Friday 27 July 2018

'Comprehensive metabolomics' and ME/CFS: lipid and energy production turn up again

The findings reported by Dorottya Nagy-Szakal and colleagues [1] describing the results of "biomarker discovery and topological analysis of plasma metabolomic, fecal bacterial metagenomic, and clinical data from 50 ME/CFS [myalgic encephalomyelitis/chronic fatigue syndromepatients and 50 healthy controls" provide the rather long blogging fodder today.

Just in case that opening quote sounds like gibberish, this was a study that in effect examined two quite prominent biological 'systems' alongside looking at symptom profiles of participants diagnosed with ME/CFS compared with controls. Metabolomics is a discipline that is no stranger to this blog, and is focused on the analysis of small molecule metabolities in a range of biological fluids (see here). The interface between the technology used to separate out and analyse said metabolites and the statistical analysis of the huge amounts of data generated as a result, are what make metabolomics the science that it is. 'Fecal bacterial metagenomics' also known as microbiomics (see here) refers to the science of cataloguing what bacterial species are present in poo(p) samples. Yes, bacteria have their own genomes too, and stool samples can therefore be a rather informative medium.

It's important to realise that this isn't the first time that metabolomics has been spoken in the same breath as CFS/ME (see here and see here for examples); something alluded to in the Nagy-Szakal paper. Indeed, this most recent paper adds to the authors other work in this area [2] (see here for my take) where the focus was on immune-related parameters and their *association* with CFS/ME in the context of the gut and its bacterial inhabitants. And once again, there are some eminent research names included on the authorship list as last time...

So, fifty participants diagnosed with CFS/ME were compared with 50 asymptomatic (I hate the words 'healthy control') participants, and their blood (plasma) and stool were analysed. Mass spectrometry played an important role in their metabolomic work, as over 550 compounds were initially separated out from the samples provided and identified.

Results: "Among the top plasma biomarkers differentiating ME/CFS patients from controls were decreased levels of betaine, complex lipids (lysophosphatidylcholine [LPC], phosphatidylcholine [PC]) and sphingomyelin (SM), and increased levels of triglycerides (TG), α-N-phenylacetyl-glutamine, ε-caprolactam and urobilin." I'm not going to go through all of those compounds individually as to their possible relevance but there are some important classes of compound being mentioned (i.e. lipids and triglycerides).

Authors also mention another group of compounds as also potentially being important: ceramides. You may have heard the word 'ceramide' before if you are/were a user of certain brands of shampoo in recent times (see here). Outside of any hair care role, ceramide "is a waxy lipid implicated in suppression of electron transport, insulin and leptin resistance and apoptosis." Among the many roles they play 'in' the body, there is some research literature to suggest that ceramides "may play a role in gut barrier dysfunction and increased gut permeability." Interesting (see here). And going back to the Nagy-Szakal results we are told that "patients with ME/CFS and IBS [irritable bowel syndromehave increased plasma levels of ceramide." Even more interesting.

Having mentioned the gut and gut issues in the form of IBS, it's also important to note that the authors made allowances for the presence of such gut dysfunction in their participant groups. And yes, one needs to remember that it was "based on self-reported diagnosis of IBS on the medical history form". As probably expected, the introduction of IBS (self-reported) did seem to affect the metagenomic (microbiomic) data obtained (something authors talked about in their last paper). More than that: "Chemical enrichment analysis of plasma metabolites revealed that metabolomic profiles of ME/CFS patients with IBS were distinguished from controls by levels of TG, ceramides, phosphatidylethanolmines (PE) and metabolites in the carnitine-choline pathway." Indeed also, take away the IBS bit from the ME/CFS findings and: "ME/CFS patients without IBS co-morbidity showed disturbances in PCs and carnitine-choline pathways, similar to the disturbances found in the overall ME/CFS cohort." Again, interesting.

Authors conclude that their results draw attention to a few areas already pertinent to CFS/ME, in particular, "lipid and energy metabolism." The word 'mitochondria' figures a few times in their results write-up and specifically how: "compounds in the choline-carnitine pathway were decreased in ME/CFS patients regardless of their IBS status." I've written about quite a bit of research on mitochondria and CFS/ME (see here and see here for examples) and how even if there aren't genetic reasons for mitochondrial issues (see here), this does not mean that there may not be more other issues with this system (see here).

We really need much more research in the area of metabolomics and ME/CFS. And patients really need it now, not some time later in the future...


[1] Nagy-Szakal D. et al. Insights into myalgic encephalomyelitis/chronic fatigue syndrome phenotypes through comprehensive metabolomics. Sci Rep. 2018 Jul 3;8(1):10056.

[2] Nagy-Szakal D. et al. Fecal metagenomic profiles in subgroups of patients with myalgic encephalomyelitis/chronic fatigue syndrome. Microbiome. 2017; 5: 44.


Monday 23 July 2018

Exposure to maternal type 1 diabetes and risk of offspring autism

"Among the 3 main types of diabetes complicating pregnancy, the risk of ASD [autism spectrum disorder] in offspring was elevated in mothers with T1D [type 1 diabetes], T2D [type 2 diabetes], and GDM [gestational diabetes mellitus] diagnosed by 26 weeks’ gestation compared with no diabetes."

So said the findings reported by Anny Xiang and colleagues [1] who undertook a look back at the records of over 400,000 children "born at 28 to 44 weeks’ gestation in Kaiser Permanente Southern California (KPSC) hospitals from January 1, 1995, through December 31, 2012." Specifically, authors were looking for a history of maternal diabetes - where diabetes refers to a state of high blood sugar levels over an extended period - as well as various potentially confounding variables as a function of a diagnosis of offspring ASD or not.

They describe how some 5800 children were diagnosed with autism over a typical follow-up period of about 7 years. Pertinent to their research question, researchers reported that relative to no exposure to maternal diabetes, various types of diabetes seemed to elevate the risk of a diagnosis of ASD. The statistics were: "the adjusted HRs [hazard ratios] for exposure to maternal diabetes were 2.36... for T1D, 1.45... for T2D, [and] 1.30... for GDM by 26 weeks’ gestation." The 'adjusted' part of those stats means that those potentially confounding variables - "birth year, maternal age at delivery, parity, education, self-reported race/ethnicity, median family household income based on residence census tract, history of comorbidity (≥1 diagnosis of heart, lung, kidney, or liver disease; cancer), and child’s sex" - were taken into consideration.

Should we be surprised by this *association*? Well, not really. On more than one occasion on this blog I've talked about how maternal diabetes seems to show 'some connection' to enhanced risk for autism in offspring (see here and see here). This work residing in a wider sphere where various conditions linked to the presentation of metabolic syndrome during pregnancy seem to show some connection to autism (see here).

Xiang et al also talk about how their T1D findings "add new information" but again, I'd be inclined to suggest that this is not the first time that T1D has cropped up with offspring autism in mind (see here). The possibility of a link with T1D does add an 'autoimmune' element to proceedings and *could* tie into other work mentioning this concept and autism (see here). Much more research in this area is indicated including that related to possible biological mechanisms.


[1] Xiang AH. et al. Maternal Type 1 Diabetes and Risk of Autism in Offspring. JAMA. 2018. June 23.


