ATEC (Autism Treatment Evaluation Checklist) still rising

The paper by Shreyas Mahapatra and colleagues [1] (open-access available here) provides the blogging fodder today and some important data relating to an important instrument in autism research circles: the Autism Treatment Evaluation Checklist (ATEC).

I'm a fan of the ATEC. Not only because it was one of the first instruments specifically devised to look at measuring changes to autistic symptom severity but also because it's freely available to use. No royalty payments required; free and open for anyone and everyone to use.

Devised by the late Bernard Rimland and Stephen Edelson of the Autism Research Institute (ARI), the ATEC was born out of the need for researchers and non-researchers alike to measure how autism / autistic features can, on some occasions, fluctuate, specifically in response to intervention. It's perhaps no coincidence that the ARI also holds some important data on parent ratings of how useful certain interventions were reported to be when it comes to autism (see here). Although probably not loved by all, such ratings - derived from those who probably know their children best - provide an important rough-and-ready measure of what intervention options perhaps need a little more investigation and which should probably be avoided. The fact that they're based on the reports of over 27,000 parents also helps matters too...

Anyhow, one thing that did seem to be missing from the increasing interest (see here and see here) in the ATEC is data on "the norms on the longitudinal changes in ATEC in the “treatment as usual population." The Mahapatra paper sought to partially remedy that situation based on an "observational cohort who voluntarily completed ATEC evaluations over the period of four years from 2013 to 2017."

Based on observations for some 2600-odd children (mostly males) all of whom scored 20 or above on the ATEC total score, researchers provided some important baseline data. They for example, show how total ATEC scores, a measure of autism severity, seem to change / fluctuate as children age (see Table 1). They also show how subscale scores - Speech / Language / Communication, Sociability, Sensory / Cognitive awareness, Health / Physical / Behavior - move around as a function of 'starting position' and age too. In short, it provides researchers and non-researchers alike some data on what might be expected to happen to the presentation of autism based on ATEC scoring.

But it's not by any means a perfect start. As the authors point out: "In the selection of participants for inclusion in this study, a baseline of ASD [autism spectrum disorder] diagnosis could not be established as child’s diagnosis is not part of ATEC questionnaire" indicating that not every child who participated might have had a diagnosis of autism or ASD. There were other methodological 'issues' too that need to be kept in mind.

I'm still however happy to talk about the ATEC and its potential usefulness to lots more autism studies aside from that already discussed in the peer-reviewed literature. Assuming also that ATEC has some overlap with other more standardised measures used in autism research [2] I think the future continues to look rather rosy for this rather important instrument.

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[1] Mahapatra S. et al. Autism Treatment Evaluation Checklist (ATEC) Norms: A "Growth Chart" for ATEC Score Changes as a Function of Age. Children (Basel). 2018 Feb 16;5(2). pii: E25.

[2] Geier DA. et al. A Comparison of the Autism Treatment Evaluation Checklist (ATEC) and the Childhood Autism Rating Scale (CARS) for the Quantitative Evaluation of Autism. J Ment Health Res Intellect Disabil. 2013 Oct;6(4):255-267.

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Vitamin D and autism... another double-take?

A quick-ish post today as I bring the results published by Dong and colleagues [1] to your attention and the [translated] observation that: "Serum 25-hydroxyvitamin D level in children with ASD [autism spectrum disorder] is obviously lower than that in the healthy control group, and there are negative correlations between vitamin D levels and core symptoms of ASD." 'Obviously' eh?

It's another study from China (see here) and yet again I find myself correcting language as per the authors' use of the term 'healthy control group' when describing not-autism. In much the same way that the word 'neurotypical' is a bit of a nonsense, so the insinuation that a diagnosis of of autism automatically means 'not healthy' is far too broad a sweeping generalisation.

Anyhow, vitamin D and autism was the name of the research game for these authors; something not altogether new and novel for at least some of the authorship group (see here and see here for examples). Indeed, my use of the term 'another double-take' in the title of this post refers to the observation that this group have really gone to town with their clinical trial registered research project in this area (see here for example).

"Serum vitamin D level in ASD children was significantly lower than that of the control group... and the between-group percentage difference of normal, insufficient and deficient levels of vitamin D was statistically significant." Bearing in mind that vitamin D levels were checked using a gold-standard technique (liquid chromatography-mass spectrometry, LC-MS), I'm inclined to accept these results as they stand. I'm not saying that other methods of vitamin D analysis are all bunk, but rather that LC-MS is a mighty powerful method for sample analysis with vitamin D in mind.

Further: "There were negative correlations between serum vitamin D level in ASD children and total ABC [Autism Behavior Checklist] score or ABC subscale scores (body behavior, self-care, language and social interaction). There were negative correlations between serum vitamin D level in ASD children and total CARS [Childhood Autism Rating Scale] score and CARS subscale scores (imitation, nonverbal communication and general impression). There were negative correlations between serum vitamin D level in ASD children and SRS [Social Responsiveness Scale] behavior subscale or ATEC [Autism Treatment Evaluation Checklist] social interaction subscale." In short, vitamin D  levels seemed to *correlate* with quite a few behavioural results, although I'm slightly less inclined to read too much into such findings given the relatively small participant group included for study and the 'snaphot' study methodology.

