Temporal armchair diagnosing taken to the max: 'How Do We Explain ‛Autistic Traits’ in European Upper Palaeolithic Art?'

Headlines aplenty...

I'm not a great fan of 'armchair diagnosing' also known as 'diagnosing at a distance'. It's speculative, often inaccurate and runs the real risk of ruining lives.

The remote diagnosing of psychiatric and behavioural disorders is a particular bugbear of mine. It's something that autism research and practice in particular has had to endure for quite a few years, as a volley of historical figures for example, were revealed to be supposedly autistic. Such musings also add a temporal aspect to proceedings.

The paper published by Penny Spikins and colleagues [1] takes such temporal armchair diagnosing to the absolute max, with their contribution to the "long standing debate about the existence of ‘autistic traits’ in European Upper Palaeolithic art." Some of the media that followed these findings really went to town, as per headlines such as 'Ice Age cave artists were AUTISTIC' (capital letters were already included in the headline, not added by me - see above) and 'Autism shaped the art of survival'. Wow. All of that information from a few paintings and carvings...

So how did the the authors and the lay media arrive at such a conclusion?

Well, first and foremost Spikins et al did not say that the makers of such early art were 'autistic'. They focused on autistic traits, and in particular the idea of an "extreme local processing bias" or attention to detail trait that seems to accompany the diagnosis of autism (for some). Importantly, they note that: "Local processing bias is common in autism but also seen in individuals without autism" and "‘Autistic traits’ in Upper Palaeolithic art do not necessarily signify the work of an individual with autism." So, from the outset, we can probably do away with that rather sweeping [diagnostic evidence-free] media headline on Ice Age cave artists being autistic.

Quite a lot of the Spikins paper focuses on what's been observed - directly observed - in some of those diagnosed as being on the autism spectrum when it comes to artistic talent, which is then 'extrapolated' to such prehistoric artists. This includes some rather nice pictures drawn by individuals with autism who expressed a "marked local processing bias" compared with age-matched drawings from non-autistic individuals. We're also told that the use of the (very) famous 'are you autistic?' self-report screener that is the Autism Spectrum Quotient (AQ) by the authors, revealed that "individuals with a very high autism quotient (AQ) of 32 or above, which is taken as indicative of an autism spectrum condition within a population sample were statistically much more likely than neurotypical individuals (i.e. those with a lower AQ score) to have an interest in and experience of art outside of any school curriculum." 'Indicative of an autism spectrum condition'? Well, we'll see. And I still have some problems with what comes under the term 'neurotypical' too (see here).

Of course you can perhaps see the issue here. Take one block of 'evidence', some of it based on individual case reports and some of it based on an 'autism' screener that probably picks up an awful lot more than 'just autism' (see here and see here and see here for examples), correlate and correlate some more and hey presto, we reach the conclusion that the art must have been drawn by someone expressing an autistic trait or even someone who was autistic.

A testable hypothesis? No, it's not. We don't know who drew those paintings or made those carvings. We don't know anything about them personally and we certainly don't have any evidence about whether they expressed any significant autistic or any other kind of trait. For all we know, the paintings or carvings could also have been made by more than one person; a family or group effort if you like. We just don't know because, well, those artistic depictions were made thousands and thousands of years ago before the tools that help us record history were even a twinkle in the cosmic eye.

I don't want to come across as poo-pooing such 'observations' stressing how autistic traits are not necessarily a new thing because, in essence, I do think that some autistic traits have probably been with us from our earliest evolutionary times (see here). I say that on the basis that the traits of autism are not some 'magical' behaviours that are completely distant from the human experience; more likely they represent the extremes of what is typically seen in the general population at particular ages and stages and environments. Taking such logic back in an evolutionary sense, one can for example see how something like an 'attention to detail' could be a good survival skill if your life depended on it.

But I do think one has to be very, very cautious about such research and any 'feelgood' factor it might attempt to generate or put forward. Autism, as a clinical definition, only really came about in the last hundred years or so, and for many, any benefits derived from a 'marked local processing bias' have to be balanced with the possible downsides to such directed focus (e.g. increased rumination and anxiety). I'd also add in that the idea that Palaeolithic Art (or indeed, any kind of art) merely comes about as a result of traits that are noted in the context of psychopathology is a pretty dangerous path to take. It risks boiling down human efforts such as creativity and artistic skill to nothing more than diagnostic characteristics and feeds into narratives such as the "creativity is akin to insanity" headlines of not so long ago (see here). As I've said before, people are so much more than the labels they've received or the diagnostic term they identify with.