Friday 20 July 2018

A short-term aquatic exercise intervention for (some) individuals with CFS/ME?

I have to say that I did um-and-ah about whether or not to make this blog entry on the results published by Suzanne Broadbent and colleagues [1]. In it, researchers talked about the use of "a short-term aquatic exercise programme" with a small group of women diagnosed with chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME).

My 'in two minds' state was because the words 'exercise as intervention' and 'CFS/ME' have a rather poor history both in research and clinical terms; as proposals like 'graded exercise therapy' (GET) have the ability to invoke some rather adverse memories and reports for some/many people (see here and see here). As you can see, I did in the end decide that science should be seen and heard, even if it might be a tad uncomfortable. As hopefully you'll see, the Broadbent results might even provide some much needed focus in the area of activity and exercise with CFS/ME in mind minus any sweeping generalisations and psychobabble explanations which have typically followed such research.

Before progressing through their paper, it is worth mentioning that some of the authors on this most recent paper have some 'research form' when it comes to looking at exercise in the context of CFS/ME. Yes, there is mention of the words 'graded exercise' [2] in previous publications, but interestingly this is wrapped in the context of "immune system dysfunction in chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME)" and their looking at various biological aspects of exercise [3] with an immune system slant to it. This is not your regular 'de-conditioning' thinking...

Aquatic exercise was the name of the research game on this most recent occasion, and an open trial detailing various physiological and behavioural measures pre- and post-use of "an initial 20-min aquatic exercise session then two self-paced 20-min sessions per week for 4 weeks" with 11 women. As you can already see, this was not a controlled trial and there was no comparison group used; just an initial research foray looking at whether their fairly brief water-based exercise program might produce some meaningful results or not. I assume that the authors were conscious that water-based exercise has some advantages over er, not water-based activity, in relation to impact (aquatic exercise is typically termed 'low impact) and also strength-building (water resistance is much greater than air resistance). I might also add that others have been following the development of this trial with some interest (see here).

'First, do no harm' is a primary tenet in all of medicine, and on the basis of "no reports of symptom exacerbation" in their small participant cohort, the authors can tick an important item of their research checklist on this occasion. Alongside, authors detail results based on various physiological parameters: "6 min Walk Test (6MWT), perceived exertion (RPE), hand grip strength, Sit-to-Stand, Sit-Reach test, Apley's shoulder test" as well as monitoring heart rate after each session. There's even mention of "24- and 48-h post-session tiredness/pain scores" which, I assume, could be stretched to mean looking at aspects of an important symptom: post-extertional malaise (PEM). And on that basis the authors reported that many of those physiological parameters did show changes between pre- and post-intervention in relation to things like grip strength, the 6MWT and also pain ("24-h post-test tiredness and pain decreased"). Ergo, aquatic exercise was seemingly well-tolerated in their small participant group and further - more scientifically 'stronger' - investigations are perhaps indicated to substantiate this finding.

When I first tweeted about the Broadbent article, it did create some discussion (see here). I wasn't surprised by this given the nature of the trial and some of the references to other peer-reviewed research made by authors. It's not easy to put into words how much damage has been done by the widespread (universal?) advocacy of something like GET when it comes to ME/CFS. Suffice to say that for many people with CFS/ME, any study that mentions 'exercise' as an intervention is likely to be met with a degree of scepticism. Once bitten and all that. And I also note the words "raising the possibility that there could be future lawsuits from ME patients whose condition has worsened from the treatment" have recently been mentioned in relation to GET...

But I do think there is more research to be done in this area on the back of the Broadbent results. Minus hype, sweeping generalisation and again importantly without any 'psychological theory' input, further analysis of the physiological effects of exercise on those with ME/CFS is a must, particularly with something like PEM in mind. No, I'm not advocating research practices that unethically put people with CFS/ME onto exercise regimes, but rather smaller research steps starting, for example, with the greater use of actigraphy on a day-to-day basis. It's been a real point of contention that actigraphy - the (objective) study of rest and activity cycles - has not been more incorporated into CFS/ME research (see here). Particularly, when discussions about 'recovery' from ME/CFS have been prominent in many quarters (see here) seemingly without mention of objective ways and means of establishing parameters of such recovery. I'd also suggest that the authors' previous work on immune function following exercise could also be applied to further aquatic exercise research too...


[1] Broadbent S. et al. Effects of a short-term aquatic exercise intervention on symptoms and exercise capacity in individuals with chronic fatigue syndrome/myalgic encephalomyelitis: a pilot study. Eur J Appl Physiol. 2018 Jun 19.

[2] Broadbent S. & Coutts R. Intermittent and graded exercise effects on NK cell degranulation markers LAMP-1/LAMP-2 and CD8+CD38+ in chronic fatigue syndrome/myalgic encephalomyelitis. Physiol Rep. 2017 Mar;5(5). pii: e13091.

[3] Broadbent S. & Coutts R. Graded versus Intermittent Exercise Effects on Lymphocytes in Chronic Fatigue Syndrome. Med Sci Sports Exerc. 2016 Sep;48(9):1655-63.


Thursday 19 July 2018

Probiotics for anxiety: fine if you're a (diseased) rodent, but not yet ready for mass roll-out for humans

"While probiotic administration reduces anxiety-like behavior in rodents, the current state of clinical research does not (yet) support probiotics as an efficacious treatment for anxiety."

That was the research bottom-line reported by Daniel Reis and colleagues [1] who scoured the various peer-reviewed science databases looking "to evaluate the clinical and preclinical (animal model) evidence regarding the effect of probiotic administration on anxiety."

Probiotics, in case you don't already know, describe a range of bacteria and yeasts that are touted "as having various health benefits." Most probiotics are taken orally and are thought to be acting on the multitude of wee beasties that in particular, call our gut home (gut microbiota). Anxiety represents a 'state' that manifests as various physical and psychological symptoms. I've talked a lot about anxiety on this blog in the specific context of autism (see here for example) and how absolutely disabling it can be. Mentioning anxiety in the same sentence as probiotics provides a clue that something called the 'gut-brain axis' might be important for some...

Reis et al undertook a systematic review and meta-analysis of the pertinent research literature, having previously published their intention to do so (see here). Randomised-controlled trials matching their inclusion criteria were examined up to November 2017 including both pre-clinical (animal) and clinical (human) studies. The various results were collated, examined and boiled down to a consensus on the basis of the currently available data.

Bearing in mind that the word 'probiotic' covers a lot of ground in terms of what bacteria/yeasts and what preparations are included, the results were a bit of a mixed bag. As mentioned in the opening line to this post, if you're a rodent, the chances are favourable that taking a probiotic might *reduce* anxiety-like behaviour(s). One has to be a little careful about how one defines 'animal anxiety' but compared to placebo, probiotics - specifically including Lactobacillus (L.) rhamnosus - might be something to consider. Even better if you are a 'diseased' rodent...

When it came to the research on anxiety and probiotics in humans, the current status of the research is a little more 'complicated'. So: "Combining standardized mean differences (SMDs) for the 14 included studies revealed a pooled SMD of -0.12, indicating that probiotic administration did not result in a significant reduction of anxiety." The results did not alter where dose and duration were taken into account or whether 'healthy' or 'clinical' participants were observed. Ergo, the current state of the research (up to November 2017) does not generally suggest an action for probiotics in the treatment/management of anxiety in humans.