But yet again, this is another example illustrating that vitamin D metabolism should very much be a part of any assessment when it comes to autism (see here and see here)...

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[1] Dong HY. et al. Correlation between serum 25-hydroxyvitamin D level and core symptoms of autism spectrum disorder in children. Zhonghua Er Ke Za Zhi. 2017 Dec 2;55(12):916-919.

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A third of kids with autism have small intestinal bacterial overgrowth (SIBO)?

"Ninety-six children with autism suffered from SIBO [small intestinal bacterial overgrowth], giving a prevalence rate of SIBO was 31.0%. In contrast, 9.3% of the typical children acknowledged SIBO."

OK, some of the language used by Li Wang and colleagues [1] might not necessarily be (a) completely grammatically accurate or (b) politically or culturally sensitive (i.e. how do you define 'typical'?) but I do think their results are worthy of a lot more scientific investigation.

Focusing in on a curious term - SIBO - characterised by an over-representation of various bacteria in the small intestine, authors set about testing for the presence of SIBO in their cohort of over 300 children diagnosed with an autism spectrum disorder (ASD) alongside over 1200 age- and sex-matched not-diagnosed-with-autism controls. The test of choice for SIBO was a breath hydrogen test where a sugary drink is given and hydrogen content is later examined. The idea being that carbohydrate metabolism is a primary route for hydrogen production in the body and certain types of bacterial species are adapted to feed on sugars and burp out hydrogen under such conditions. As outlandish as it might sound, there is a condition called auto-brewery syndrome where hydrogen production goes one stage further and has been suggested to be linked to the formation of alcohol (ethanol) among other things! I kid you not.

Added to the quite high percentage of children with SIBO described by Wang and colleagues, the authors also reported some differences in the presentation of autism severity according to autism with SIBO compared with controls minus SIBO. They also noted that scores on the ATEC (ATEC rising!) seemed to correlate with a measure of gastrointestinal (GI) symptoms (6-GSI) [2] providing some interesting discussions about the old gut-brain axis thing that has pervaded autism research for decades (see here).

As there always seems to be, there is a scheme of further investigations required in this area before grand sweeping generalisations are made. I don't think anyone can really argue with the data suggesting that (a) GI symptoms are well and truly over-represented when it comes to autism (see here) with new data emerging all of the time [3] and (b) behind such GI symptoms there is likely pathology; whether something like irritable bowel syndrome (IBS) (see here) or indeed, in some cases, something altogether more novel (see here). The Wang study also points the finger of suspicion at the presence of certain bacteria in a certain part of the digestive system as potentially being something important to this area of study. Indeed, allied to recent discussions on the use of a low carbohydrate diet (a.k.a the ketogenic diet) as being something potentially important to at least some autism [4] (see here for my take), there are some interesting reports that could be particularly relevant to the SIBO findings being described and importantly, their management (see here also).

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[1] Wang L. et al. Hydrogen breath test to detect small intestinal bacterial overgrowth: a prevalence case-control study in autism. Eur Child Adolesc Psychiatry. 2017 Aug 10.

[2] Adams JB. et al. Gastrointestinal flora and gastrointestinal status in children with autism--comparisons to typical children and correlation with autism severity. BMC Gastroenterol. 2011 Mar 16;11:22.

[3] Prosperi M. et al. Behavioral Phenotype of ASD Preschoolers with Gastrointestinal Symptoms or Food Selectivity. J Autism Dev Disord. 2017. Aug 31.

[4] El-Rashidy O. et al. Ketogenic diet versus gluten free casein free diet in autistic children: a case-control study. Metab Brain Dis. 2017 Aug 14.

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Gluten & casein free diet vs. ketogenic diet for autism: Fight!

OK, use of the word 'fight' in the title of this post looking at the study results published by Omnia El-Rashidy and colleagues [1] is a bit melodramatic but the findings do provide some rather interesting talking points when it comes to the whole 'diet and autism' thing (see here). Not least that this is, I think, the first peer-reviewed research occasion when the use of a gluten and casein-free (GFCF) diet in the context of autism has been pitted under experimental conditions against another dietary intervention of some interest, the ketogenic diet. The GFCF diet by the way, involves the removal of foods containing the proteins gluten, found in bread and other cereal-based products and casein, the primary protein found in milk and other dairy products. The ketogenic diet is not a million miles away from the GFCF diet but focuses more on the use of high fat and low carbohydrate foods (see here). Both diets have at least some experimental evidence to suggest that they may impact on autistic and related symptoms at least for some on the autism spectrum. But the evidence is not exactly strong yet [2] for any universal effect(s)...

The results of the El-Rashidy study: both diets seemed to be associated with improvements on various autism-related measures (including the ATEC) when compared with a "third group" who "received balanced nutrition and served as a control group" for 6 months. But on some measures the ketogenic diet (KD) came out on top: "ketogenic scored better results in cognition and sociability compared to GFCF diet group."

