatment. Fifty allergens were treated consisting of 100 treatment occasions (twice a week); the study ran for a year. Controls received no NAET treatment during that time.
• Parents or primary caregivers completed the ATEC and a couple of other measures grading outcome.
• Results: 23 children in the NAET treatment group were described as improving to such an extent that "..they were able to function in regular school classes instead of special education classes". By contrast, none of the control group improved or "..were able to function in regular school classes". 
• There were also statistically significant group improvements on all of the subscales of the ATEC and total score when comparing treatment vs. control groups. The results also include a case study of a young boy with autism who was reported to improve considerably during the study period.

At first glance and without knowing what NAET was, I think most people would be impressed with these results. Twenty-three out of 30 participants using NAET went from an SEN to mainstream classes because of their improvement and none from the control group. Indeed this should really be 23 out of 26 children bearing in mind the participants who dropped out of the treatment group and I assume a protocol not including intention-to-treat. All of the ATEC subscales showed significant group improvements for the treatment group compared to controls and as far as I can see, no significant adverse effects were reported. Not bad at all.

But here's the thing. If I were to compare these [preliminary] results with any other intervention experimentally looked at for autism, these findings would probably indicate that NAET ranks up near the top of the table of autism interventions even if only for those allergy-related cases. My question therefore is why has this paper not created more excitement and a thirst for more research in this area?

The answer lies perhaps with a few 'issues' with this study and techniques described. As per the authors' comments, applied kinesiology is rather on the periphery when it comes to modern medicine and indeed its failings when appropriately tested. My attention is immediately drawn to a recent study by O'Reilly and colleagues** examining the professional view of alternative medicine with autism in mind which highlights some of the main issues. I would imagine that applied kinesiology is probably not central to the traditional medical model. That and the continuing attention raised with other complementary techniques such as the recent Singh/British Chiropractic Association saga and an even more recent post detailing a checklist for intervention therapies. At this point I might add that I offer no opinion on whether things like applied kinesiology work or not; merely that its principles and rather subjective methods have not (yet) produced unequivocal data on reliability or response.

One could also highlight that some of the methodology of this study as being a potential source of bias. So, for example, this was not a double-blind study and as far as I can see no placebo condition was applied. The question of how this type of method could be double-blinded and placebo-controlled is the counter argument which would require some sideways thinking in any future study design. As for the placebo effect, one should never underestimate how powerful an action this can exert on a person when specific elements are in place e.g. administered by a doctor in a white coat with lots of encouragement about positive effects, bearing in mind also who was rating participants on outcome.

I am also interested in the medical treatment as usual instructions provided to parents of participants in both groups. "In both groups, parents were instructed to continue any medical treatments the child was receiving prior to enrolment in the study". Unfortunately I can't see anywhere in the article information about what these treatments were, how they changed over the experimental period and importantly, whether any other interventions were introduced during the long study duration. Is it indeed likely that 30 children with autism would not adjust/undertake educational, behavioural or other intervention for a whole year?

I don't want to be overly critical or anything about this paper just because it details techniques which I don't understand or don't fit with the current way of thinking. Indeed the dietary trial I was involved with has similar methodological failings in terms of lacking double-blindedness and final analysis based on a per protocol decision. Having said that there is a difference between changing a persons diet and asking them to hold a carrot or a jar containing a carrot or other carrot essence whilst someone manipulates their back (as per the story of the discovery of NAET).

I know quite a few people would probably like to draw a line under this study and put it down to a fluke finding with methodological issues. Personally, if there is any possibility that NAET, for whatever reason including a placebo effect, might be able to clinically impact so positively on a persons functioning and quality of life as to move them from SEN to mainstream school, I would like to see a more methodologically-sound, independent study undertaken on it. Bearing in mind also the potential power of touch and massage as per this previous post, it is not beyond the realms of possibility that independent of the allergy-perspective, there may not have been some effect from the acupressure side of things, which itself needs a little bit more investigation particularly from a safety perspective.

To finish a treat for my oldest offspring with a catchy tune from recent Brit winners One Direction (God, did I actually link to this ..?)

* Teitelbaum J. et al. Improving communication skills in children with allergy-related autism using Nambudripad's Allergy Elimination Techniques: a pilot study. Integrative Medicine. 2011:10; 36-43

** O'Reilly M. et al. Complementary or controversial care? The opinions of professionals on complementary and alternative interventions for Autistic Spectrum Disorder. Clinical Child Psychology & Psychiatry. February 2012.

Gestational age at delivery and special educational need

An article by Boyle and colleagues* (full-text) published in the BMJ provided some food for thought recently with the conclusion that even babies born at what would be considered term (37-38 weeks) may suffer from poorer health than those born at 39 - 41 weeks. To me this seems like a very narrow window when it comes to something like birth timing and future health outcomes bearing in mind what risk means and the myriad of potential confounding variables.

Autism is not specifically mentioned in the Boyle article but nevertheless there is some opinion on a possible relationship between gestational time and associated risk. Indeed, I don't know about you but to me it seems like almost every week a new study is published suggesting that adverse conditions at birth might place a person at elevated risk of developing an autism spectrum condition. OK perhaps I over-exaggerate with the 'every week' bit but certainly this is a recurring theme. As if to prove a point take a look at this paper recently published by Movsas and Paneth** on gestational age and symptom severity in autism.

There are other examples suggesting that low birth weight increases the risk, breech presentation, planned caesarean section, hyperbilirubinema... the list goes on. Indeed so numerous are the factors, studies and accompanying media reports that I very often don't even read them in their entirety anymore given the wealth of evidence that is being built up around our entrance into the world.

On the one hand, in a world full of questions about autism - its aetiologies (plural) and natures - such reports have contributed to a valuable area of research with regards to risk and also potentially mechanisms pertinent/contributory to at least some cases. With a condition which has by far raised more questions than science has currently answered, these kinds of 'pointers' might turn out to be important ones.