Of course that does not mean that every study on animals and humans found the same direction (or lack) of effect. We are told that: "At the level of individual trials, 12 of the 22 included animal studies found that probiotics significantly reduced anxiety-like behavior on at least one outcome measure" and "3 of the 14 included clinical studies (encompassing 1527 individuals) found that probiotics significantly reduced symptoms of anxiety." I might also direct your attention to earlier meta-analyses that found that probiotics did seem to affect psychological symptoms in people including anxiety (see here). One therefore needs to be mindful of the limitations of such systematic reviews and meta-analyses and the sweeping generalisations that are made as a result.

But... the results, as they currently stand, suggest that more investigation and perhaps less 'hype' is required around the topic of probiotics for anxiety.

And speaking of meta-analyses over-turning other meta-analyses, I'm not sure I would describe fish oils for a healthy heart as 'nonsense' as one media report did on the basis of a new review. Particularly when other reviews not-so-long ago along similar lines, came to a slightly different opinion with regards to some groups of people...


[1] Reis DJ. et al. The anxiolytic effect of probiotics: A systematic review and meta-analysis of the clinical and preclinical literature. PLoS ONE. 2018; 13(6): e0199041.


Wednesday 18 July 2018

Another blood test for autism?

"These results form the foundation for the development of a biochemical test for ASD [autism spectrum disorder] which promises to aid diagnosis of ASD and provide biochemical understanding of the disease, applicable to at least a subset of the ASD population."

OK, use of the word 'disease' in the context of autism is really, really not OK in this day and age. Researchers, peer reviewers and their publishing journals should be doing something about this kind of language. There are however some potentially important aspects to the work published by Daniel Howsmon and colleagues [1] worth talking about. Not least is their observation on how "folate‐dependent one carbon metabolism (FOCM) and transsulfuration (TS) pathways" that have been quite readily *associated* with autism might be linked to quite a bit more than just uncovering the biochemistry of at least some autism (see here for example).

Before progressing further into these findings, I note there has already been some media interest in them (see here) with a byline reading: "First physiological test for autism proves high accuracy in second trial." We'll see about that...

So, after quite a long introduction about 'biomarkers for autism' and how they "come with their own set of challenges before they reach clinical translation", authors report further results building on some of their previous work in this area [2] that I've already covered on this blog (see here). On that previous research occasion, the suggestion was that between 5 and 7 metabolites linked to folate and/or transsulfuration pathways provided a 'best fit' when it came to picking out children diagnosed with autism from those not diagnosed with autism.

This time around, there was an 'extension' to that work: "(a) By comparing univariate analysis with four different multivariate methods on FOCM/TS data for ASD biomarker development to ensure that the identified results are not restricted to FDA [Fisher Discriminant Analysis] and (b) to test and validate multivariate FOCM/TS biomarkers on data collected from a new cohort of ASD participants." The words 'training data' and 'validation data' are used quite a bit throughout the Howsmon article, illustrating how different statistical classification methods were initially applied to training data from the cohort used in their first paper, which were then tested on a new cohort of participants (n=154) diagnosed with an ASD. Given some of the names included on the authorship list, it's no surprise that participant data with regards to the metabolites being looked at were drawn from other studies looking at the possible clinical value of preparations like folinic acid (see here) and sapropterin (see here) with autism in mind.

When those different statistical classification methods were applied and data was crunched, a few observations were made. The headline result was that one model/method produced the best 'potential' biomarker results and it was the same/similar method to that previously discussed by the authors. To quote: "An FDA model using five variables was shown to slightly outperform the other models on this new validation data set." That being said, the accuracy rates (including false positive and false negative rates) hovering around the high 80%s have to take into account that two of the metabolites thought to be important on the last research occasion - % DNA methylation and 8‐OHG - "were not present in the validation set" on this research occasion. This is a pity and a weakness of the current study.

So, do we at last have a 'physiological test' with 'high accuracy' for picking out autism from not-autism? Erm, not quite yet. With all due respect to the authors, their data is interesting and does partially back up their original findings, but we're not quite there yet with regards to rolling out any sort of biological test for autism. Indeed, in these days of the plural 'autisms' (see here) and acknowledging that the diagnosis of autism rarely presents in some sort of diagnostic vacuum (see here) it could be worthwhile re-evaluating whether we're ever likely to see a 'one biological test to diagnose them all' situation.

Further investigations are however indicated and of course, this more recent information does add to the quite rich data already generated suggesting that quite a bit more focus on things like methionine, homocysteine, cysteine and glutathione in relation to autism could be an important research path to follow. I'm also minded to suggest that different research teams taking on a 'possible biomarker for autism' type research perhaps need to talk more to each other (see here) pooling findings, resources and perhaps participant groups too...


[1] Howsmon DP. et al. Multivariate techniques enable a biochemical classification of children with autism spectrum disorder versus typically‐developing peers: A comparison and validation study. Bioengineering & Translational Medicine. 2018. May 14.

[2] Howsmon DP. et al. Classification and adaptive behavior prediction of children with autism spectrum disorder based upon multivariate data analysis of markers of oxidative stress and DNA methylation. PLoS Comput Biol. 2017 Mar 16;13(3):e1005385.


Tuesday 17 July 2018

The prevalence of autism in China meta-analysed

"Based on diagnostic criteria the pooled prevalence of ASDs [autism spectrum disorder] was 39.23 per 10,000... specifically, the prevalence of autism was 10.18 per 10,000."

That was the conclusion reached by Fei Wang and colleagues [1] following their "comprehensive meta-analysis of the pooled prevalence of ASDs in China" based on data from 44 studies comprising about 2.3 million people aged below 18 years of age. Relying on data published from database inception up to February 2017, authors trawled the peer-reviewed scientific domain  - "PubMed, EMBASE, PsycINFO, China National Knowledge Infrastructure, Chinese biomedical literature service system (SinoMed) and Wan Fang" - looking for pertinent articles regarding the epidemiology of autism in China. Their results covered "30 provinces/ municipalities/ autonomous regions in China" and were in the most part conducted in the 21st century. A few studies (n=7) were rated as being of 'high methodological quality' with the remaining meeting guidance for 'moderate quality'.

Accepting that diagnosis via DSM or ICD was not the only inclusion criteria - also including "screening tools [such as the Clancy Autism Behavior Scale (CABS), Children Autism Spectrum Test (CAST) and Checklist for Autism in Toddlers (CHAT)]" - the collected figures arrived at 0.39% and 0.01% for ASD and autism are quite a bit lower than we're typically used to seeing. Take for examples, the most recent stats from the US CDC on [estimated] ASD prevalence (see here) talking about 1.7% of 8-year olds diagnosed with autism or the data from Northern Ireland (see here) (2.9% of school-aged children), and you can see quite a stark difference. Only when Wang took into account the prevalence of ASD solely based on those studies utilising screening tools does the figure of 429.07 per 10,000 equating to 4.29% look anything like the data from those other countries.