The authors rightly note that more needs to be done in this area before any sweeping generalisations are applied. So: "this study is a single center study with a small number of patients and a great deal of additional wide-scale prospective studies are however needed to confirm these results." Add to that issues such as a lack of double-blinding (a real Achilles heel when it comes to dietary intervention research in the context of autism) and there are several more investigations needed in this area; also potentially including measurement of some biological parameters to further elucidate possible mechanisms of effect (see here for one important suggestion). But don't completely disregard all of the peer-reviewed literature in this area as bunk just yet (see here). And that for some on the autism spectrum, there may truly be a diet-sensitive phenotype to examine [3]...

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[1] El-Rashidy O. et al. Ketogenic diet versus gluten free casein free diet in autistic children: a case-control study. Metab Brain Dis. 2017 Aug 14.

[2] Piwowarczyk A. et al. Gluten- and casein-free diet and autism spectrum disorders in children: a systematic review. Eur J Nutr. 2017 Jun 13.

[3] Whiteley P. Nutritional management of (some) autism: a case for gluten- and casein-free diets? Proc Nutr Soc. 2015 Aug;74(3):202-7.

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Open label study of probiotics and autism

"We concluded that probiotics have beneficial effects on both behavioral and GI [gastrointestinal] manifestations of ASD [autism spectrum disorder]."

So said the study results published by Sanaa Shaaban and colleagues [1] detailing observations from their "prospective, open-label study" following some 30 children diagnosed with an autism spectrum disorder (ASD) before and after 3 months of probiotic usage. The study details were posted in a clinical trials repository (see here) and note how various measurements were taken as participants took a preparation containing "100 × 106 colony forming units of three probiotic strains; Lactobacillus acidophilus, Lactobacillus rhamnosus and Bifidobacteria longum."

Including some notable authors on the paper who are seemingly not adverse to [scientifically] examining some of the more non-traditional interventions put forward with autism in mind (see here and see here), researchers caution about their latest findings. So: "this study is a single center with a small number of patients and a great deal of additional wide-scale randomized controlled trials are needed to critically confirm the efficacy of probiotics in ASD." Yes, indeed; blinding for example, is a rather important part of the scientific process and other studies 'in progress' have adopted such factors (see here). Set against a growing tide of research suggesting that those trillions of wee beasties that inhabit our deepest, darkest recesses (the gut microbiome) might have more than a passing connection to some autism - some aspects of autism - this area of study is crying out for quite a bit more attention (see here also) not least on hows-and-whys (see here). The way that someone might potentially 'impact' on the gut microbiome in a probiotic sense is also potentially important (see here).

I have only one further point to make about the Shaaban results in relation to the observations that behavioural signs and symptoms (as assessed by the ATEC) seemed to show a relationship with GI symptoms following probiotic use. I'm wondering whether this potential tie-up might learn something from work looking at probiotic use in something like irritable bowel syndrome (IBS) (see here) and onward what happens to psychiatric issues that are seemingly over-represented in cases of IBS (see here). I say that on the basis that bowel issues seem to be most definitely over-represented when it comes to a diagnosis of autism (see here) and the whole 'gut-brain axis' thing continues -across decades - to persist with autism in mind (see here)...

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[1] Shaaban SY. et al. The role of probiotics in children with autism spectrum disorder: A prospective, open-label study. Nutr Neurosci. 2017 Jul 7:1-6.

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Low dose suramin and autism: a small RCT with potentially big results

'Low dose' has been a feature of my autism research reading this week; first starting with the results from Dan Quintana and colleagues [1] talking about some important effects following intranasal delivery of low dose oxytocin and then moving on to the primary reason for this entry with results from Robert Naviaux and colleagues [2] (open-access) continuing a research theme looking at suramin and autism (see here for some background).

For those interested in the oxytocin-autism research base, I can recommend following Dr Quintana on Twitter (find him here).

In relation to the Naviaux findings  - the "Suramin Autism Treatment-1 (SAT-1) trial" - well, they are open-access but I want to provide some overview and then a little bit of discussion. I might add that this research team are making research waves in several areas of medical science as per their research foray into chronic fatigue syndrome (CFS) recently (see here). Such 'metabolomic' research is pertinent to their autism research too.

This time around as on previous research occasions, the focus was on suramin - the "century-old sleeping sickness drug" - and, as far as I can see, the first time said drug has been tested experimentally with children diagnosed with an autism spectrum disorder (ASD). The accompanying ClinicalTrials.gov trial entry is here.

As per the title to this blog entry, this was a small trial including only 10 participants, all male, aged between 5-14 years old. This was a randomised-controlled trial (RCT) with a placebo element to it too, so half of the participants got suramin - "a single, intravenous infusion of suramin (20 mg/kg)" - and half got saline as a control. Alongside looking at behaviour and functioning, researchers also took blood and urine samples "for safety and toxicity monitoring at 5 times throughout the study." This was accompanied by quite a bit of effort to look at the possibility of adverse events related to suramin or placebo administration.

Results: "A single intravenous dose of suramin was associated with improved scores for language, social interaction, and decreased restricted or repetitive behaviors measured by ADOS, ABC, ATEC, and CGI scores. None of these improvements occurred in the five children who received placebo." The authors also do the right thing by stating: "The generalizability of these findings is unknown." I'm particularly impressed that the ATEC gets a showing given the rise and rise of this autism research tool (see here) in various placebo-controlled contexts (see here).