On the other hand, there does seem to be a tendency to present this relationship slightly out of context; in that autism receives all the attention in relation to something like premature/pre-term babies yet at the expense of a much larger relationship between something like birth dates and special educational needs (SEN) as a whole.

To illustrate this point, my attention turned to quite a powerful study published a few years back by MacKay and colleagues** (full-text) which looked at the rate of SEN based on population registry data where detailed birth data was also present. I should at this point describe a few details about how things worked.

The study was conducted in Scotland which, at the moment, is still part of the United Kingdom (UK). For those unfamiliar with UK healthcare system, we have the National Health Service (NHS) which is paid for through direct taxation and currently means that all citizens, irrespective of income or status, have a right to free healthcare at the point of need. From cradle to grave, each person has a unique NHS number, which alongside some quite copious amounts of note-taking, provides an impressive bank of health information about a person. Health services often overlap with other areas such as social and educational services (most of the time) which can form quite a detailed picture of a citizen as evidence by the Child Health Profiles reports for example which are accessible to all and provide a wealth of information. Having experienced first-hand how much information is gathered at birth and the early years, I can vouch for this being a pretty good system.

In addition, I quote from the study: "Under the Special Educational Needs and Disability Act of 2001, both schools and local education authorities in the United Kingdom have a statutory duty to identify, assess, and make provision for children with SEN". SEN covers quite a lot of diagnostic ground including learning disability, autism spectrum conditions, ADHD, dyslexia and dyspraxia.

So with these details in mind, the study:

• Based on a large school-aged population covering 19 Scottish local authority areas, details of 514,188 children above 4 years and below 19 years of age were included for study.
• School census data showing SEN status was linked to the Scottish Morbidity Record (SM2) via birth certificate data.
• Complete data was available for 362,688 children of whom 17,784 (4.9%) had a record of SEN.
• In amongst the large amount of results obtained, a few key points were noted including: low birth weight (<2500 g) was associated with an increased risk of subsequent SEN (unadjusted odds ratio [OR] 2.22). This finding was linked to the primary finding that preterm delivery also correlated with risk of SEN, with extreme prematurity (24-27 weeks) carrying the greatest risk (OR = 6.92) steadily declining as children were born closer to their due date but then increasing for infants born overtime after their due date (42 weeks).
• Importantly, whilst preterm births (<37 weeks) increased the risk of SEN, only a relatively small proportion of SEN was linked to prematurity (5.3%) compared with SEN with a history of 39 weeks gestation (1.7%). 
• As per the description of SEN, autism as a diagnosis is included. Having said that, no specific data is provided on the distribution of particular diagnoses in the presented dataset so we can't readily ascertain any specific relationship between autism diagnoses and preterm birth from the current paper.

If you have a bit of time free and are interested in this kind of study, I would encourage you to have a look through the MacKay article in its entirety. For me, the important point to take from this study is that autism, some cases of autism, may very well be linked to preterm birth and onward to factors such as birth weight but such a relationship does not appear to be exclusive to autism and might not necessarily take into account other SEN diagnoses working as comorbidities. Perhaps a smaller detail is that with the current lack of a national autism register here in the UK, SEN status with a focus on autism might be a rough-and-ready way to provide a figure on autism rates at least in the UK pediatric population?

To finish, my car journeys are currently filled with the sound of the Beautiful South and the line - She's a PhD in “I told you so,” you've a knighthood in “I'm not listening” as featured in the song Don't marry her (the clean version).

* Boyle EM. et al. Effects of gestational age at birth on health outcomes at 3 and 5 years of age: population based cohort study. BMJ. March 2012
DOI: 10.1136/bmj.e896

** Movsas TZ. & Paneth N. The effect of gestational age on symptom severity in children with autism spectrum disorder. JADD. March 2012.

*** MacKay DF. et al. Gestational Age at Delivery and Special Educational Need: Retrospective Cohort Study of 407,503 Schoolchildren. PLoS ONE. 2010; 7: e1000289.
DOI: 10.1371/journal.pmed.1000289

Estimating parental occupational exposures and autism

Under pressure @ Paul Whiteley

I've spent quite a bit of time ducking in and out of an analytical chemistry lab down the years. Aside from a surprising lack of bubbling test tubes - cue the media representation of a scientist complete with white lab coat and safety specs holding up a funny coloured liquid to the light whilst looking inquisitively - there are a few things that you pick up quickly while at the bench. So interesting acronyms like COSHH (Control of Substances Hazardous to Health) and MSDS (Materials Safety Data Sheet) become watchwords, all in the name of 'elf and safety.

Reading MSDS-s in particular, can give you quite a wake-up call about how even routinely used chemicals can hide some pretty damaging effects as per this example for the solvent methanol. Don't even ask me about the commonly used solvent acetonitrile, also called methyl cyanide - that's cyanide but not the sparkling variety. Even good old dihydrogen oxide - 'water' to you and me - has its own MSDS. You and fire brigades across the globe will be glad to know that it's non-flammable.

Regular readers of this blog will probably have seen a few common threads running through the various posts with particular emphasis on how our modern-day physical environment may potentially impact on various facets of human (and animal) biology and functioning. I have tried not to fall too far into the 'synthetic is bad' pothole simply because such sweeping generalisations about all the various 'chemicals' making up our environment are not supported by the available evidence base. That however does not mean that certain compounds may not be able to potentially exert an effect on health and wellbeing, either at an individual or group level, in the short- or long-term, and even impact on our future generations. Sounds suspiciously like epigenetics again to me...