What could all this mean? Well, we do have to be a little careful not to read too much into these collected statistics. As per another paper [2] published at roughly the same time as the Wang paper, there may be various factors - 'challenges' - influencing the particular status of autism screening and case ascertainment in China that might need consideration. As far as I can see, there is for example, no national screening guidance for autism covering all of China, so "inconsistencies in screening and diagnostic procedures... and discrepancies between diagnostic criteria" are going to be potentially significant variables. Indeed, other studies have pointed to a 'high prevalence rate of suspected autism' in some parts of China (see here) which is directly contrary to the Wang findings. Alongside other potentially important factors such as 'willingness' to screen for autism and socioeconomic factors influencing 'ability' to screen for autism, and the picture that emerges is a complicated one.

But... one also has to entertain the possibility that the prevalence of autism in China *might* be different to other countries around the globe. I've kinda touched upon this quite recently (see here). I don't want to speculate too much about why this might be at this point, but some combination of genes and elements of environment could be relevant (see here) with lots more science to be done...


[1] Wang F. et al. The prevalence of autism spectrum disorders in China: a comprehensive meta-analysis. Int J Biol Sci. 2018 May 12;14(7):717-725.

[2] Pang Y. et al. Challenges of case identification and diagnosis of Autism Spectrum Disorders in China: A critical review of procedures, assessment, and diagnostic criteria. Research in Autism Spectrum Disorders. 2018; 53: 53-66.


Monday 16 July 2018

"A strict and lifelong gluten-free diet can help recover vitamin D level without any supplementation"

The quote titling this post - "A strict and lifelong gluten-free diet can help recover vitamin D level without any supplementation" - comes from the results published by Fabiana Zingone & Carolina Ciacci [1].

These authors inspected the peer-reviewed literature looking at vitamin D levels in relation to the archetypal 'diet can affect health' autoimmune condition that is coeliac (celiac) disease. They looked at both something called calcifediol, otherwise known as 25-hydroxyvitamin D (25(OH)D), and also something called calcitriol, also known as 1,25-dihydroxyvitamin D3. The difference between the two 'forms' of vitamin D is that one represents the 'pre-hormone' version  - (25(OH)D) - that is typically quantified to give a 'where you're at' measurement of biological vitamin D levels, and the other - 1,25-dihydroxyvitamin D3 - is the 'active' metabolite. Through the wonders of something called mass spectrometry, these and other 'forms' of vitamin D are able to be quite accurately measured [2] in various biological fluids.

Zingone & Ciacci reported that "most of the studies on vitamin D in adult CeD [coeliac disease] report a 25 (OH) vitamin D deficiency at diagnosis that disappears when the patient goes on a gluten-free diet, independently of any supplementation." This finding really intrigued me. It got me thinking of a few things; notably about mechanisms and biological relationships and indeed, how applicable such a finding could be to the general 'not coeliac' population or those 'around the diagnostic edges' of CeD.

OK, it should be noted that part-and-parcel of CeD is an issue with malabsorption, where 'the body does not fully absorb nutrients' (see here). The inflammatory processes at work in CeD do some pretty awful things to the structure and functioning of the mucosal lining of the bowel which aren't really conducive to optimal absorption of nutrients from food. The implementation of a gluten-free diet does help matters; and so logic dictates that absorption of something like vitamin D from food sources will be improved when a gluten-free diet is implemented. I've also blogged about how this process *may* also be part of the effect noted in relation to [some] autism and the use of similar dietary intervention strategies (see here). Alongside, I'll mention that, done right, a gluten-free diet is actually not the most unhealthiest diet in the world either.

Having already sort-of mentioned something like non-coeliac gluten/wheat sensitivity in the contest of the 'diagnostic edges' of CeD, I do wonder if there could be a further plan of research there too. Y'know to look at questions like whether such not-quite-coeliac-disease conditions also (a) manifest as having low levels of vitamin D when not diet treated and (b) whether the use of a gluten-free or other diet (see here) might similarly positively effect vitamin D levels in those circumstances?

There's also another potentially important explanation to consider which was tweeted by Dr Emily Deans (she of the fabulous Evolutionary Psychiatry blogs): could vitamin D deficiency be a marker of something more general? To quote from Dr Deans' tweet (shown pictured above): "Because it’s [vitamin D] an inverse acute phase reactant and goes down with illness and up with health." There is some sound logic behind such an observation insofar as vitamin D insufficiency/deficiency being associated with all manner of physical and behavioural/psychiatric diagnoses/conditions/states (see here and see here for examples). Correction of vitamin D deficiency is all well and good when it comes to correcting biological measures, but outside of treating something like rickets, the evidence for extra-skeletal effects from such supplementation is currently not that great.

Finally, I'll draw your attention back to some work suggesting that vitamin D might itself have some interesting effects on gut barrier function (at least in mice) (see here). One wonders what this could also mean for CeD and the spectrum of gluten-related issues?


[1] Zingone F. & Ciacci C. The value and significance of 25(OH) and 1,25(OH) vitamin D serum levels in adult coeliac patients: A review of the literature. Dig Liver Dis. 2018 Apr 13. pii: S1590-8658(18)30702-3.

[2] van den Ouweland JM. et al. Vitamin D and metabolites measurement by tandem mass spectrometry. Rev Endocr Metab Disord. 2013 Jun;14(2):159-84.


Saturday 14 July 2018

Shocker alert: gut problems in autism impact on sleep (again)

"Increased odds of sleep problems were most frequently associated with gastrointestinal distress (GID) and non-verbal IQ (NVIQ), followed by male sex and age."

That was one of the findings reported by Ann Johansson and colleagues [1] who set out to examine "the relationship between sleep problems and characteristics of children with ASD [autism spectrum disorder] in a large, nationwide sample." Mention of the words 'Simons Simplex Collection' in the Johansson article provides a clue as to the source population examined in this study and some of the hows-and-whys of the research. From what I also understand, this paper is part of a doctoral thesis by Johansson looking at some of the possible genetics of sleep with autism in mind (see here). Indeed, if one scrolls to page 70 of the thesis, one finds the study in question...

The Simons Simplex Collection Sleep Interview (SSCSI) was the instrument of choice for assessing sleep issues. This is a short parent-report questionnaire that includes both a composite score for total sleep issues and subscale scores for things like 'sleep duration issues'. Alongside, GID was classified "if they were reported (yes/no) to have bloating/excess gas, celiac disease, constipation, diarrhea, ulcers, gastroesophageal reflux disease, inflammatory bowel disease (Crohn’s disease, ulcerative colitis), irritable bowel syndrome, abdominal pain, unusual stools, vomiting, and/or other GID." Throw in scores on the ADOS "used to measure ASD severity" and crunch the data...

I've inserted the word 'again' into the title of this post because this is not the first time that functional gastrointestinal issues 'over-represented' in autism have been connected to sleep issues (see here). This time around, researchers mention that over 40% of their cohort (2000+ children) "were categorized as having mild or moderate/severe sleep problems" according to their SSCSI composite score. 'Difficulty falling asleep' seemed to be one of the more frequently reported issues. GID - gastrointestinal distress - was the strongest factor linked to sleep issues (odds ratio = 2.79), again based on the SSCSI composite score for sleep issues. There were other combinations of symptoms potentially linking to sleep noted by the authors but I'm minded to put them to one side for now.