In relation to the safety aspect to suramin, well, it seemed to do alright. We are told that: "Extensive monitoring revealed no serious toxicities" so one can assume that the 'first, do no harm' tenet was upheld in this trial. But there was one important side-effect noted: "Five children who received suramin developed a self-limited, evanescent, asymptomatic, fine macular, patchy, morbilliform rash over 1–20% of their body." The rash was short-lived and did not require specific attention/intervention but it's worthwhile noting it especially when nothing similar was reported in the placebo group.

Going back to the mention of this research group delving into CFS with metabolomics in mind, so similar results are reported on the basis of examination of plasma samples from participants. Various biological pathways seemed to be affected by the infusion of suramin, not least "the importance of the cell danger response (CDR) [3]... and purinergic signaling." Interestingly, authors also noted effects in relation to "1-carbon, folate, methionine, and cysteine metabolism" too, potentially linked to other findings independently reported in relation to autism (see here for example).

Reiterating again that this was a small study (albeit using the gold-standard in scientific methodologies) these results are rather interesting and potentially quite important. They most definitely point to the requirement for further large-scale studies to look at any effects in a larger participant group and to 'zoom in' on potential best-responders to this type of intervention. I end with an important conclusion from the authors who again, have not over-stated their findings:

"Suramin is not approved for the treatment of autism. Like many intravenous drugs, when administered improperly by untrained personnel, at the wrong dose and schedule, without careful measurement of drug levels and monitoring for toxicity, suramin can cause harm. Careful clinical trials will be needed over several years at several sites to learn how to use low-dose suramin safely in autism, and to identify drug–drug interactions and rare side effects that cannot currently be predicted. We strongly caution against the unauthorized use of suramin."

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[1] Quintana DS. et al. Dose-dependent social-cognitive effects of intranasal oxytocin delivered with novel Breath Powered device in adults with autism spectrum disorder: a randomized placebo-controlled double-blind crossover trial. Transl Psychiatry. 2017 May 23;7(5):e1136.

[2] Naviaux RK. et al. Low-dose suramin in autism spectrum disorder: a small, phase I/II, randomized clinical trial. Annals of Clinical & Translational Neurology. 2017. 26 May.

[3] Naviaux RK. Metabolic features of the cell danger response. Mitochondrion. 2014; 16: 7-17.

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Naviaux, R., Curtis, B., Li, K., Naviaux, J., Bright, A., Reiner, G., Westerfield, M., Goh, S., Alaynick, W., Wang, L., Capparelli, E., Adams, C., Sun, J., Jain, S., He, F., Arellano, D., Mash, L., Chukoskie, L., Lincoln, A., & Townsend, J. (2017). Low-dose suramin in autism spectrum disorder: a small, phase I/II, randomized clinical trial Annals of Clinical and Translational Neurology DOI: 10.1002/acn3.424

Double-blind randomised, placebo-controlled trial of vitamin D in autism

Update 14th May 2019: The paper by Saad et al has been retracted (see here).

It was inevitable ("it is your destiny") that I would formulate a post about the paper published by Khaled Saad and colleagues [1] reporting results based on "a double-blinded, randomized clinical trial (RCT)" looking at the potential usefulness of a vitamin D supplement on "the core symptoms of autism in children." Inevitable because the peer-reviewed research literature looking at the sunshine vitamin/hormone in relation to autism is getting rather voluminous (see here and see here for examples) with the promise of lots more to come (see here). The fact that the name Saad in relation to this area of autism research has appeared before on this blog (see here) indicates that this researcher/research group are no strangers to this area of autism science.

First, thanks to Alex for the Saad paper. And so... utilising the premier research design, where 109 children* (aged 3-10 years old) diagnosed with an autism spectrum disorder (ASD) were randomly allocated to receive vitamin D drops - "300 IU [international units] vitamin D3/kg/day, not to exceed 5,000 IU/day" - or a placebo drops over 4 months and then tested blind "by the Childhood Autism Rating Scale (CARS), Aberrant Behavior Checklist (ABC), Social Responsiveness Scale (SRS), and the Autism Treatment Evaluation Checklist (ATEC)" before and after their vitamin D or placebo, some interesting results emerged. Their trial and protocol, by the way, was also registered. [*Actually, 120 children were initially allocated to vitamin D or placebo but 11 were lost to follow-up or discontinued participation in the study.]

Results: well first and foremost the tenet 'do no harm' seemed to be adhered to as we are told that "vitamin D was well tolerated by the ASD children" at least for the study duration. This is particularly important in light of that case report a few weeks back talking about vitamin D toxicity in the context of autism (see here). Indeed: "The serum levels of 25-hydroxycholecalciferol (25 (OH)D) were measured at the beginning and at the end of the study" kinda shows that authors were probably mindful of possible toxicity issues [2] alongside wanting to get a little more information about baseline vs. endpoint levels of the stuff. Having said all that the use of vitamin D was not completely side-effect free as 5 children taking the vitamin D drops reported symptoms such as "skin rashes, itching, and diarrhea."

Further: "The autism symptoms of the children improved significantly, following 4-month vitamin D3 supplementation, but not in the placebo group." Scores on the CARS (Total scores) showed a "significant decrease" in the vitamin D group compared with the group taking the placebo drops. This was in the direction of vitamin D supplementation positively impacting on the presentation of autistic symptoms. Scores on the ATEC also showed something akin to improvement for those taking the vitamin D drops. As one might expect, measured levels of vitamin D - "serum levels of 25 (OH)D" - rose in the vitamin D supplemented group compared to those in the placebo group.