With this in mind, a recent paper by McCanlies and colleagues* was always going to be of interest and the suggestion that parental occupational exposure to certain chemical compounds might be more common to parents of children with autism compared to controls. Admittedly based on quite a small participant group (N=174) derived from the CHARGE study, the authors who included Irva Hertz-Picciotto, reported that "... exposures to lacquer, varnish, and xylene occurred more often in the parents of children with ASD". With sentences like that you can see how headlines can be made. There is however some 'devil in the detail' about such statements which becomes apparent from the full-text paper:

• Of the 174 families included in this study (based on an original cohort of 249 children), 93 families had a child with an autism spectrum condition and 81 had 'unaffected' children.
• Both parents were quizzed via a structured telephone interview about their jobs and likely exposure to chemicals found in the workplace before, during and shortly after pregnancy. So questions relating to the place of employment, what the company did/made and respective work duties were amongst the data collected.
• One of three industrial hygienists also independently assessed potential occupational exposures initially based on a list of 49 agents supplied by the study authors. Industrial hygienists did not have access to participant grouping (autism or control) nor access to identifiable parental responses. They were however provided with some data relating to things like job history, tasks and responsibilities. Exposure level based on the 49 agents was then estimated and coded on a 0-3 scale where 0 = none and 3 = high estimated level of exposure.
• Results: several possible exposures were identified. The most common exposures identified by industrial hygienists in the autism group were toluene (30.4%), metals (30.4%) and nickel (30.4%). The least common exposures were carbon disulfide (1.1%) and perchlorate (1.1%). For the control group, top of the pops were metals (32.5%) and aluminium (30%).
• Parental self-reports suggested that disinfectant exposure was most frequently cited in the autism group (42.5%) same also with control parents (37.2%) during the index (pre-pregnancy) and pregnancy time frames.
• When it came to assigning odds ratios (OR) (based on forest plots), lacquer exposure, varnish and xylene showed the strongest differences between the autism vs. control group from the industrial hygienists results. Parent self-reported OR data suggested that solvent and asphalt exposure were the better differentiators between the groups but when adjusted, no association was significantly so. 
• Interestingly when it came to pesticide exposure, the industrial hygienists actually suggested that a slightly greater percentage of parents in the control group were exposed to things like insecticides and herbicides than the autism group parents, although overall the numbers were quite small.

I've thought quite a bit about this study and what the results might mean. Granted it was a pilot study and all in all no significant group differences were noted between the autism and control groups, so no smoking gun for all cases. Having said that nothing rules out a possible effect from individual level exposures as perhaps showing some relationship - remembering the recent post on HPPE and cognitive functions - and as yet the cumulative impact of more than one exposure cannot be forgotten. Bear in mind also that no specific biological measures of exposure were included in this trial; so even though exposure patterns were estimated, in reality, no real evidence of effect (or not) can be truly gained from this study as it stands.

Genes and environment is a relationship also worth bearing in mind when reading such studies, as per the recent data looking at the Rett syndrome MECP2 issue combined with PBDE exposure (in mice). The genetics of autism is, er, complicated, very complicated (2193 genes, etc, etc. so far). I would perhaps be interested to see if at an individual level, there is any relationship between exposure pattern and genes. The primary question being: where do you start to look?

As discussed in previous posts, we all live in a very different 'chemical' world these days compared with only a couple of hundred years ago. Granted, quite a bit of the progress made in terms of industrialisation is as a direct result of that new synthetic chemical world and so we should be cautious about forming too many sweeping prejudices about how bad the chemical soup is that we live in (ever wondered what chemical components are present in your PC/laptop/tablet/phone that allow you to read this post?).

To quote that wise old sage Darth Vader "don't be too proud of this technological terror you've constructed..".  Wise words indeed. It could be argued that we have been playing with fire for quite a few years now in terms of not keeping up with the potential individual and importantly, cumulative effects of the compounds we have ingeniously invented. In particular what effect they may / may not have on the developing infant.

More research please.

To end, if I had to have one, this would be my favourite Fleetwood Mac song: Go your own way.

* McCanlies EC. et al. Parental Occupational Exposures and Autism Spectrum Disorder. JADD. March 2012.
DOI: 10.1007/s10803-012-1468-1

A novel blood based biomarker for detecting autism?

I read the title to the paper by Momeni and colleagues* (full-text) with some degree of excitement it has to be said. Who wouldn't read the title to a paper "A novel blood-based biomarker for detection of autism spectrum disorders" and not wonder if this could be something special. After all, what is the one primary thing lacking in autism research circles: a biomarker, or set of biomarkers which could objectively, reliably, consistently, universally and reproducibly differentiate autism from not autism. Think of the implications. Think of the possibilities.

The truth however is that whilst this is an interesting paper, excitement eventually has to give way to cold, hard, unfeeling science as questions about whether diagnosing autism by biochemistry over observation might so easily be done.

The paper is full-text but a short summary follows - hold on to your hats:

• Blood samples from 32 Iranian children with autism (by clinical opinion only) and 31 asymptomatic controls, median age 5-6 years were initially drawn for analysis. In the end, samples of plasma from 28 children with autism and 30 controls were analysed via SELDI- and MALDI-ToF mass spectrometry. In English, these are both methods of ionising a sample using a laser - exploding it into its constituent chemical parts - which are then scrutinised based on the mass-to-charge ratio (m/z) to give a molecular weight measured in Daltons (Da). The clever bit is that by using these technologies the authors were able to fragment and fragment the compounds into their basic amino acid parts via MS/MS. If you think the physics is impressive, you ought to see these systems in action. A confirmatory method was also used based on FTICR mass spectrometry but lets not get too into this aside from saying that the results were about as accurate as you can get with current available technology.
• Peptides were the target of this study; in particular peptide profiles. With the aid of some nifty software which normally accompanies systems like those used, target compounds were isolated between the autism vs. control groups revealing three peptides to be most [significantly] discriminating between the groups showing a mass-to-charge ratio of 1864 (up-regulated in autism), 1978 (down-regulated) and 2020 Da (up-regulated). These mass-to-charge ratios have been simplified given that the sensitivity of the findings went to 3 decimal places.
• All these peptides, 16-17 amino acids long, matched up with known peptide sequences from the C3 complement protein. Think immune system, inflammation and autism (yet again).
• Some data on exactly how discriminatory these peptides were between autism and control samples is given confirming some interesting findings.