In short, Palaeolithic art is interesting and adds to our understanding of how we evolved. But it simply cannot provide an accurate window on any states and traits of those who created it...

To close, there's a wedding on today apparently. Best wishes to the happy couple. And not to make light of our Royal Family, but The Windsors TV show is absolute comedy gold (particularly Harry Enfield)...

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[1] Spikins P. et al. How Do We Explain ‛Autistic Traits’ in European Upper Palaeolithic Art? Open Archaeology. 2018; 4: 262-279.

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The continuing trials and tribulations of PACE

I honestly hadn't intended talking about the PACE trial - "pacing, graded activity, and cognitive behaviour therapy: a randomised evaluation" in relation to chronic fatigue syndrome (CFS) - quite so much on this blog. Others have done it so much better than I ever could.

My interest however keeps being piqued in relation to the results originally produced suggesting that: "CBT [cognitive behaviour therapy] and GET [graded exercise therapy] can safely be added to SMC to moderately improve outcomes for chronic fatigue syndrome" and the subsequent myriad of voices quite unanimously suggesting that one perhaps needs to be a little careful with such sweeping generalisations (see here).

OK, for anyone new to this topic, below are a few of the previous occasions that it has been discussed on this blog in chronological order:

• Chronic Fatigue Syndrome and various factors (2014) (see here)
• Chronic fatigue syndrome and the detrimental application of the 'biopsychosocial model' (2016) (see here)
• PACE-gate! (2016) (see here)
• PACE trial recovery data and chronic fatigue syndrome (2017) (see here)
• PACE trial recovery data and chronic fatigue syndrome - a reply (2017) (see here)

I want to add a few more 'science references' to this issue because some important things are being discussed in the peer-reviewed domain, in the context that CBT and GET at the moment, are considered 'best practice' here in the UK and beyond when it comes to CFS. That may change in future times (see here) as it has in other parts of the world (see here) but that's where we are at the time of writing. I might add that the addition of new references to this post is a rather more descriptive thing minus too much additional commentary from me, and that the views represented are those of the authors. I wrote this post on 9 April 2017 so it is accurate up to that point.

OK, starting with the editorial from Keith Geraghty [1] mentioned in that PACE-gate! post, we have an authors reply to some of the points raised [2]. The main crux of the reply is to correct "misunderstandings and misrepresentations of the PACE trial." Next up was a paper by Leonard Jason [3] (someone with quite an impressive research track record when it comes to CFS) and some comments on the pacing intervention (adaptive pacing therapy, APT) used and "patient selection ambiguity." This is a particularly interesting paper because APT - "based on the envelope theory of chronic fatigue syndrome" where the symptoms of CFS are "not reversible by changes in behaviour" - did not hit the 'research spot' according to the original PACE trial results.

I want to next include the paper by Luis Nacul and colleagues [4] into proceedings, and a role for "selection bias and disease misclassification" when it comes to studies on CFS (and myalgic encephalomyelitis, ME). To quote from them: "When studies using the broad Oxford criteria... were excluded, a virtual disappearance of effect for graded exercise therapy (GET), cognitive behaviour therapy (CBT) and other psychological therapies recommended by the NICE guidelines (National Institute for Health and Care Excellence.. was revealed." Guess which criteria (among the many available) were used in the original trial?

Onward. The paper by Steven Lubet [5] titled: 'Investigator bias and the PACE trial' sets out quite an 'accusation' in that: "the PACE investigators “impartiality might reasonably be questioned”." This is a theme that crops up again shortly. The paper by Tom Kindlon [6] asked whether graded exercise in particular, could be thought of as 'safe and risk-free'? I set this question within the context that the original PACE trial did find that: "Non-serious adverse events were common" and GET did seem to produce the largest number of 'serious adverse effects' in number if not in participants.

Nearly there. Next up is the paper from Carolyn Wishire [7] who, when talking about "lively discussion", reports on various potential forms of bias in behavioural intervention studies using the PACE study as a kind of template. This author was the lead on the recent peer-reviewed commentary (open-access) re-analysing the 'recovery' data subsequently published in relation to the PACE trial. Then, we have the paper by Jonathan Edwards [8] who notes that the PACE trial represents a lesson in how research design needs to develop further when it comes to science in general. To quote: "The failure of the academic community to recognise the weakness of trials of this type suggests that a major overhaul of quality control is needed." And finally Charles Shepherd [9] provides further commentary on the PACE trial and a call for independent review.