Caveats? Well, one big caveat sticks out: the reliance on parent-reported responses to a questionnaire about sleep without any reference to objective measures of sleep. I've gone on and on (and on) about the use of actigraphy when it comes to sleep research relating to various diagnostic labels (see here and see here for examples) and well, keep coming to the same conclusion about a strong requirement for such objective measures on sleep-wake cycles. I appreciate that there may be some 'consumer resistance' to wearing a wristband for example, to measure activity and rest cycles (see here), but surely someone, somewhere can engineer something when kids don't want to wear such gadgets? Insofar as the classification of GID also relying on parental report, I'm a little kinder to this because the evidence is pretty good for suggesting that parents might be tuned into what is typical and what is not typical from a functional bowel habits perspective in their offspring (see here)...

No mind, the results do accord with other independent data on how gut issues present in autism can seemingly have some far-reaching effects. As to 'how', well, I would always start with the obvious explanation: pain and discomfort caused by bowel issues affecting sleep, and then work back from there. Indeed, as if I need to say it again, bowel issues (both functional and more pathological) are truly 'over-represented' when it comes to a diagnosis of autism (see here) and science and clinical practice really need to do a lot more to tackle such issues as and when they are reported/detected...


[1] Johansson AEE. et al. Characteristics of sleep in children with autism spectrum disorders from the Simons Simplex Collection. Research in Autism Spectrum Disorders. 2018; 53: 18-30.


Friday 13 July 2018

"little evidence for the involvement of Mg2+ in the mood disorders"?

Mg2+ described in the title of this post refers to magnesium, a mineral that participates in quite a few important biological reactions in the human body. Outside of its proposed involvement in a variety of somatic conditions and diagnoses, a deficiency in magnesium has also been *linked* to various psychiatric and behavioural issues too (see here). The findings reported by Danny Phelan and colleagues [1] however, stress caution in making too many sweeping generalisations on the basis of the currently available peer-reviewed data, albeit with hints that magnesium might have some role to play for some...

The name of the research game for Phelan et al was 'systematic review and meta-analysis', which basically means identifying, collating and 'boiling down' the [currently available] relevant research into some sort of coherent whole. Some 58 research articles including over 45,000 participants were used for 'quantitative synthesis' across a variety of different effects: the prevalence/incidence of depression as a function of magnesium intake, magnesium levels as a function of mood disorder status, magnesium concentration according to mood disorder severity and mood disorder status as a function of magnesium treatment. The results were interesting...

"Adherence to a diet high in Mg2+ was associated with a lower prevalence of depression in cross-sectional studies... but not in longitudinal cohorts that assessed the incidence of new-onset depression." Taking into account the difference in study design, this finding translates as a suggestion that "dietary Mg2+ intake may play a part in the pathology of depression" with the caveat that cause-and-effect was not proven. Accepting also that 'depression' as an umbrella term covers quite a bit of diagnostic ground, authors observed that: "There were no studies which reported on the effects of dietary Mg2+ on symptoms of bipolar disorder" so no conclusions can be currently formed either way.

Next: "Against expectations, we found higher Mg2+ levels in bodily fluids in patients with a mood disorder relative to healthy control subjects." This is a peculiar finding and one that needs further explanation beyond possibly just reflecting "the hypothesis that an increase in Mg2+ may underlie the clinical efficacy of (fast-acting) antidepressants" or dehydration *caused by* the use of pharmacotherapy indicated for mood disorders. I might add that such a findings could just be indicative of magnesium showing a epiphenomenal relationship with mood disorder too.

Finally: "In line with expectations, we found that treatment with Mg2+ supplements was associated with a decline in depressive symptoms." The authors yet again mention that study design/type may have something to do with the results observed; in particular, that a such an effect seemed to be confined to those studies with no placebo condition.

I was initially a little unsure about the 'cautiousness' expressed by Phelan et al on a possible role for magnesium in [some] mood disorders. Statements like: "Our results provide little evidence for the involvement of Mg2+ in the mood disorders" didn't seemingly really reflect the findings being reported on, but with a bit of further critical thinking I've changed my tune a bit. I would still perhaps argue that it would have been more accurate to say something along the lines of 'there is evidence out there for an effect on dietary magnesium potentially being associated with a lower instance of depression but that evidence is not as methodologically strong as one would hope'. But oh-um. Certainly I think we can conclude that there is an additional scheme of research to follow to aid in future position statements on this topic.

And then there is the question of 'why?'. Why should magnesium affect mental health? And what about any effects from various 'different types' of magnesium available?

To close, I've linked to this before but here it is again: possibly the best opening to a film ever...


[1] Phelan D. et al. Magnesium and mood disorders: systematic review and meta-analysis. BJPsych Open. 2018 Jul;4(4):167-179.


Thursday 12 July 2018

Risk of poisoning in ADHD: meta-analysed

There was something inevitable about the results published by Maite Ruiz-Goikoetxea and colleagues [1] looking at the currently amassed scientific data "quantifying the risk of poisoning in children/adolescents with ADHD [attention-deficit hyperactivity disorder]."

Inevitable, because the results of their meta-analysis observing that "ADHD is associated with a significantly higher risk of poisoning" kinda tallies with other enhanced risk(s) in relation to general injury coinciding with this diagnosis, mentioned by the same authorship group (see here).

Poisoning - "defined by the World Health Organization as “an injury that results from being exposed to an exogenous substance that causes cellular injury or death”" - covers quite a bit of ground. The authors headed into this particular topic on the basis of their previous research foray (which I blogged about) on meta-analysing injury risk in the context of ADHD [2]. They started out with the premise that "a plausible hypothesis is that ADHD symptoms (inattention, hyperactivity and impulsivity) could lead to a similar increase in the risk of poisoning."

Nine studies including some 85,000 children and adolescents diagnosed with ADHD and 1.4 million not-ADHD controls, were included in their meta-analysis. Diagnosis of ADHD were garnered from various sources but most commonly 'administrative coding' on the basis of diagnosis and/or medication being dispensed for ADHD. Exposure to a poisoning event was also analysed; predominantly based on the use of registry data and predominantly utilising the ICD classification of poisoning.

"Overall, poisoning cases were uncommon" is an important point made by the authors; indicating that the absolute numbers of poisoning cases in ADHD and not-ADHD were actually low. So: "The median number per study of poisoned individuals that suffered from ADHD was 14..., whereas the median number per study of poisoned individuals who did not suffer from ADHD was 29." Bearing in mind there were more not-ADHD participants than diagnosed ADHD participants cumulatively reviewed by Ruiz-Goikoetxea et al, the calculated prevalence rates (per 1000) of poisoning "ranged between 3.5 and 60 (median 16) in children and adolescents with ADHD and between 0.8 and 37.3 (median 4.8) in children and adolescents without ADHD."

Still, the calculated risk - relative risk - was elevated in relation to poisoning events in those diagnosed with ADHD to the tune of something like them being three times more likely to suffer a poisoning event. Authors also noted that: "the relative risk of poisoning in individuals with ADHD compared to individuals without it was statistically higher than the overall relative risk of physical injuries" thus hat-tipping their previous research efforts.