These are interesting results providing some of the first double-blind RCT findings in relation to vitamin D supplementation and autism. I particularly like the fact that alongside well-validated instruments such as the CARS for 'measuring autism', the authors also included the ATEC, an instrument that I have growing fondness for (see here). They also measured functional vitamin D levels (albeit via an ELISA assay - I'd prefer via mass spec!) so it's not difficult to see that minus any unknown variables, the behavioural changes seem to match the biological changes to vitamin D status.

There is more to do and indeed, more research in this area is already underway. Larger groups of participants still following that gold standard research methodology will give a more accurate picture and perhaps provide some details about potential best responders to such an intervention (something already hinted at in the Saad data). And then there is the question of 'how' vitamin D might be affecting the presentation of [some] autism. Well, far be it from me to speculate too much, and also taking into account what Saad et al have to say on this matter, I suggest that we might learn a thing or two from looking at vitamin D use in other areas of medicine (see here) and taking things from there...

For now, here is what the UK Government says about vitamin D and the population at large although not everyone is convinced...

Music: Kate Bush and This Woman's Work....

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[1] Saad K. et al. Randomized controlled trial of vitamin D supplementation in children with autism spectrum disorder. J Child Psychol Psychiatry. 2016 Nov 21.

[2] Vogiatzi MG. et al. Vitamin D supplementation and risk of toxicity in pediatrics: a review of current literature. J Clin Endocrinol Metab. 2014 Apr;99(4):1132-41.

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Saad K, Abdel-Rahman AA, Elserogy YM, Al-Atram AA, El-Houfey AA, Othman HA, Bjørklund G, Jia F, Urbina MA, Abo-Elela MG, Ahmad FA, Abd El-Baseer KA, Ahmed AE, & Abdel-Salam AM (2016). Randomized controlled trial of vitamin D supplementation in children with autism spectrum disorder. Journal of child psychology and psychiatry, and allied disciplines PMID: 27868194

Camel milk and autism: two humps or three?

In a previous post with the cringe-worthy title: 'Camel milk for autism: one hump or two?' (you can see why I could never be a comedian) I talked about some rather intriguing research [1] asking whether, under double-blind, placebo-controlled conditions, camel milk could affect various clinical measures of severity when it comes to the label of autism, some autism. The answer was very possibly, yes; with the strong requirement for quite a bit more follow-up research in this area.

Lo and behold, yet more data has emerged from the research pen of one Laila Al-Ayadhi and colleagues [2] (open-access available here) on the topic of camel milk and autism and specifically the idea that: "camel milk could be [a] very promising therapeutic intervention in ASD [autism spectrum disorder]." Again, under double-blind, placebo-controlled conditions, Al-Ayadhi et al describe how 2 weeks of camel milk (raw or boiled) seemed to show some 'significant differences' on schedules such as the CARS (Childhood Autism Rating Scale), SRS (Social Responsiveness Scale) and the ATEC (Autism Treatment Evaluation Checklist). The placebo (cow milk) group by contrast, didn't show anything at all in terms of significant changes between baseline and post-intervention testing occasions.  The ATEC in particular, is something I'm quite keen to see more autism investigations using (see here).

I have some time for Dr/Prof. Al-Ayadhi and colleagues given some previous musings on their wide and varied research with autism in mind (see here). This recent work continues one of their important themes based on the idea that not all mammalian milk forms are alike (see here) and hence, following a tradition potentially implicating milk and dairy products in some autism (see here), a switch to other varieties of milk outside of those normally populating our diet might be beneficial for at least some. Other more 'N=1' reports [3] have offered similar discussions on this topic.

As per my previous musings on this topic, I can't readily offer a substantial and/or universal reason for what it is about camel milk that may be important to some people on the autism spectrum. Lactose content, milk protein structure or nutritional content are perhaps some of the most pertinent variables to consider given that all have some research 'history' when it comes to at least some autism (see here for some discussion on the seemingly forgotten work by Tim Buie et al on lactose issues and autism for example). In other peer-reviewed publications, Dr/Prof. Al-Ayadhi has talked about the antioxidant properties of camel milk as being key [4]. I'm hoping that in future times I might be able to discuss further this area of investigation as and when some research ideas in my own day job reach fruition.

And just in case you think I'm advocating camel milk for all autism, no I'm not. As we've seen from other research outside of autism recently, personalised nutrition is the way forward [5] not sweeping generalisations...

Music to close and a song that's growing on me (I think I need some earworm therapy).
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[1] Al-Ayadhi LY. et al. Behavioral Benefits of Camel Milk in Subjects with Autism Spectrum Disorder. J Coll Physicians Surg Pak. 2015 Nov;25(11):819-823.

[2] Bashir S. & Al-Ayadhi LY. Effect of camel milk on thymus and activation-regulated chemokine in autistic children: double-blind study. Pediatr Res. 2014 Apr;75(4):559-63.

[3] Adams CM. Patient report: autism spectrum disorder treated with camel milk. Glob Adv Health Med. 2013 Nov;2(6):78-80.