And rest.

There is quite a lot to take in from those various publications and I don't doubt that this is not the last we are going to hear about the PACE trial. Allied to articles such as this one describing how: "Physicians used to dismiss the disease as psychosomatic" (past tense) it certainly would not out of place to suggest that there are still questions that need to be answered about the design and results obtained from the PACE trial and their applicability to the (very) wide CFS/ME population. To quote again from the paper by Edwards [8]: "If they are still ill [those diagnosed with CFS/ME], presumably these approaches have failed and the priority is to find something more effective." Wise words indeed.

To close, it's here... the first glimpse of The Last Jedi.

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[1] Geraghty KJ. ‘PACE-Gate’: When clinical trial evidence meets open data access. J Health Psychology. 2016. Nov 1.

[2] White PD. et al. Response to the editorial by Dr Geraghty. J Health Psychology. 2017. Jan 24.

[3] Jason LA. The PACE trial missteps on pacing and patient selection. J Health Psychology. 2017. Feb 1.

[4] Nacul L. et al. How have selection bias and disease misclassification undermined the validity of myalgic encephalomyelitis/chronic fatigue syndrome studies? J Health Psychology. 2017. March 1.

[5] Lubet S. Investigator bias and the PACE trial. J Health Psychology. 2017. March 7.

[6] Kindlon T. Do graded activity therapies cause harm in chronic fatigue syndrome? J Health Psychology. 2017. March 20.

[7] Wilshire C. The problem of bias in behavioural intervention studies: Lessons from the PACE trial 2017. J Health Psychology. March 23.

[8] Edwards J. PACE team response shows a disregard for the principles of science. 2017. J Health Psychology. March 28.

[9] Shepherd CB. PACE trial claims for recovery in myalgic encephalomyelitis/chronic fatigue syndrome – true or false? It’s time for an independent review of the methodology and results. J Health Psychology. April 9.

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Edwards, J. (2017). PACE team response shows a disregard for the principles of science Journal of Health Psychology DOI: 10.1177/1359105317700886





White, P., Chalder, T., Sharpe, M., Angus, B., Baber, H., Bavinton, J., Burgess, M., Clark, L., Cox, D., DeCesare, J., Goldsmith, K., Johnson, A., McCrone, P., Murphy, G., Murphy, M., O’Dowd, H., Potts, L., Walwyn, R., & Wilks, D. (2017). Response to the editorial by Dr Geraghty Journal of Health Psychology DOI: 10.1177/1359105316688953

The best books... are those that tell you what you know already

The title for this post comes from a quote in George Orwell's Nineteen Eighty-Four. I'm using it to plug the fact that as from today - Monday 28th April 2014 - my book is out.

'Autism: Exploring the Benefits of a Gluten- and Casein-Free Diet. A practical guide for families and professionals' is available from the publishers site (Routledge) and lots of other real and virtual bookstores. I'm pretty sure that the book title is self-explanatory but just in case you need more information about it, here is the accompanying blurb on what we've tried to do:

"Once considered a rare condition, increasing numbers of children are being diagnosed as being on the autism spectrum, making it one of the most common and often challenging childhood developmental diagnoses. Whilst experts around the globe strive to unravel and truly understand how autism develops and presents itself, comparatively little is still known about the condition despite decades of research and investigation.

What is becoming clear is that autism is an extremely diverse condition with a presentation often complicated by a heightened risk of various accompanying behaviours and conditions outside of autism, variably affecting quality of life and future outcomes. Based on years of experimental study and thousands of personal observations, a growing body of research suggests that some challenging characteristics present in autism may be positively affected by the introduction of a gluten- and casein-free (GFCF) diet.

Autism: Exploring the Benefits of a Gluten- and Casein-Free Diet offers parents, teachers, and other education or health professionals with an easy-to-read alternative to sifting through the combined science. Written by leading experts in autism research, food, nutrition and dietetics, the book cuts through the jargon to offer readers a no-nonsense, accessible and authoritative overview of how diet might affect some characteristics of autism, and provides a range of useful recipes and handy hints for making mealtimes fun for children with autism and related conditions who are embarking on such a dietary change".