Still here? Good. I have tended to focus more on the technology and biomarker 'potential' over the actual results and what they might mean because it strikes me that this is the more important aspect to the study. As impressive as the technology and methodology are though, its already been indicated that (a) the participant numbers were pretty low, (b) no control group was looked at in terms of for example, either learning disability or speech and language disorder without autism (thanks Jon) and (c) the discriminatory power of the study (AUC) was not perfect. I can't argue these points because I agree with them. Added to the fact that unlike in the Yang study discussed a few months ago looking at similar metabolomic methods for diagnosing schizophrenia, there was no training and test sets to confirm the findings, we have to be very careful. I'm not even going to mention the uneven sex ratios between the groups, comorbidity and medication as possible confounders (oops, just did).

What I do like about this study though is that is serves as a template for how this area of work could be done if there was suitable interest in applying metabolomics to autism and related conditions. I know there is some interest because even some of the autism research royalty are starting to venture into these areas. I am sure that Momeni and colleagues created a very large bank of data from this study of which we are only seeing a very small amount. So for example, I am guessing that the analysis was all done in positive ion mode over negative ion mode. If this and other external datasets were to be put together, a potential treasure trove of information would be created.

I still remain excited about this study despite the flaws and potential sources of bias and confounds and look forward to follow-up research in this important field of study.

* Momeni N. et al. A novel blood-based biomarker for detection of autism spectrum disorders. Translational Psychiatry. March 2012.
DOI: 10.1038/tp.2012.19

Autism and psoriasis

Spring blossom has sprung @ Paul Whiteley

Trawling the web, as one does, looking at new research studies on this, that and t'other often provides a few 'memory lane' moments.

For example, some weeks back I stumbled upon some interesting discussions on whether okra might have the ability to induce male sterility. Strange you might think that lady's fingers might be a good male contraceptive, but there is some good science behind it specifically based on the actions of a compound called gossypol.

Why is gossypol part of my vocabulary? Well my better-half did some research on this compound a few years back, primarily derived from the cotton plant (Gossypium), with a view to its potential anti-psoriatic abilities. Real pharmacognosy in action. The anti-psoriatic abilities of gossypol got me thinking about psoriasis with autism spectrum conditions in mind.

Psoriasis is a topic which has cropped up before on this blog with regards to autoimmunity and how having one autoimmune-related condition might raise your risk of developing another (or others). Psoriasis is a bit of a blanket description for several manifested skin conditions. It is basically a fault in the production of skin cells; cells pile up on top of each other forming patches or plaques which can cause some quite serious physical discomfort, also having been linked to secondary bacterial infections. More recently is the suggestion that the disease might not just be skin related and not necessarily having just a physical effect. Prevalence and incidence studies are rife on psoriasis; this study suggested a prevalence of 2.5% among a European (German) population.

There is a limited body of literature which suggests that psoriasis might be more common in autism, and families of people of autism, than compared to control populations. The paper that struck me is this one from Lisa Croen and colleagues* looking at immune comorbidities in autism. I say paper but in this form it was actually a conference proceeding from IMFAR 2008. The findings however, based on quite an impressive sample size (autism; n=5565; controls; n=27,825) suggested some interesting differences when it came to the prevalence of autoimmune conditions. Psoriasis came top of the pops; being diagnosed twice as often in autism cases vs. controls.

Croen appears again with regards to the literature on familial psoriasis and 'risk' of autism. This paper** (open-access) suggested that within a 4-year period surrounding pregnancy, maternal psoriasis appeared with greater frequency in cases of autism vs. controls. That being said, their overall conclusions were that maternal autoimmune disorders were unlikely to be strongly related to risk of autism in offspring. I'm not too sure about this last statement in light of more recent findings. Bakkaloglu and colleagues also reported one case of psoriasis in one parent of a child with autism in their study of 30 children compared with none in 39 controls.

Appreciating that the absolute numbers of people with autism with comorbid psoriasis is likely to be quite small (that's what we found at least) I do wonder about the whole autoimmune effect. I would be hard-pressed to say that autism, all autism, is an autoimmune condition because the universal population data really don't bear this out. Having said that, the move towards biological phenotypes would perhaps be an ideal vehicle to see if autoimmune comorbidity reflects a sub-group of those on the autism spectrum. So those cases where coeliac disease, Crohns disease, ulcerative colitis, type-1 diabetes or psoriasis are mentioned: a phenotypic subgroup perhaps? Again not directly linked, but schizophrenia has also been tied into psoriasis albeit with the similar caveats to that of autism. I do also wonder whether the the phototherapy sometimes used for psoriasis might also have some relation to vitamin D status and onward links?

I finish with some Orange Crush from REM (they were great, weren't they).

* Croen LA. et al. Immune comorbidities in children with autism spectrum disorders. IMFAR 2008

** Croen LA. et al. Maternal autoimmune diseases, asthma and allergies, and childhood autism spectrum disorders. Archives of Pediatrics and Adolescent Medicine. 2005; 159: 151-157

Clean-up on IL-6 please

Cytokines, those little chemical messengers so intimately involved in processes like inflammation, are fast becoming a favourite topic of mine. I'm not an immunologist or cell biologist so can't readily claim to have an in-depth knowledge about their formation or action. Better perhaps to describe me as an amateur enthusiast but not necessarily to the Bedroom Biotech Inc. degree.

What I have come to understand is that not all cytokines are created equal. So alongside the different classes of cytokines, there are different functions to cytokines although with quite a bit of overlap in what they can do. In the case of inflammation for example, some cytokines have been termed pro-inflammatory and some anti-inflammatory. Anti-inflammatory cytokines like interleukin-10 (IL-10) for example, have cropped up in autism research as per previous posts like this one. Not one for sweeping generalisations, IL-10 has shown more than a passing interest to autism potentially reduced in some tissues in some cases.