[4] Al-Ayadhi LY. & Elamin NE. Camel Milk as a Potential Therapy as an Antioxidant in Autism Spectrum Disorder (ASD). Evid Based Complement Alternat Med. 2013;2013:602834.

[5] Zeevi D. et al. Personalized Nutrition by Prediction of Glycemic Responses. Cell. 2015 Nov 19;163(5):1079-1094.

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Al-Ayadhi LY, Halepoto DM, Al-Dress AM, Mitwali Y, & Zainah R (2015). Behavioral Benefits of Camel Milk in Subjects with Autism Spectrum Disorder. Journal of the College of Physicians and Surgeons--Pakistan : JCPSP, 25 (11), 819-823 PMID: 26577969

Efficacy of foetal stem cell transplantation in autism...

The recent news that researchers might be one step closer to 'curing' type 1 diabetes following the publication of the paper by Pagliuca and colleagues [1] brought back into focus how stem cell therapy might hold some promise for all manner of conditions. The idea that researchers could generate "hundreds of millions of glucose-responsive β cells from hPSC [human pluripotent stem cells] in vitro" still faces a few challenges, including overcoming the immune assault central to the autoimmune condition that is type 1 diabetes. I have but one comment to make about the immune system and autoimmunity in this context: worm pills (see here)...

The question of whether an advance has been similarly made following the publication of the paper by Jeff Bradstreet and colleagues [2] (open-access available here) is perhaps open to some discussion with their observations that: "Statistically significant differences (p<0.05) were shown on ATEC/ABC scores for the domains of speech, sociability, sensory and overall health, as well as reductions in the total scores when compared to pre-treatment values" based on the use of foetal stem cells (FSCs) "in treating children diagnosed with ASDs [autism spectrum disorders]". Further details about the study can also be found in the latter slides of the presentation shown here.

Stem cell therapy in the context of autism is still a scientific hot potato. I've covered previous, very preliminary, forays into this research area before on this blog (see here). It is with the same cautions and caveats that I discuss the latest paper from Bradstreet et al.

So:

• This was a study of some 45 children diagnosed with an autism spectrum disorder (ASD) (mean age = 6-7 years). Diagnosis was confirmed by some of the gold-standard assessment instruments including ADOS and ADI. There were quite a few exclusion criteria applied to study entrants such that those with epilepsy, or "a neurological or co-morbid psychiatric disorder" were not examined. Learning disability without autism was also "considered exclusion criteria" as was a diagnosis of Asperger syndrome.
• The study was based in Kiev in the Ukraine where "stem cells harvested from 5-9 weeks old human fetuses following voluntarily – elective pregnancy terminations (legally available in the Ukraine)" were used. I don't doubt that there may be some who have strong views about this practice as per commentary from other authors (see here). Hematopoietic stem cells (HSCs) after harvesting were tested for various bacterial, fungal and viral infections as were the women who previously carried.
• Long quote coming up... "Stem cell transplantation of suspensions containing cryopreserved fetal stem cells were preceded by pre-medication of the subject via intravenous slow infusion of diphenylhydramine (Darnitsa, Ukraine) 10 mg and prednisone (Darnitsa, Ukraine) 15 mg on Day 1 and diphenhydramine (Darnitsa, Ukraine) 10 mg on Day 2". At this point, I'll draw your attention to some other work previously discussed on this blog on a possible role for corticosteroid therapy for some types of autism (see here) which included the use of prednisolone, the active metabolite of prednisone. After which the stem cells were administered...
• Results: "Early post-transplantation effects were reported in 78% of children: 26% of these children became calmer; eye contact was improved in 9%, while 29% had better appetite and 23% had an improved affect". Importantly, the authors report that no adverse effects were initially noted and "No transmittable diseases were noted during the 12 month follow-up". They also make mention of how initial effects may well have been [partly] as a consequence of the corticosteroid and other medication initially administered.
• Scores on the ATEC and ABC bore out the positive group changes noted between baseline (before stem cell therapy) and at 6 and 12 month follow-up which were also accompanied by various immunological changes "indicative of improved cell-mediated immunity in children".

OK. Despite these results the authors themselves are still cautious about their findings and stress: "future research studies are urgently needed and larger randomized -placebo controlled trials are needed to further characterize potential FSC-associated improvements in ASDs". This was a straight forward observational trial (before and after) which lacked control groups and in particular a placebo-controlled element so one has to be slightly hesitant about the strength of any findings. For those however who might be pulling on this study because of the use of something like the ATEC to measure autistic presentation, I'll draw your attention to some work suggesting that this instrument might be rather useful for monitoring intervention options for autism (see here).

As previously described, feelings run deep about the use or not of stem cells when it comes to autism not least because of the lack of data on long-term safety (and efficacy) in this context, the source 'material' for stem cells and the lack of information on just what might be going on in biological terms consequent to the behavioural results described. Examining this research from a cold, dispassionate, scientific point of view, I have to say that I'm becoming rather interested in what might be potentially going on during this and other studies [3] if not just as a function of other work by the late Paul Patterson and colleagues overlapping with this area [4] (discussed in a previous post). 

That being said, I'd like to see a lot more research done in this area before this kind of intervention enters anything like mainstream autism practice...