OK, so 'leading expert' might be a bit OTT for my part. Still, my co-authors and I have tried to provide a balanced overview of what the GFCF diet is and importantly what it isn't and where we're up to research-wise. GFCF recipes y'say? Yes, we've also put a few of them in the book too. Enjoy!

A wish-list for gluten and casein free diet autism research

I think that this is possibly the first time that I've actually talked about one of my own research papers as being central to a post on this blog. I'm not altogether sure of the wisdom and etiquette of how and indeed whether to do this - see this commentary bearing in mind I'm blogging post peer review publication - so fingers crossed that this works...

Hopefully not... @ Paul Whiteley  

It's actually been a year or two since I've been part of a peer-reviewed publication, mostly due to investigations being in progress and also having some other things running in the background.

This trend should hopefully be reversed over the coming months/year with other, more original research, almost ready for peer-review submission.

I don't want to make too much of a meal of our latest paper* (open-access) discussing use of a gluten- and casein-free (GFCF) diet with autism in mind because it is a review paper rather than introducing any novel, earth-shattering results or insights. That and the fact that the paper is free for all to view, applaud or criticise as they see fit.

The basic message that we wanted to put across in the paper is that despite some rumblings to the contrary, research on the potential effectiveness of such dietary intervention for some cases of autism has and continues to be undertaken, some of it even under randomised, controlled conditions albeit with some methodological gaps.

Assuming also that you see autism as being more of 'the autisms', said research with all its frailties and methodological incompleteness, suggests that at least for some people on the autism spectrum, there may be some merit in looking at the possibility of a dietary effect, even if not working on core symptoms and even if due to some other underlying comorbidity. Gut-brain axis anyone?

Interestingly, it was one of the reviewers for our paper who suggested that we might also want to put together a kind of wish-list of what we think should be included in further autism-diet research with the focus on determining potential best- and non-responders. A few factors came up based to quite a large extent on some of my previous mutterings on this blog including:

• Some investigation on the possible presence of known gastrointestinal (GI) conditions related to gluten and or casein such as coeliac (celiac) disease and its markers, its not-quite-coeliac-disease relations and lactose intolerance.
• Measurement of gut permeability and that favourite term, leaky gut, now also potentially featuring in mouse models of autism.
• Looking at any potential influence of those trillions of gut-dwelling bacteria who call us home.
• Examination of food-related enzymes including those used for chopping up peptides and more generally those involved in carbohydrate metabolism.
• Screening for potential inflammatory comorbidity, be it signs of central inflammation or more specific GI inflammation including everyone's favourite molecule of the hour, (General) zonulin.

Finally, another of the important messages that we wanted to present in the paper is that more emphasis is needed to examine the clinical outcomes when implementing things like dietary intervention for people with autism. It's all well and good reporting statistical results and p-values, but when it comes to something as invasive and life-changing as altering someone's diet, we should really be evaluating how that change impacts on their life and whether it makes a significant difference to their day-to-day quality of life or not. Something along the lines of what was looked at in the paper by Sarris and colleagues** (open-access) albeit in an area outside of autism research. Perhaps even a lesson for other interventions potentially indicated for autism there too...?

To close, since we're on the topic of 'me', how about a little Me First & the Gimme Gimmes? A choice of artist cover song for you: Carly Simon or Elton John?

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* Whiteley P. et al. Gluten- and casein-free dietary intervention for autism spectrum conditions. Front Hum Neurosci. 2013; 6: 344.

** Sarris J. et al. Participant experiences from chronic administration of a multivitamin versus placebo on subjective health and wellbeing: a double-blind qualitative analysis of a randomised controlled trial. Nutrition Journal. 2012; 11: 110.

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Paul Whiteley, Paul Shattock, Ann-Mari Knivsberg, Anders Seim, Karl L. Reichelt, Lynda Todd, Kevin Carr, & Malcolm Hooper (2013). Gluten- and casein-free dietary intervention for autism spectrum conditions Frontiers in Human Neuroscience, 6

Parent power: autism and carnitine

For many years, science and the conducting of science, was seen as quite an exclusive club. Men and women in white laboratory coats holding up test tubes containing brightly coloured liquids to the light and inquiringly looking at each other as if to say 'yes, it's turned red/yellow/green' denoting some major experimental breakthrough. It always reminds me of comic Michael McIntyre and his 'wine at the restaurant' routine - 'yes, it's wine' (apologies for the mild swearing in the link). Nowadays with the onset of wider educational provision and a greater exposure to science via things like the web, the exclusivity of the science club has perhaps been reduced and science is gradually becoming a concept and field for all (as it should be).