There are some other details included in the Ruiz-Goikoetxea that are noteworthy insofar as age-effects - "poisoning incidence has two peaks across the child life span" - and how "the poly-pharmacy status in many ADHD patients could increase the likelihood of an accidental poisoning." But the bottom line is that, yet again, a diagnosis of ADHD seems to put someone as some significantly heightened risk of injury, and we should be doing everything we can to minimise any additional risks to those diagnosed.


[1] Ruiz-Goikoetxea M. et al. Risk of poisoning in children and adolescents with ADHD: a systematic review and meta-analysis. Sci Rep. 2018 May 15;8(1):7584.

[2] Ruiz-Goikoetxea M. et al. Risk of unintentional injuries in children and adolescents with ADHD and the impact of ADHD medications: a systematic review and meta-analysis. Neuroscience & Biobehavioral Reviews. 2018; 84: 63-71.


Wednesday 11 July 2018

The [estimated] global prevalence of schizophrenia in 2016... 0.28%

The findings reported by Fiona Charlson and colleagues [1] looking at the "GBD [global burden of disease] 2016 estimates of schizophrenia prevalence and burden of disease with disaggregation by age, sex, year, and for all countries" provide the brief blogging fodder today.

As per the title of this post, when all the data were captured (from a "total of 129 individual data sources") and numbers crunched, the "global age-standardized point prevalence of schizophrenia in 2016 was estimated to be 0.28%."

Authors talk about schizophrenia as a "low prevalence disorder" highlighting also how there were no sex differences noted and how: "Age-standardized point prevalence rates did not vary widely across countries or regions." Schizophrenia it appears, does not care if you are a man or a woman or where you live. What it does seem to do, quite generally, is affect your quality of life and other life chances, as per another quote from the Charlson findings: "Schizophrenia contributes 13.4... million years of life lived with disability to burden of disease globally." Oh, and it appears to be increasing in frequency too: "Globally, prevalent cases rose from 13.1... million in 1990 to 20.9... million cases in 2016."

I personally, found the Charlson estimate - 0.28% - to be lower than I would have expected. Having talked for example, about schizophrenia prevalence rates in specific countries on this blog (see here) and mention of figures such as 0.83% [2], the global figure seems someway behind. Interestingly also, in the United States, there has been some 'discussion' about the revision of the prevalence estimates of schizophrenia there too (see here), where a quite long-standing 1.1% estimate - "1-year prevalence of schizophrenia in adults in the US" - was recently revised down to 0.3% (a figure not a million miles away from the Charlson estimate).

I guess, there's more to do when it comes to the establishing a precise prevalence of schizophrenia...


[1] Charlson FJ. et al. Global Epidemiology and Burden of Schizophrenia: Findings From the Global Burden of Disease Study 2016. Schizophr Bull. 2018 May 12.

[2] Chan KY. et al. Prevalence of schizophrenia in China between 1990 and 2010. Journal of Global Health. 2015;5(1):010410.


Tuesday 10 July 2018

"anxiety occurring as a consequence of ASD symptoms"

Although not necessarily a popular idea, I have for a while been coming around to the possibility that various 'comorbidities' associated with a diagnosis of autism or autism spectrum disorder (ASD) represent more than just 'comorbidity'. I'm not specifically talking about medical comorbidity such as epilepsy or seizure disorder being intricately related to autism (although there is evidence for such a relationship) but rather that co-occurring clinical and sub-clinical psychiatric issues such as depression and anxiety potentially 'come about' partially as a result of the presence of autistic traits and characteristics (see here and see here).

As I said, this is not a universally popular idea. In the age of the emergence of an 'autistic identity' and an increasingly vocal group of people wanting to discuss what role societal factors play with regards to quality of life in the context of autism (see here), the idea that autistic traits themselves might in some way predispose for various other, often very disabling conditions, is not easy to reconcile. Even more so if the implication for managing things like anxiety and/or depression might mean 'targeting' core autistic features for intervention...

The findings such as those reported by Elizabeth Shephard and colleagues [1] "testing the specificity of early-life (infant and toddler) predictors of mid-childhood ADHD [attention-deficit hyperactivity disorder] and anxiety symptoms compared to ASD symptoms" provide however, another tier of evidence that (a) autism rarely exists in some sort of diagnostic vacuum (see here), and (b) something like the symptoms of anxiety appearing alongside autism could "reflect the presence of common developmental pathways or convergence in early behavioural manifestations."

Shephard et al discuss results obtained from the British Autism Study of Infant Siblings (BASIS) initiative, a collaboration based here in Blighty aiming to "provide a platform for the study of infants at-risk for autism in the UK and to facilitate collaborative links between scientists working in the area." High-risk (i.e. having a sibling diagnosed with ASD) and low-risk infants were followed and tested for various symptoms and traits covering autism and also ADHD and anxiety at various points during their childhood development: "7, 14, 24 and 38 months, and 7 years of age." Importantly, because measuring things like anxiety in young children is still quite a challenge, researchers used other soft signs and symptoms - fearfulness and shyness - as "early-life predictors of anxiety symptoms." Some nifty statistical methods were applied to the collected data.

Results: "Increased activity levels and poor inhibitory control were correlated with ADHD symptoms and not ASD or anxiety; these associations were unchanged in path models controlling for risk-group and ASD symptoms." The authors interpreted these findings as evidence that "these disorders may have distinct developmental origins and are therefore unlikely to reflect a common condition" with a specific focus on autism and ADHD. Ergo, when one sees the data pointing to a rather large over-representation of ADHD in the context of autism (see here), this does not necessarily translate into autism being ADHD or vice-verse or them sharing a common developmental pathway.

Additionally: "early‐life markers of anxiety (without ASD) were associated with later anxiety..., but were also associated with later ASD symptoms." When looking at those early-life markers of [possible] anxiety, and how they *linked* to the symptoms of autism, authors highlighted how "these disorders are difficult to differentiate early in life, which could reflect the presence of common developmental pathways or convergence in early behavioural manifestations of these disorders." In other words, there may be some intricate links between them.

Of course, lots more research is needed in this area, as authors mention about the use of "parent‐rated measures of early‐life predictors and mid‐childhood symptoms of ADHD, anxiety and ASD" and what that could mean for the quality of the information obtained. Personally, I'd be inclined to suggest that parents are often 'under-rated' in their contributions to autism research (see here for example) including on the specific issue of anxiety and autism (see here). But I guess every study can be improved in some respect.

What's more to say on this topic? Well, I'm minded to bring in some other, rather 'left-field' evidence for how autism and anxiety might be more intricately linked than hitherto suggested, in the form of some work looking at selective mutism and autism (see here). How, a condition centrally identifying with anxiety (selective mutism), also seemingly heightens the risk of autism being subsequently diagnosed well beyond what would be expected. I don't doubt that there other examples of anxiety-related conditions also potentially increasing the likelihood of autism presenting clinically further strengthening the 'beyond just comorbidity' sentiments.

And set within this emerging research/clinical picture [2], we then go back to the idea that some autistic traits might be 'promoters' of something like anxiety in the context of autism, and back to the important question of what to do about them...


[1] Shephard E. et al. Early developmental pathways to childhood symptoms of attention-deficit hyperactivity disorder, anxiety and autism spectrum disorder. J Child Psychol Psychiatry. 2018 Jul 2.