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[1] Pagliuca FW. et al. Generation of Functional Human Pancreatic β Cells In Vitro. Cell. 2014 Oct 9;159(2):428-439.

[2] Bradstreet JJ. et al. Efficacy of fetal stem cell transplantation in autism spectrum disorders: an open-labeled pilot study. Cell Transplant. 2014 Oct 9.

[3] Lv YT. et al. Transplantation of human cord blood mononuclear cells and umbilical cord-derived mesenchymal stem cells in autism. J Transl Med. 2013 Aug 27;11:196.

[4] Hsiao EY. et al. Modeling an autism risk factor in mice leads to permanent immune dysregulation. Proc Natl Acad Sci U S A. 2012 Jul 31;109(31):12776-81.

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Bradstreet JJ, Sych N, Antonucci N, Klunnik M, Ivankova O, Matyashchuk I, Demchuk M, & Siniscalco D (2014). Efficacy of fetal stem cell transplantation in autism spectrum disorders: an open-labeled pilot study. Cell transplantation PMID: 25302490

Increasing parental age and autism severity?

An interesting paper by David Geier and colleagues [1] (open-access here) caught my eye recently, concluding that there was a lack of support for the suggestion that: "increasing parental age was associated with increasing autism spectrum disorder phenotypic severity".

"the snozzberries taste like snozzberries".

Before progressing through the paper and its possible implications, the eagle-eyed out there might have already spotted the name Dr Brian Hooker on the authorship list of the Geier paper. Outside of his other peer-reviewed work [2], I probably only need to mention the letters 'CDC' and everything that has [so far] followed including (at the time of writing) a removal statement retraction statement (updated: 04/10/14) for another paper [3]...

Anyhow, the idea behind the Geier paper stems from the quite widely disseminated notion that there may be a connection between increasing parental age at conceiving and an increased risk of offspring autism. I've covered it a few times on this blog (see here and see here). The authors elaborate about a recent hypothesis suggesting that "there must be a linkage between increasing genetic load and increasing parental age in autism spectrum disorder pathogenesis" based on studies like the one from Kong and colleagues [4] (covered in a previous post) and Lampi and colleagues [5]. Further, that as a consequence of an increasing genetic load (all those SNPs et al), "there should be a significant relationship between increasing parental age and increasing autism spectrum disorder phenotypic severity of subjects diagnosed with an autism spectrum disorder".

The paper is open-access but maybe a few details are in order:

• Participants (N=351), diagnosed with DSM-IV autism, were drawn from "patients presenting for outpatient genetic consultations at the ASD Centers, LLC". Mean age was approximately 9 years of age, most male and most reporting developmental regression following birth. Details of age of parents at time of offspring birth were analysed alongside use of the ATEC (Autism Treatment Evaluation Checklist) at initial clinical presentation. These variables formed the crux of the study.
• Results: "Overall, it was observed that no significant relationships were observed between increasing autism spectrum disorder phenotypic severity and increasing maternal or paternal age". Except, that is, for something that seemed to suggest that older maternal age at birth of child seemed to correlates with "improved sociability" in offspring. The authors report that their observations: "provide important insights into the apparent lack of a relationship between increasing parental age and increasing autism spectrum disorder phenotypic severity".

Of course one has to be careful with any study of correlation/association, particularly when it comes to something as simple as just looking at ATEC scores of severity of behaviours in the autism domains and parents age at time of birth of their children. I personally would also have liked to see some further discussion on whether the broader autism phenotype (BAP) for example, might have been an influencing variable too in light of studies like the one from Hasegawa and colleagues [6]. Also, the participant group is quite large - as the authors note - but even there I think back to the sort of sample numbers that those [big data] studies in Taiwan are including (see here) as to where we should be heading.

That all being said, I don't want to downplay the Geier results. Another quote might be useful here: "most observed de novo genetic events are unconnected to an autism spectrum disorder diagnosis, and those that do confer risk are distributed across many genes and are not necessarily sufficient for disease". This ties in rather nicely with the recent discussions on common variations and autism risk (see here) and how Gaugler and colleagues [7] questioned how much weight to give to de novo mutations in the grand scheme of autism 'causation'. This also might imply that non-genetic events, or at least non-structural genetic events headed under the general banner of environment might also play some contributory role to at least some cases of autism. Again, something which has cropped up on this blog before (see here).

Music to close. Given the recent vote near these parts, one of Scotland's most famous exports... Franz Ferdinand and Do You Want To.

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[1] Geier DA. et al. An Evaluation of the Effect of Increasing Parental Age on the Phenotypic Severity of Autism Spectrum Disorder. J Child Neurol. 2014 Aug 27. pii: 0883073814541478.

[2] Hooker B. et al. Methodological issues and evidence of malfeasance in research purporting to show thimerosal in vaccines is safe. Biomed Res Int. 2014;2014:247218.

[3] Hooker BS. Measles-mumps-rubella vaccination timing and autism among young african american boys: a reanalysis of CDC data. Transl Neurodegener. 2014; 3: 16.

[4] Kong A. et al. Rate of de novo mutations and the importance of father's age to disease risk. Nature. 2012 Aug 23;488(7412):471-5.