I say all this because a few weeks back, the topic of parents of children with autism becoming involved in formally conducting scientific research on autism was raised on a external post I had some discussion about. Acknowledging that parents are perhaps the best scientists when it comes to their own children (observation, measuring, recording, the n=1, etc) the point being made was that quite a few areas of research in autism have, for one reasons or another, been driven forward by parents as a result of their combined professional qualifications and personal interest in autism. The example in that post was Lorna Wing and her pretty exceptional career in autism research perhaps partially as a result of her daughter.

There are quite a few other examples of parent power - too numerous for me to list here. My route into, and continued interest in autism research, was via another parent and retired Pharmacist, Paul Shattock OBE, and his desire to experimentally look at dietary intervention for some cases of autism (he is the Shattock P name that appears on nearly every paper I have been involved with). Another parent who has stepped up to the research mark is Prof. Jim Adams from Arizona State University and his impressive array of papers published on autism this year (2011). Jim is Presidents Professor of Engineering and Material Sciences but perhaps more relevant to this post, is a scientist with a daughter with autism.

Without turning into the Jim Adams appreciation society, his 2011 papers can be viewed here, here, here, here and here. I have already posted an entry about one of his papers on gastrointestinal bacteria and autism which made some interesting observations albeit with a few gaps. In this post, I want to discuss a recent paper by Jim and colleagues on a possible role for L-carnitine for autism (a copy of the full-text should be available here).

I first perhaps need to make a distinction between carnitine and a similar sounding compound, carnosine (the 'L-' bit takes us into the area of chirality which, although making me shudder, I am sure your friendly neighbourhood chemistry tutor can help explain). Carnitine is found in quite a few foodstuffs and can be biosynthesized, and is involved in energy production. Carnosine, a dipeptide of the amino acids beta-alanine and histidine, has a few potential effects, not least as an antioxidant.

Both compounds have shown up on the autism research radar. L-carnosine did pretty well in this small double-blind, placebo-controlled trial a few years back for example. Carnitine has however had the lion's share (get it, carnitine = Latin for 'flesh') in terms of research coverage starting at a link with mitochondrial problems and working onwards ever since. Indeed the study highlighted by Pauline Filipek and colleagues on carnitine deficiency in autism represents one of the very earliest studies suggestive of possible mitochondrial involvement in some cases of autism before the more recent interest.

Back to the Adams paper. I am not going to beat around the bush on this. I know some people might raise an eyebrow reading this paper when they see some of the authorship list and some quite high-profile recent media coverage. I'm not going to point to which authors and am not making any reference to, or judgement about this, because as far as this post (and blog) goes, it is all about the science (the journal Editors and peer-reviewers I assume have done their job for it to get through to publication and that's good enough for me). The basics then: a double-blind, placebo-controlled trial of 34 participants with ASD, aged between 3-10 years, mean ~ 6 years (notice the group were largely pre-pubescent) looking at the effects of L-carnitine vs. placebo over 3 months. Outcome measures were CARS, ATEC, and hand muscle testing among other things. A nice touch was that treatment adherence and side-effects data were also collected by parents of participants over the course of the trial. Various other lab exams were undertaken at baseline and study end (3 months).

The results. There were a few improvements noted on the various schedules included. Total CARS scores reduced, indicative of a group reduction of autistic symptoms (p=0.02). The ATEC domain of sensory/cognitive awareness also showed a significant group reduction (p=0.009). From the various lab exams, only levels of serum total and free carnitine were significantly different between the groups (as you would probably imagine given your experimental arm). Importantly also, adherence and side-effects were not significantly different between the groups, with only 'minor' side-effects reported. Additional correlations are reported between the various study instruments and outcomes but the correlation coefficients (r-squared values) were nothing too spectacular bearing in mind the small participant group numbers.