Quite a bit more attention has been paid to some of the more pro-inflammatory cytokines in relation to autism spectrum conditions; interleukin-6 (IL-6) figuring quite heavily in the various reports. I say pro-inflammatory, but as with many things in life, it is not quite as black-and-white as that, given that these compounds are normally intricately tied into one and another in terms of signalling and activation.

Two recent reports caught my attention specifically with IL-6 and autism in mind. The first report by Garcia-Oscos and colleagues* has generated quite a bit of interest with regards to the suggestion that IL-6 might have a 'hyper-excitability' factor in terms of what it might specifically do to GABA-A receptors in the rat brain. To my Mr Men understanding, GABA is an inhibitory neurotransmitter. Reducing the number of, or altering the ability of certain receptors for GABA means that its inhibitory powers are going to be reduced. The suggestion therefore is that elevated levels of IL-6 over long periods leads to an imbalance in synaptic communication away from inhibition to excitatory as has been associated with conditions like epilepsy and autism.

The second paper by Wei and colleagues** also looked at IL-6 in the (mouse) brain suggesting a similarly perturbed balance between excitation and inhibitory synaptic transmissions when IL-6 was 'added', Said mice also displayed certain behaviours which are either core to an autism diagnosis (social interaction) or more peripheral (anxiety).

These coincidental accounts of IL-6 showing some influence to the delicate excitation/inhibition balance of synaptic signalling and potential link to autism is interesting. I have to admit that when I hear about cytokines, I don't automatically think about their effect on the brain given that many of the papers I come across are talking about links to other organs such as the gut***. Indeed, realising that IL-6 and various other cytokines can cross the blood-brain barrier (BBB) as well as as interacting to affect the sterling work undertaken by the BBB gives a new perspective on just what some of these critters might do when levels are perturbed.

* Garcia-Oscos F. et al. The stress-induced cytokine interleukin-6 decreases the inhibition/excitation ratio in the rat temporal cortex via trans-signaling. Biological Psychiatry. December 2011.
DOI: 10.1016/j.biopsych.2011.11.018

** Wei H. et al. Brain IL-6 elevation causes neuronal circuitry imbalances and mediates autism-like behaviors. Biochmica et Biophysica acta. February 2012.

*** Arrieta MC. et al. Reducing small intestinal permeability attenuates colitis in the IL10 gene-deficient mouse. Gut. 2008; 58: 41-48
DOI: 10.1136/gut.2008.150888

On the broader autism phenotype

I think most people would be satisfied with the description of autism as a spectral condition epitomised by the phrase 'if you've met one person with autism, you've met one person with autism'. The term 'autism spectrum' denotes the heterogeneity apparent and that the presentation of core symptoms varies intra-diagnosis according to symptom domain as well as inter-person across different individuals. This is independent of the fluctuations in presentation across different situations and not including variables like maturation, co-morbidity and any effect from intervention.

A spectrum also implies other things including degrees of severity between two poles; ranging from very severe 'disability' at one end to 'difference' at the other end (as per this description from Lorna Wing) depending on your definition and how you grade severity. In between you have a mix of ability and disability. I should point out that by using the term 'difference' I am not in anyway suggesting that those at that end of the spectrum are in any way less deserving of the appropriate support and services. High functioning - however you describe this - does not always mean 'can function'.

At the less severe end of the spectrum, a cut-off point is generally accepted to exist in some shape or form; in diagnostic terms denoting presentation which somehow surpasses a clinical threshold and in cold hard psychiatric terms implies psychopathology. The rights and wrongs of where the threshold has been currently set still continues to create lively debate. The presence of that diagnostic threshold however does not necessarily denote the 'end of the autism spectrum' from a real-world behavioural perspective. It implies the end of the diagnostic spectrum but not that the subtle presentation of certain autistic traits cannot be present beyond the clinical spectrum. Enter the broader autism phenotype (BAP) as evidence of this extra-diagnostic spectrum of presentation.

I first heard about the BAP quite early on in my research career. Prof. Ann Le Couteur, one of the early proponents of the BAP discussed some of the ins and outs of the concept and in particular based on studies of siblings of children with autism, how issues like speech and language problems and social interactive issues were picked up from time to time which did not quite fulfil autism diagnostic criteria either in measure or severity. I also remember quite a few people talking about the overlap with certain personality traits such as introversion and more recently some work looking at autistic traits in conditions such as feeding disorders.

Much of the early work on BAP was tied into the genetic basis of autism based on twin studies, the strength of which has recently come under scrutiny. With this in mind, a recent paper by Davidson and colleagues* caught my eye with their suggestion ".. that BAP traits occur at low rates in simplex families". The results reported in this recent paper were based on an examination of the Simons Simplex Collection which as the name suggests contains details of samples from around 2700 families with one child diagnosed with an autism spectrum condition. Davidson et al looked at over 1500 of these families with the purpose of trying to further elucidate what the BAP is and how it could be appropriately tested for and measured.

I'm intrigued about the potential for differences in BAP traits according to whether a family has one child with autism or more than one. The obvious issue with this study is its exclusive analysis of simplex families, so nothing to compare against in terms of multiplex families outside of external datasets. That and the reliance on a snapshot of where a family is in terms of autism not necessarily ruling out any elevated risk of autism recurrence in simplex families should for example they have other children. This last point is perhaps a fundamental flaw in any simplex analysis.

Putting these issues aside, the first thing that comes to mind is whether the weighting of genetics vs. environment might be different in simplex families where BAP traits are infrequent. In other words, is there a suggestion that environmental factors might trump genetic factors in such cases compared to other families where BAP traits are more frequent in other family members? It is perhaps not as easy to say one is genetic and the other is environment because such simple arguments have not been borne out by the research data and most (if not all) conditions are likely to be the result of an interplay between nature and nurture. Think epigenetics for example.