[5] Lampi KM. et al. Parental age and risk of autism spectrum disorders in a Finnish national birth cohort. J Autism Dev Disord. 2013 Nov;43(11):2526-35.

[6] Hasegawa C. et al. Broader autism phenotype in mothers predicts social responsiveness in young children with autism spectrum disorders. Psychiatry Clin Neurosci. 2014 Jun 6. doi: 10.1111/pcn.12210.

[7] Gaugler T. et al. Most genetic risk for autism resides with common variation. Nature Genetics. 2014. July 20.

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Geier DA, Hooker BS, Kern JK, Sykes LK, & Geier MR (2014). An Evaluation of the Effect of Increasing Parental Age on the Phenotypic Severity of Autism Spectrum Disorder. Journal of child neurology PMID: 25163730

Measuring autism: ATEC rising?

Throughout many of my posts talking about autism research and in particular, the plethora of research suggesting that product A or diet B or drug C might impact on presentation, one important issue has surfaced again and again: how do we measure autism, or more specifically, how do we measure change in the presentation of autism?

Measuring up? @ Wikipedia  

A couple of years back (yes, it's been that long!) I posted about assessing change in autism. With what I thought was a great David Bowie link - ch-ch-changes - I talked about how autism research really needed to get its act together when it came to devising a comprehensive and open-access tool which could be universally adopted to assess interventions.

Importantly too, a tool to assess across different interventions to pick out (a) likely important interventions, (b) start to work on those all-important responders and non-responders groupings which one would expect from a heterogeneous condition(s) like the autisms and (c) provide a picture of how autism ages and the ebbs and flows of symptoms as a result of factors like maturation or even comorbidity.

It is with all this in mind that I'm posting about the study by Geier and colleagues* (open-access) who suggested that the parent-report measure, the Autism Treatment Evaluation Checklist (ATEC) might show more than a modicum of overlap with a more professionally administered schedule, the Childhood Autism Rating Scale (CARS).

The ATEC is a bit of rising star in the autism research assessment world in recent years. In my previous changes post, I referenced the very respectable paper by Magiati and colleagues** (see the authorship list) and their conclusion: "This study provides some preliminary evidence of the ATEC's potential value for monitoring progress of children with ASD over time". That is, bearing in mind the quite small participant group (N=22). Subsequently, the ATEC also seems to have made it across another language too***.

The ATEC has the advantage of being parent-administered and freely available without training. I appreciate that when one looks at the types of study which have used the ATEC to date, one might get the sense that the type of research is not exactly 'mainstream' when it comes to it's use (see here), but please dear readers, refrain from making any snap judgements about the potential of the instrument on that basis.

The Geier paper is open-access and actually pretty easy-going to read. The main findings:

• There was a significant correlation between total scores on the ATEC and CARS. That finding was based on CARS being administered first by one of the authors "formally trained in the administration of the CARS" and then "the participant's parent completed at ATEC form". In-between the professional and parents were not privy to the "scores generated from their respective completed tests".
• Specific domains of the two instruments also seemed to correlate well, particularly when it came to the sensory/cognitive awareness domain.
• The addition of items related to health/physical behaviour as part of the ATEC was an added bonus bearing in mind how much attention is starting to turn towards some of these comorbidities in relation to autism (see here).

Again, the Geier study was relatively small in terms of participant numbers (N=56) and as the authors pointed out, this was a snapshot study looking at comparing the instruments at one single time point rather than using different times. I'm also minded to bring into the conversation the paper by Ben-Sasson and colleagues**** at this point, and their suggestion that mums and dads don't always say the same things when it comes to the reporting of the presentation of autism. A variable which perhaps needs more investigation with regards to any parent-report measure methinks.

Still, I'm not going to take anything away from the recent results and the 'not bad' report for ATEC. Indeed, in these times of austerity and dwindling resources, combined with the increasingly important point that parents are the experts on their own children (see here and here), the addition of ATEC as a free and relatively resource-friendly instrument must be seen as a bonus to any future study.

Even I'm thinking very seriously about adding it to the list in my future work...

To close, Pavement and the ever-so mellow Shady Lane.

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* Geier DA. et al. A Comparison of the Autism Treatment Evaluation Checklist (ATEC) and the Childhood Autism Rating Scale (CARS) for the Quantitative Evaluation of Autism. J Ment Health Res Intellect Disabil. 2013 Oct;6(4):255-267.

** Magiati I. et al. Is the Autism Treatment Evaluation Checklist a useful tool for monitoring progress in children with autism spectrum disorders? J Intellect Disabil Res. 2011 Mar;55(3):302-12.

*** Memari AH. et al. Cross-cultural adaptation, reliability, and validity of the autism treatment evaluation checklist in Persian. Iran J Pediatr. 2013 Jun;23(3):269-75.

**** Ben-Sasson A. et al. Cross-parent reliability in rating ASD markers in infants. Dev Neurorehabil. 2013 Aug 7. [Epub ahead of print]

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Geier DA, Kern JK, & Geier MR (2013). A Comparison of the Autism Treatment Evaluation Checklist (ATEC) and the Childhood Autism Rating Scale (CARS) for the Quantitative Evaluation of Autism. Journal of mental health research in intellectual disabilities, 6 (4), 255-267 PMID: 23914277