What can we surmise from all this? Well, L-carnitine was generally speaking well tolerated (first do no harm). More than that, it didn't seem to have any specific effects on the various blood chemistry examined during the study which is perhaps a good thing. Even more than that, it was associated with some clinical benefits, at least over the course of the 3-month study period. The authors list a number of strengths and limitations; strengths not least that this was a 'gold-standard' trial with that all important placebo arm (perhaps only lacking a cross-over period if I was to be a nit-picker). It was a small participant group but I don't tend to hold this against studies; one could argue that this is still a pilot study, being only the second study on this topic for autism that I have found. Generally speaking, finding a significant group effect is the first order of the day, followed by subsequent studies to look for those all-important best and non-responders.

What does it all mean? Good question and I wish I had a good answer for you. Carnitine is involved in fatty acid metabolism and ATP production. It enables fatty acid transport from the cytosol to the mitochondria, having a sort of backstage pass through the inner mitochondrial membrane. There is a suggestion (and it is indeed only a suggestion) that problems with either having enough available carnitine or with one or more of the carnitine acyltransferase enzymes might be linked to autism. The fact that there is a dearth of research in this area sadly means that I can offer no more information than this.

To end, I link to a video which gives us a real insight into the science of today.

Adaptive..yawn..trial design

My name is Paul and I am interested in clinical trial design.
OK, it is hardly the chat-up line of the year. I also don't think I am going to win any awards for most interesting hobby; certainly not combined with my other interest in all things related to gut bacteria and gut hyperpermeability. I do, however, stand by my curious amateur/semi-professional interest in how clinical trials are designed and run and how such design can impact on the results obtained.
My interest was piqued recently by this communication from the National Institutes of Health (NIH) and their proposal to use adaptive trial design in HIV research.
There is a good description of what an adaptive trial could contain here in the curiously titled Orphanet Journal of Rare Diseases. The article by Chow and Chang is a keeper for me because they go through, in quite some detail, the various manifestations of adaptive design as well as providing a point-by-point checklist of things to watch out for when using such a trial design.
The basic premise of an adaptive design is that during a clinical trial, adjustments are made according to the data that is produced. So for example suppose you want to look at a specific intervention - dietary change for example. You have your randomly assigned groups (dietary change vs. diet as usual) and commence with the study. Suppose you set specific 'goals' for your dietary change group reflective of some change you are expecting, which at some point, you need to measure. You bring in an independent person to break the allocation codes and look at the data produced at that point. If you have reached / exceeded those goals, you then alter the trial to bring the diet as usual group onto the dietary change and continue with both groups in the experimental group. Its called a 'drop-the-loser' design and just happens to be the same design that we used on our ScanBrit trial.
This is just one example of an adaptive trial design. There are lots of other combinations. One of the main strengths of such a design is that it is flexible and responsive to what happens during your trial, particularly for very early clinical trials where a new drug, diet, instrument, etc is under preliminary evaluation.
Kudos to the NIH for bringing adaptive design centre stage.

Measuring evidence in autism

A few weeks back I had the pleasure of an email conversation with Dr Gary Mesibov on the topic of one of his recent papers titled: 'Evidence-based practices and autism'. Some with an interest in autism will know Dr Mesibov is the current Director of Division TEACCH at the University of North Carolina at Chapel Hill.
Although brief, my main reason for contacting Dr Mesibov was related to his views on the use of evidence-based practices guiding good autism practice. Readers may know that this is a topic particularly relevant to the UK following the announcement that NICE are formulating guidelines on best autism practice for children/young people and adults.

Dr Mesibov's recent paper on evidence-based practice (EBD) is an intriguing look at the history, formulation and current guidance on EBD in Psychology and Education fields and how it may/may not relate to autism spectrum conditions. Some of the EBD guidance included in Dr Mesibov's paper, from the very mysteriously titled 'Division 12' group (an off-shoot of the American Psychological Association), can be found here (see Tables 1 and 2).

Without wishing to plagiarise Dr Mesibov's work, the main elements of his writings, as I interpret them (which may be a bias in itself), are: (a) much of the guidance on EBD whilst interesting, has not been applied specifically to autism; (b) that which has been applied, suggests that very few, if any, interventions for autism make the grade - see the recent post on evidence lacking for autism interventions; (c) one of the main reasons why autism research does so badly is because of the difficulties in ascertaining long-term positive outcome following intervention; (d) the large heterogeneity in autism does little to improve the situation; (e) the use of the randomised-controlled trial (RCT) methodology, whilst useful for looking at the manipulation of one variable, loses some of its 'applicability' when applied to more comprehensive intervention programmes that contain multiple components, as many of the educational and behavioural interventions for autism might.