If the data from Davidson is accurate however, this might provide a good opportunity to look at factors such as regression, comorbidity and early adverse events to determine any difference in individuals with autism among high and low BAP trait families. At the very least if offers another potential phenotypic distinction which could be added to those already being looked at.

* Davidson J. et al. Expression of the Broad Autism Phenotype in Simplex Autism Families from the Simons Simplex Collection. JADD. March 2012.
DOI: 10.1007/s10803-012-1492-1

Of toad skins and psychiatry

Karma Chameleon @ Paul Whiteley

In the episode 'Missionary: Impossible', a memorable scene sees one Homer Simpson licking toads and experiencing what might be described as an altered state of consciousness.

Joking aside, there is actually some truth in the potential psychoactive properties of some species of frog/toad as exemplified by the Colorado River toad, whose skin excretes quite a potent cocktail of compounds including 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) and bufotenin, both with psychoactive properties. Whether you would actually get a 'high' from oral ingestion of such products is entirely another question and one which I am not all that interested in finding out. I should also add a caveat here just in case anyone stumbled on this post looking for something other than autism research: please don't go licking your friendly neighbourhood amphibians. You might just end up with something rather more unpleasant than you bargained for (see here).

Strange then you might think that a compound found on the skin of a toad might also turn up in human urine samples from people with no evident exposure to such amphibians. Stranger still that elevated levels of that compound were reported in certain groups of people, say diagnosed with autism or schizophrenia. But that's exactly what was found by Emanuele and colleagues* a couple of years back, and not for the first** or second time*** as bufotenin entered the autism research arena. One of the earliest entries I've found mentioning bufotenin (and DMT) and autism is this paper by Piggott**** from 1979.

Bufotenin is an interesting compound in terms of its chemistry and biological effects. It has that famous indole ring so characteristic of the amino acid tryptophan potentially hinting at its chemical relations. Its psychoactive, hallucinogenic effect perhaps warrant its inclusion on various controlled drug schedules around the world. In short, it is quite a character. So why then do elevated levels of this compound appear elevated in the urine of some people with autism and other conditions and what are the potential implications?

Well I don't have a reliable answer for the 'why' question but the chances are that some tryptophan chemistry and perhaps a modicum of bacteria might have some involvement. The words indolethylamine N-methyltransferase (INMT) come up quite a bit in relation to bufotenin bioformation and some suggestion that INMT activity might be heightened in certain psychiatric presentations. I recently discussed the tryptophan-bacteria connection in relation to the production of IAG and autism but who is to say that it just stops there.

As to the implications, well there are a few clues from the Emanuele paper which can be summarised:

• Urinary bufotenin levels were measured in three groups of people: adults with 'severe' autism confirmed by CARS (n=15), adults with schizophrenia (medication free or naive) (n=15) and asymptomatic volunteer control participants (age and gender ratio matched) (n=15) .
• Blinded analysis of samples for bufotenin was via mass spectrometric analysis (coupled to HPLC) using a previously published method. This means that analysis was pretty reliable.
• Compared to controls, mean urinary levels of bufotenin were elevated in both the schizophrenia and autism groups (p<0.001 and p<0.05 respectively). Visually, the distribution of results were more pronounced in the autism group, whereas the schizophrenia group showed less overlap with controls. 
• Based on the measurement of adaptive behaviours using the Vineland Adaptive Behaviour Scale (VABS), a significant positive correlation between urinary bufotenin levels and hyperactivity scores on the VABS was observed for the autism group. No correlations with pertinent schedules were observed for the schizophrenia group.

Accepting that participant numbers in this study were low and the degree of overlap between controls and the autism /schizophrenia groups, these are interesting findings. The obvious question based on the VABS hyperactivity connection is whether bufotenin levels have ever been specifically looked at in cases of AD(H)D - the answer: not to my knowledge (well, not according to PubMed). Whether any of the participants with autism (or schizophrenia) were ADHD comorbid, we don't know. Indeed, I am not an expert on VABS (although have reported on it as part of one study) so cannot readily comment on its 'usefulness' and accuracy to measure hyperactivity. It strikes me that future work in this area perhaps needs to utilise more applicable scales looking at things like inattention and impulsivity also.

The next question is what effect elevated levels of bufotenin might have on a person. The short answer is that nobody really knows outside of the more psychedelic observations. Whilst it would be easy to speculate on the 'recreational' actions of the compound, we are perhaps wise to bear in a mind a few points such as: (a) these studies were looking at urine samples and urine content for bufotenin representing the end point of the metabolic journey, and (b) aside from a few trials administering bufotenin to 'volunteers' to look at short-term effects, chronic (long-term) exposure has yet to be properly mapped out. Bear in mind also that some level of this compound were found in just about everyone examined, so there may potentially be some 'function' for this compound in the complicated tapestry that is human biochemistry. This paper even goes so far to say that it may have some intestinal function.

The report by Emanuele and colleagues is not a new publication but nevertheless has been of some interest to me for a while. Those who follow the autism research scene will remember some rumblings a few years back over a patent***** about a certain peptide called dermorphin, normally found on the skin of some species of South American frogs and with quite some opiate potency, which was suggested to show linkage to some case of autism. As it happens, not much more was ever done on the findings aside from mention in this paper on Rett syndrome and some criticism based on the analytical methods and results obtained. Maybe dermorphin and DPP-IV are fodder for a later post.

To finish, and with no connection at all to this post, a tribute to Robert Sherman whose fame some will not have heard of until you hear this piece of music which he penned.

* Emanuele E. et al. Elevated urine levels of bufotenine in patients with autistic spectrum disorders and schizophrenia. Neuro Endocrinology Letters. 2010;31:117-121.

** Narasimhachari N. & Himwich H. GC-MS identification of bufotenin in urine samples from patients with schizophrenia and infantile autism. Life Sciences. 1973; 12: 475-478.

*** Takeda N. et al. Bufotenine reconsidered as a diagnostic indicator of psychiatric disorders. Neuroreport. 1995;6:2378-2380.