[2] Spain D. et al. Social anxiety in autism spectrum disorder: A systematic review. Research in Autism Spectrum Disorders. 2018; 52: 51-68.


Monday 9 July 2018

On gender reassignment seeking behaviour and autism

The results published by Josephine Fielding & Christopher Bass [1] provide the blogging discussions today. Specifically the observations that: (i) there seems to be a growing demand for gender reassignment services here in Blighty (tied into the concept of gender dysphoria: "where a person experiences discomfort or distress because there's a mismatch between their biological sex and gender identity"), and (ii) there is a "high rate of psychiatric comorbidity" present in those attending gender reassignment services, including that: "Twelve patients (7.8%) had autism spectrum disorder."

OK, first I'll mention that whilst the authors use the term 'psychiatric comorbidity' with reference to conditions like depression and social phobia (social anxiety disorder) being present in their participant group, autism really shouldn't be included under such an umbrella term. Autism is a developmental label that, whilst seemingly carrying a heightened risk for various psychiatric disorders appearing alongside (see here for example), is not currently defined as a psychiatric disorder.

Next up: this is not the first time that the words 'autism' and 'gender dysphoria' have been linked together (see here and see here). Indeed it seems to be one of the 'hot topics' of recent peer-reviewed research times (see here). There's still some 'discussion' about whether a diagnosis of autism is important to gender dysphoria, or whether one or more of the over-represented comorbidities appearing alongside *might* play a more important role, but there is some interest in this area.

Fielding & Bass examined "the pattern of referrals and characteristics of people aged over 18 seeking gender reassignment in Oxfordshire over a 6-year period (2011-2016)" as a consequence of "an extraordinary increase in the number of referrals to both adult and child and adolescent gender clinics, with services becoming overwhelmed." The included details for over 150 attendees and noted both an increase in referrals (albeit not uniform) and also a gradual reduction in the mean age of attending participants. Then to the crux of today's post: "Of those who attended for assessment, 60 (39.2%) had a current psychiatric comorbidity, and 81 (52.9%) had a past history of mental illness." Depression was by far the most common psychiatric diagnosis (approaching 20%) but a diagnosis of autism was also mentioned in a significant minority.

What does this data mean apart from the obvious? Well, it's interesting that autism is specifically mentioned by the authors. Interesting because, yet again, a diagnosis of autism is a factor to potentially consider when it comes to gender dysphoria and onward possible gender reassignment seeking behaviour. Science doesn't yet know all it needs to know about why this *relationship* should exist outside of some speculation on how those on the autism spectrum may be less likely to conform to traditional notions of gender for example. I'm sure that there's some psychobabble explanation for this talking about autism and 'social norms' and the like but...

I note that Fielding & Bass also mention a role for social media in relation to their findings and how gender identity may be developing "possibly because of the increased availability of information about non-binary genders from social media, the internet and peers." Again, I don't know if those on the autism spectrum are more likely to be on social media than their peers or are perhaps more responsive to the idea of 'non-binary genders' as a result. But I daresay there are further investigations that could be done on this topic. Minus any sweeping generalisations and without trying to depict autistic people as universally being overly responsive to gender-related observations on social media and the like, one might also be inclined to look at how the notion of an 'autistic identity' perhaps overlaps with things like sexual identity too. It's something that I've noticed before under other circumstances (see here). I'm careful not to conflate sexual identity with gender identity, but it has always struck me that there are parallels between those who see autism as so much more than a diagnostic label and how autistic identity is seen as akin to sexual identity (i.e. inborn, immutable, 'part of who I am'). I'm no expert in this area but do see the need for further study in this area.


[1] Fielding J. & Bass C. Individuals seeking gender reassignment: marked increase in demand for services. BJPsych Bull. 2018 Jun 12:1-5.


Saturday 7 July 2018

"Cognitive behavioral therapy for children with autism spectrum disorder"

I'll admit that I was the one with the furrowed brow when the paper by René Kurz and colleagues [1] cropped up on my research radar. Detailing results from a "prospective observational study", authors set out to examine "the effectiveness of cognitive behavioral therapy (CBT) in children with autism spectrum disorder (ASD)." They concluded that: "CBT is an effective therapy for children with ASD." You'll note that I've underlined the word 'children' in those past sentences...

OK, CBT represents one of the talking therapies that seem so popular these days. The NHS Choices website describes it as being based on "the concept that your thoughts, feelings, physical sensations and actions are interconnected, and that negative thoughts and feelings can trap you in a vicious cycle." Kurz et al applied such principles to autism, and specifically what effect CBT had based on pre- and post-scores on the Aberrant Behavior Checklist (ABC) over 12 months. They observed significant changes to things like irritability, lethargy and hyperactivity, and called for further investigations.

Why my furrowed brow on this topic? Well, several reasons. Methodologically, the Kurz study was pretty weak. A participant group of 9 boys, including pre- and post observations over 12 months, no control group, no blinding, no comparison intervention... not exactly a stand-out study. It's not inconceivable that changes to behavioural presentation might have been due to lots of other reasons aside from the use of CBT (and that's before one considers how N=9 might impact on the statistical methods used by the authors).

Then there's the use of CBT. I know that CBT is finding some favour when it comes to 'managing' certain conditions/symptoms over-represented in relation to autism such as anxiety (see here for example). The purpose however of the Kurz study was slightly more specific: "To evaluate prospectively the effectiveness of cognitive behavioral therapy (CBT) in children with autism spectrum disorder (ASD)." It strikes me that in much the same way that CBT is being utilised in relation to another set of conditions (see here), the focus on the 'biopsychosocial' angle in the context of autism harks back to a shady past. And yet again, I'm going to emphasise the word 'children' in the Kurz study group.

I don't want to totally poo-poo things like talking therapy in the context of 'some' autism. I don't doubt that for some on the autism spectrum, there could be some merit in 'breaking down' thoughts and feelings in order to try and help resolve some more problematic features. I don't doubt that just being able to talk to someone about things like feelings and the like is probably going to be useful for some people including young children aged 6 or 7 years old.

But the idea that children (with a mean age of about 6 years old) are somehow going to be responsive to CBT in the context of their autism seems to be based on something a little more 'old-fashioned' in the authors' thinking. Y'know, going back to those days when sweeping (and illogical) psychological theories had a stranglehold on the way that autism was viewed. I'm also minded to mention that CBT and related therapies are not somehow 'side-effect' free, even if science needs to do more to report on possible adverse effects (see here).

The evidence for using something like CBT in the general context of autism is not great (see here). Part of this is because methodologically vigorous trials are still few and far between [2] and with regards to using children as participants, even more few and far between. I know psychology and psychological theory upon which CBT is based, still wants to play a part when it comes to autism - one need only look at the continuing fixation on Theory of Mind (ToM) to see that. But there must come a time when one steps back and asks whether a talking therapy will significantly impact on the core features of a developmentally-defined condition with strong evidence for an organic basis? Would we for example, ever entertain the use of CBT 'for' a condition like phenylketonuria (PKU) for example, where autism can and does occur alongside? No, we wouldn't.