I might add that his overall conclusions are not 'anti-EBD'; indeed quite the contrary. He does however suggest a slightly modified EBD regime which covers many of the points raised above.

To many people, I am sure that some of the points Dr Mesibov raises would be considered heresy. The RCT is after all at the top of the evidence tree (if I was to be a nit-picker though, I might argue that it is topped by the meta-analysis or even the meta-analysis of a meta-analysis). But think about it: suppose you want to examine an educational intervention which might have 6 or 7 important parts to it which may need to be delivered slightly differently according to the person they are being targeted at. How do you formulate a good RCT around that? I might also add that others in autism research have also questioned the usefulness of the RCT (this time applied to ABA).

Don't get me wrong. I am a big fan of the RCT; particularly when you have one intervention/drug/analyte and are comparing them between homogeneous groups. Want to look at the effects of an antibiotic on a particular strain of bacteria? The RCT is your man or woman.

The question is whether RCT applied to a heterogeneous, behaviourally-defined condition looking at multi-component educational or behavioural intervention is necessarily the best course of action? I think the US Agency for Healthcare Research and Quality has already made its mind up (see page 11) although nice to see that the art of medicine might also come into intervention decisions as per my previous post.

On the Hippocratic Oath

I have more than a passing interest in all things Greek - particularly the language, which I have been learning for the past 10 years or so, and the history. When I say history, I am not talking so much about recent history, more the Classical period; the time when Greece was truly the cradle of modern European Civilisation.

One figure in particular is of interest: Hippocrates of Kos. Hippocrates (pronounced Hipp-o-kra-tees not hippo-crates - a la Bill and Ted and their colourful use of 'So-crates'!) was a physician, or at least the Classical equivalent to a physician, often referred to as the Father of Modern Medicine.

What did he do? Well he is credited with bringing medicine out of the realm of superstition and into a more real-world way of thinking with such notions as disease being caused by natural phenomena. One might say he is one of the first people to bring evidence-based practice to the forefront. There are quite a lot of other things he did and, assuming you have the time, I could recommend finding out more about his, and his students, teachings.

One of the more notable achievements of Hippocrates (or at least ascribed to Hippocrates and his followers) was the introduction of a code to which physicians subscribe to as part of their license to practice Medicine. The Hippocratic Oath forms the fundamental moral and ethical guidelines for practicing Medicine. For those lucky enough to be able to read Ancient and/or Modern Greek, excerpts of the original texts can be found here.

Whilst not a medical Physician myself, I have taken a little time to study what the Oath says and potentially implies. Herein I share some interesting parts of said Oath.

Depending on which version is used, there are some interesting points to be made.

First, the language used. Throughout all versions of the Oath there is use of the word 'art'. The various versions posted on Wikipedia (original, classic and modern) all contain 'art' and implicitly imply that medicine, whilst being science is also part art. I have to say that against all my scientific training and background, I do kinda like this. I like it because it suggests that science can take Medicine so far, but art perhaps takes it that little bit further. Importantly, it puts physicians in the driving seat when it comes to the care they provide for individuals perhaps differing from person to person. This article says pretty much the same. Remember also my post on autism and n=1?

Second, the Oath acknowledges that physicians, whilst respected for their science and their art, are not infallible. To quote from the modern text: "I will not be ashamed to say that I know not..". I think it is a mark of great strength when someone can admit that they don't know something and ask advice from those who might. This part of the Oath directs physicians to do just that.

Third, the Oath talks about treating 'people' not diseases or conditions. In these modern times, where finances for healthcare are being squeezed and contact time with patients is an issue to meet targets (certainly here in the UK), it is perhaps important to step back and understand that the patient is key, not the condition, disease, injury or state. The implication for autism for example is that 'underneath' the presentation of symptoms is a person (and their family, as also discussed in the Oath) and that the duty of care is to that person, whatever care they may or may not require either as a result of their autism or resultant from any associated co-morbidity.

Finally, the modern Oath quotes: "Above all, I must not play at God". Medicine has seen a few examples of physicians trying to play God. Here in the UK we had Dr Harold Shipman not so long ago; lest we forget his victims that ran into the hundreds in numbers. Away from just mortality (which this sentence of the Oath is specifically focused on) the message here is that physicians have an extremely important responsibility over their patients and their care; a responsibility that resonates throughout the medical and peripheral professions.
Some final words from a protagonist in our friendly neighbour-hood Spiderman movie (or was it Chris Eubank): "With great power comes great responsibility".