**** Piggott LR. Overview of selected basic research in autism. JADD. 1979; 9:199-218.

**** Shanahan MR. et al. Peptide diagnostic markers for human disorders. Ortho-Clinical Diagnostics Inc. European Patent: EP0969015A2

Antibiotics and autism: friend or foe?

Ear @ Paul Whiteley

An interesting headline caught my eye recently: 'Scientists shocked to find antibiotics alleviate symptoms of schizophrenia'. I'm cautiously intrigued. Intrigued enough to post this entry on antibiotics in relation to autism spectrum conditions with some potential overlap with the 'shocking' headline.

Bacteria is something which has cropped up quite a bit on this blog and its derivative. Most of the more intriguing posts have concerned the trillion or so bacteria residing in our deepest, darkest bowels alongside various suggestions on how such bacteria might (a) have quite a close connection to our health and wellbeing or (b) how different types of bacteria might be more prevalent in certain groups.

In amongst some of the discussions, some mention of the use of antibiotics (antimicrobials if you wish) has also been made. With autism spectrum conditions particularly in mind, the surprising effects from certain types of antibiotic use has been noted. I refer for example, to this study by Sandler and colleagues* which suggested that administration of quite a powerful antibiotic, the glycopeptide antibiotic vancomycin, seemed to tie in with some short-term improvements in various facets of behaviour seen in autism. The authors speculated on a gut flora-brain connection which, in light of subsequent findings, might eventually turn out to have been quite a good forecast.

Backing up slightly I perhaps should mention a few things. As any good Doctor / Pharmacist will tell you, the term 'antibiotics' is a bit of a catch-all for a large group of medications targeting various, different kinds of bacteria. So as one might imagine, treating cellulitis thought to be due to staphylococcal infection will involve a different antibiotic compared with cellulitis caused by streptococcal infection. Not all bacteria are created equal; the trick is to link bacteria to antibiotic. I should also point out that generally speaking, antibiotics tend not to be very selective in the bacteria they target; thinking shock-and-awe rather than precision bombing when it comes to bacterial destruction of like-minded species. That and the fact like many of our medications, there may be more effects than those merely detailed on the patient information leaflet.

An interesting study has surfaced suggesting that antibiotic administration, a certain type of antibiotic called D-cycloserine (not chirality again), might have some interesting effects on some behaviours linked to autism. The study by Deutsch and colleagues** carried out on BALB/c mice who might share some characteristics relevant to autism, suggested that the social behaviours of young mice were "attenuated" following D-cycloserine administration. In effect, mice were observed to become more social. The authors suggested that the effects were more central, in that cycloserine is known to act on the NMDA receptor.

Not for the first time has D-cycloserine turned up in autism research circles. On that occasion suggesting that administration to people with autism, not mice, again targeted one of the core symptoms of autism, the sociability side of things. Indeed looking around the research landscape, D-cycloserine seems to have developed a bit of a following for quite a few, behaviourally-related conditions including OCD and schizophrenia albeit not universally so and not necessarily with sociability in mind. Not bad for a drug more commonly used to treat TB.

A possible role for other antibiotics in cases of autism litter the research landscape. Paribello and colleagues*** discussed the possible usefulness of minocycline - the same antibiotic listed in the headline at the start of this post - and Fragile X syndrome; something which has cropped up again fairly recently. I note that minocycline is one of the drugs of choice for spirochaete infections potentially taking us back to some 'speculations' on Lyme disease (if we were to stick to its normal action). Indeed there is further speculation about this Lyme connection in this article by Kuhn and colleagues**** recently published.

Several interesting studies indeed, but antibiotics are potentially a bit of a double-edged sword with regards to autism. I say this because of the various suggestions linking a medical history of antibiotic use to autism particularly where ear infections (otitis media) seem to be frequent. I know, I know, correlation/association does not imply causation and all that; nevertheless, I tread very carefully with the reports detailing a possible connection (and their retort).

We are all told that we should be cutting back on our antibiotic use as bacteria become more and more resistant to them. The scariest scenario is that of conditions such as tuberculosis (TB) becoming totally resistant to our antibacterial defences leaving us with lots of potential problems. With this in mind, the long-term use of specific antibiotics for some cases of autism is probably not going to be a strategy that most people would desire or want. That, and the potential longer term side-effects of antibiotic administration which might compound existing peripheral issues noted in cases of autism, means that other intervention strategies need to be identified.

Not being a bacteriologist or anything related I can't speculate much further aside from asking about two related issues: (1) how about competition rather than eradication? and (2) set yuck factor to 10 but what about the growing interest in bacterial transplantation as a potential area of investigation?

To finish, paying homage to the spooky appearance of fireballs in the sky over England and Mars being so close, Jeff Wayne and Eve of the War. You might not be alone... (although Martian invaders are probably not about to take over Earth just yet).

* Sandler R. et al. Short-term benefit from oral vancomycin treatment of regressive-onset autism. Journal of Child Neurology. 2000; 15: 429-435.

** Deutsch SI. et al. d-cycloserine improves sociability and spontaneous stereotypic behaviors in 4-week old mice. Brain Research. 2011

*** Paribello C. et al. Open-label add-on treatment trial of minocycline in fragile X syndrome. BMC Neurology. 2010; 10: 91.

**** Kuhn M. et al. Long term antibiotic therapy may be an effective treatment for children co-morbid with Lyme disease and Autism Spectrum Disorder. Medical Hypotheses. February 2012.

But it's only a survey study of the GFCF diet and autism...

Treelight @ Paul Whiteley

I briefly touched upon the recent study published by Pennesi and Cousino Klein* examining the efficacy of a gluten- and casein-free (GFCF) diet for children with autism a few days back. Having had some contact with the authors and a chance to look at the full-text of the paper, I feel I can post some more details about how the study was done and just what can be inferred from the results obtained.