[1] Kurz R. et al. Cognitive behavioral therapy for children with autism spectrum disorder: A prospective observational study. Eur J Paediatr Neurol. 2018 May 30. pii: S1090-3798(17)31856-1.

[2] Weston L. et al. Effectiveness of cognitive behavioural therapy with people who have autistic spectrum disorders: A systematic review and meta-analysis. Clin Psychol Rev. 2016 Nov;49:41-54.


Friday 6 July 2018

"weak evidence that EIBI may be an effective behavioral treatment for some children with ASD"

Today I bring to your attention the 'Cochrane does...' findings reported by Brian Reichow and colleagues [1] which concluded that: "There is weak evidence that EIBI [early intensive behavioral intervention] may be an effective behavioral treatment for some children with ASD [autism spectrum disorder]."

The Cochrane in the term 'Cochrane does...' refers to the Cochrane Database of Systematic Reviews, an important resource that provides systematic reviews on various aspects of healthcare that help inform practice and policy. I've talked about them a few times previously on this blog (see here and see here). EIBI - "a treatment based on the principles of applied behavior analysis" - is something that has been part and parcel of the autism research scene for many years. It aims to 'target' the early presentation of autism in both severity and "functional behaviors and skills" among other things; in the context to 'modify' the presentation of autism and "lessen the impact of symptoms on children's functioning."

The Reichow review found five studies that examined EIBI in the context of autism or autism spectrum disorder (ASD) and included over 200 children. They concluded that: (a) "No adverse effects were reported across studies" following the important tenet: first, do no harm, (b) there was "weak evidence that children receiving the EIBI treatment performed better than children in the comparison groups after about two years of treatment on scales of adaptive behavior, intelligence tests, expressive language (spoken language), and receptive language (the ability to understand what is said)", and (c) "Differences were not found for the severity of autism symptoms or a child's problem behavior."

Although the overall key message from authors was one that: "The evidence supports the use of EIBI for some children with ASD", the authors caution that the evidence base in this area remains weak. They mention that: "only a small number of children were involved in the studies, and only one study had an optimum design in which children were randomly assigned to treatment groups." There is a requirement for more [longitudinal] investigation following more 'rigourous' methodological designs.

I've always been in two minds about the usefulness of EIBI and autism, and indeed, early behavioural intervention in general. Yes, infants and young children are always going to be reactive to the behaviour of those around them, but the inference that the course of autism can be universally and significantly 'affected' by [various] structured programs of this type, has always been a challenge to me (see here). I've been particularly worried about headlines reporting that something like 'super-parenting' could potentially affect the presentation of autism (yes, someone did actually say that) and the connotations stemming from them. I also have concerns coming from a perspective that the behavioural presentation of autism probably comes about for various reasons in various people; some of them are likely linked to biology, as per the examples of various inborn errors of metabolism manifesting autism (see here) and autism presentation following viral or bacterial infection (see here and see here). In such cases, it strikes me that one perhaps needs to look at the biology first rather than the presented (secondary) symptoms in a sort of 'catch-up' manner. I know that last sentence is likely not to sit well with some people who follow the sweeping generalisation that autism is innate and immutable, but there are some good examples in the peer-reviewed research literature on well-controlled intervention studies of this type (see here and see here). And yes, there needs to be more longitudinal follow-up in these areas too...

I'm not totally poo-pooing the idea of EIBI in the context of autism, but rather, would wish to see greater long-term, controlled evidence before grand sweeping generalisations and big headlines are made. A better focus on 'sub-groups' might also be quite useful when it comes to possible best- and non-responders [2] to the various interventions put forward with autism in mind...

To close, a crow with a Yorkshire accent. This is what the internet was made for.


[1] Reichow B. et al. Early intensive behavioral intervention (EIBI) for young children with autism spectrum disorders (ASD). Cochrane Database Syst Rev. 2018 May 9;5:CD009260.

[2] Paynter J. et al. Differential outcome subgroups in children with autism spectrum disorder attending early intervention. J Intellect Disabil Res. 2018 May 23.


Thursday 5 July 2018

Baby teeth, metals and autism part 2

Consider this post on the findings reported by Paul Curtin and colleagues [1] which concluded that "altered zinc-copper rhythmicity precedes the emergence of ASD [autism spectrum disorder]" an extension of other previous discussions on this blog (see here). The research starting material was, once again, baby teeth, including teeth derived from an interesting initiative called "the Autism Tooth Fairy Project" based in Texas, USA.

On the last blogging occasion, the paper by Manish Arora and colleagues [2] was central to my discussions, and the use of some really interesting analytical technology to look at levels of various metals in tooth layers: Laser ablation-inductively coupled plasma mass spectrometry. Fast forward a year or so, and authors (including Arora) moved on to bigger and better things, this time focusing specifically on the metals zinc and copper "from the second trimester to approximately 1 year postnatally." Such a feat was achieved because baby teeth, much like the rings of a tree, provide a sort of 'album' of levels of such metals over a child's earliest years. Both these metals and their ratio also have some previous research 'form' when it comes to autism (see here).

"Our participants were recruited from four different studies being undertaken in three countries." Yep, so alongside teeth from the RATSS study initiative (aptly named the 'roots' of autism/ADHD study) forming a discovery dataset, authors also examined teeth gathered as part of other research initiatives including a favourite here in Blighty: the Avon Longitudinal Study of Parents and Children (ALSPAC). These non-RATSS teeth formed a replication set (to try and replicate the data found in the discovery set). Add in some nifty statistical analysis and set lasers to stun or should that be ablate...

Results: authors reported finding "strong evidence for abnormalities in zinc-copper cycles in ASD characterized by shorter duration, lower complexity, and less determinism." A quick translation: well, I'll be honest and tell you that I'm not exactly sure what that actually meant. I think it had something to do with the way the data were analysed, being "analogous to a spectrogram." Suffice to say that levels of copper and zinc were seemingly different in those diagnosed with autism compared with not-autism controls at different tooth time periods. When all this metal data was analysed using some statistics designed to try and 'classify' those with autism from those not-autistic, authors also noted zinc-copper cycles in teeth "allowed for a robust classification of ASD cases and controls." So: "Using optimal threshold criteria, this model was 90% accurate in predicting ASD cases, with 100% sensitivity for ASD diagnosis and 85% specificity to controls." Those stats aren't bad when one considers the importance of sensitivity and specificity to any classifying 'test'.

Although interesting, one has to bear in mind that this research was based on the use of baby teeth and their possible 'retrospective' association with autism. Nobody is advocating pulling out baby teeth as some sort of autism test! The focus on metals however, and specifically "measures of metal rhythmicity" provides some welcome information about how such 'rhythms' *might* show differences in relation to autism. This could reflect things like differing 'exposure' patterns or, more likely, some innate differences in the biological 'processing' of such metals. On that last point, this work potentially fits in with what is emerging in other independent data: metal (various metals) metabolism in the context of some autism seems to be 'unusual' (see here).


[1] Curtin P. et al. Dynamical features in fetal and postnatal zinc-copper metabolic cycles predict the emergence of autism spectrum disorder. Science Advances. 2018. 30 May.

[2] Arora M. et al. Fetal and postnatal metal dysregulation in autism. Nat Commun. 2017 Jun 1;8:15493.