Autism and n=1

The post carries a warning that it is best to read whilst sitting comfortably with a glass of wine and an open mind. Sitting comfortably? Feet up? Then I shall begin.

Without wishing to sound condescending to the non-scientist, a bit of explanation is required about this entry (to the scientists also, apologies in advance for any over-simplification). One of the ways that the letter n is used in science and mathematics is to denote the number of people (subjects, participants, etc) taking part in a particular experiment or study (or arm of a study). I use 'people' as an example, but n can also denote other things (living, dead or inanimate) under investigation.

The use of n in this 'science-y' way stems from the premise that greater evidence of any effect (or non-effect) from a particular 'thing' (drug, intervention, pollutant, etc) is garnered by increasing the number of n's in order to make a finding more generalisable to a larger population from that being studied - in effect increasing the chances that 'chance' alone does not account for a particular finding or connection based on a large sample size.

Still with me? OK. Now as large an n as is possible drawn from a particular population (sample) without actually looking individually at an entire population (which would be impractical) is one of the things that science strives towards in order to show the probability of an effect or non-effect.

This notion however makes some important assumptions; primarily that all your grouped n's are the same or roughly the same, and that the specific 'thing' you are testing in respect of your sample/s represents the only thing you are testing and hence is not affected by other 'things' which could bias your result.

A textbook example is that of the effect of a particular antibiotic on a bacterial organism or strain. Antibiotic A is proposed to affect organism B; add antibiotic A to organism B sitting in a petri dish (which will have an n of many thousands or millions); compare the same antibiotic with organism C sitting in another petri dish (which should show little or no effect) and watch how many organisms B and C die as a result of A in their respective petri dish. If antibiotic A kills many thousands of n's of organism B but only a few of organism C, you could suggest that A probably is quite an effective antibiotic against B but not C. Your logic is therefore based on and confirmed by a large n.

Works well in this example doesn't it? Well, that is until you start applying the same 'petri' dish logic to humans not bacteria or more precisely when applying it to certain human characteristics which might not be as measurable as the binary 'life or death' response of a bacterial organism.

Don't get me wrong. I am not saying that applying n in this fashion is completely useless; far from it. What it does however confirm is that our use of science as a measure of 'absolute' particularly when applied to human beings, is flawed; whereas using science to ascertain 'probability' is closer to what is probably(!) produced.

So where does autism come into this? Well we know that autism is an extremely heterogeneous condition; the presentation varies from person to person and is affected by lots of different things such as genetic make-up, age and maturation, other co-morbidities and the environment. Whenever a particular hypothesis is tested with regards to autism, say that intervention A might help ameliorate behaviour B or if factor C makes behaviour D more likely, we generally employ the rule of larger n (in amongst lots of other methodological rules and methods) to see if there is any effect, bearing in mind the end-point of generalising a finding to a population.

The fundamental flaw in this design is, going back to the title of this post, n=1. That is: how do we know that we have a homogeneous group in amongst a heterogeneous condition? Answer: we don't. Autism like many other 'behaviourally-led' conditions in its strictest definition has to fall into a n=1 category, i.e. each person is 'different' and unique.

Yes, we try and control for different things during our various studies. We try and make sure that ages are similar in our large n, we try and match our n's for things like gender, intellectual level, co-morbidity; we even try and look at n's who present 'similarly' in terms of core autism symptoms. Ultimately however we can never make all our n's the same; hence bias is introduced.

The moral of this story is this: studies showing A related to B often using large n's in autism are not showing anything approaching an absolute as a result of the 'n=1' argument. They show that many different n=1's when grouped together provide a signpost to the probability of an effect or non-effect. Within this group of n=1's are participants who, because of their various differences, may show a large effect to a particular thing being tested, whereas other n=1's might show no effect at all. The implication for autism research is to start looking at the characteristics of those 'responders' and 'non-responders' rather than giving blanket 'yes' or 'no' answers and importantly, to communicate this effectively (see my previous post on evidence-based medicine).

So the next time you hear someone say 'oh that does not work' or 'oh that is not linked' with regards to autism, remember the n=1.