I freely admit that there is a bit of a conflict of interest here on my part because it's an area that I've done some work on. This probably also accounts for the number of 'my research says this' statements that litter this post for which I will apologise now.

Had the results reported in this most recent paper been less kind to this kind of dietary intervention, I dare say my scientific mettle might have been tested as it was when another trial was reported on a few years back, although as far as I know not published in peer-review format yet. Suffice to say that I am slightly more relieved that years of my life have not been debunked with this latest offering; at least on this occasion.

Anyway, back to the recent GFCF study and some details:

• The aim of the study was to examine subgroups within the autism spectrum and various dietary implementation factors related to the GFCF diet.
• A 90-item online questionnaire on various aspects around the use of a GFCF diet was developed and administered via SurveyMonkey, a popular website used quite a bit in research and marketing circles. 
• Completed responses collected over 5 months in 2008 (N=387) were analysed. 
• Two groups of parental responses were initially analysed: (a) those who removed all foods containing gluten and casein from the diet of their child with autism (n=223) and (b) those who only removed some gluten- and/or casein-containing foods from their child's diet (n=70). When comparing whole dieters vs. partial dieters, significantly more improvements were noted for whole dieters based on measures of core and peripheral autism related behaviours (echolalia, repetitive behaviours, etc), social behaviours (eye contact, social response, pointing, language production) and physiological symptoms (bowel functions, seizures, etc).
• Groupings based on reported dietary errors (N=271), ranging from absolutely no breaks at all to more frequent diet-breakers and everything in between both in and outside of the parental home, suggested that breaking the diet now and again was not necessarily the be-all-and-end-all when it came to outcome. So fairly consistently those who broke the diet one or two times a year were actually reported to show more improvements than those who were strictest with the diet.
• The length of time diet was in place also suggested some interesting trends; those who followed diet for more than 2 years showed the greatest number of improvements when it came to autism-related and physiological symptoms. Having said that, there was also a bit of spike in the 6-12 month duration group across the survey item groups.
• Probably one of the most important findings from this paper is in relation to experiences of children with autism and comorbid gastrointestinal (GI) or allergy-related symptoms in terms of responses across the survey groups. These children seemed to do consistently better than those without GI or allergy symptoms. This trend also continued when looking at those diagnosed with a food allergy or suspected to have a food sensitivity.

Based on these results, a few things in particular caught my eye.

The suggestion that those with autism comorbid to bowel issues did better on diet is interesting if not exactly new. I think back to the Harland Winter trial on the GFCF diet which still needs to report its findings and how this might further inform any relationship (or not). Given also the various studies pointing towards diet and bowel issues in autism such as the rates of lactose intolerance and the carbs angle, one can perhaps see where there might be some overlap. The allergy side of things has also been covered in previous research and it will be interesting to see how the 'defining the gluten spectrum' game-changer paper might also feed into any future work in this area.

The other interesting detail relates to the time on diet - effectiveness data. I can remember my first study in this area which seemed to confirm that dietary intervention of this type is not a 'quick-fix', short-term thing. One of the important things we found in our last autism dietary research foray was some indication of a plateau effect from such dietary intervention. That is, after a period of time, diet didn't exactly 'stop working' but rather results suggested that positive changes to outcome slowed down compared with earlier testing occasions. Aside the possibility of a faltering placebo effect(!), I never really had a good explanation for this, aside from either some kind of homeostatic mechanism related to gut bacteria or gut permeability kicking in - our bodies love balance and equilibrium - or that a GFCF diet might affect more peripheral areas of autism (e.g. inattention, hyperactivity) rather than core areas. This last point implies that what you see [simplistically] is a kind of peeling away of the accompanying issues to reveal the true 'autistic core' presentation over the months of dietary intervention. What the new study adds to that issue is to pinpoint where that plateau might occur (after about a year) but at the same time also show a sort of 'second wind' whether due to diet or perhaps other factors (maturation, other interventions, etc).

If I was in real scientific rottweiler mode, it would be very easy to savage this study based on lots of different confounders and potential forms of bias being present. One could easily ask questions like 'how do you know respondents were parents of children with autism?' 'how can you confirm diagnosis?' and 'do concepts like constipation and diarrhoea mean the same to everyone?'. And the answers to these questions would be 'we don't', 'we can't' and 'not necessarily'. Don't even start down the path of bias via self-selection, retrospective recall et al. Having said that, and with specific reference to the reporting of bowel issues in autism, the recent paper by Gorrindo and colleagues** hinted that parents "were sensitive to the existence, although not necessarily the nature, of GID [gastrointestinal dysfunction]". I'm sure than many parents are indeed over-joyed to hear that they do officially now know the difference between normal bowel habits and problem bowel habits in their own children!

The point however is that this study knew what is was and what limitations it had. It didn't claim to be the gold standard randomised, double-blind, placebo-controlled trial of a GFCF diet despite the fact that quite a few people have pointed out that it wasn't.

OK maybe I would take some issue with one line in the conclusion section: "These findings provide additional support for the use of this diet in treatment of some children with ASDs..". They do but they don't insofar as the methodological restraints on a survey methodology. The continuation of the sentence is however important: ".. and substantiate the importance of further investigations into the various, nuanced biological and diet implementation factors that interact to optimize and attenuate the diet’s effectiveness for treating these children".

I think Dr Martha Herbert summarised it all quite well: “This study supports the need for taking diet impacts in autism seriously and pursuing them, and learning not only whether they work – because they won’t work for everybody – but also how they work when they do” according to comments on this site. I can't really say more than that.

* Pennesi C. & Cousino Klein L. Effectiveness of the gluten-free, casein-free diet for children diagnosed with autism spectrum disorder: Based on parental report. Nutritional Neuroscience. February 2012.
DOI: 10.1179/1476830512Y.0000000003

** Gorrindo P. et al. Gastrointestinal Dysfunction in Autism: Parental Report, Clinical Evaluation, and Associated Factors. Autism Research. January 2012.
DOI: 10.1002/aur.237