On postpartum paracetamol metabolites and risk of offspring ADHD: details matter

The findings reported by Yuelong Ji and colleagues [1] provide the blogging fodder today, as once again the topic of acetaminophen (a.k.a paracetamol) use during pregnancy and offspring risk of attention deficit hyperactivity disorder (ADHD) is in the spotlight. I say 'once again' because this topic has cropped up time and time again on this blog (see here for example).

On this research occasion, the starting point was the Boston Birth Cohort (a cohort that has been mentioned before) and specifically, an analysis of "maternal plasma acetaminophen metabolites levels measured within a few days after delivery and ADHD diagnosis in the offspring" as a measure of paracetamol exposure. The metabolites in question were "unchanged acetaminophen, acetaminophen glucuronide, and 3-(N-Acetyl-l-cystein-S-yl) acetaminophen." All were measured in blood plasma using one of the gold-standard chemical analytical techniques: mass spectrometry. A diagnosis of ADHD was extracted from medical records on the basis of ICD-9 and/or ICD-10 definitions.

Results: taking into account other potential confounding variables, authors reported finding "a significant positive association between maternal blood acetaminophen metabolite levels measured within 1–3 days postpartum and ADHD diagnosis in offspring." It's perhaps however important to understand how such a finding was arrived at, bearing in mind that ADHD was not the only diagnostic fruit examined in the Ji study. So: "The main exposures analyzed in this study were maternal acetaminophen metabolite levels, which were inverse normal transformed to approximate the normal distribution." What this means is that rather than reporting the specific levels of each paracetamol metabolites across different diagnoses and a 'neurotypical group' ("Children without any diagnosis of ASD [autism spectrum disorder], ADHD, developmental delays, or intellectual disabilities were classified as neurotypical (NT)"), authors chose to covert the raw values into groupings. Groupings were based around "no detection, below median, above median of detected values." I'm not altogether sure that this is the best way to report results; certainly I would have liked to have seen the raw values for each metabolite according to group as a comparator; but that's just my research preference. Researchers mention that they did not see any association between paracetamol metabolites and any other diagnostic label, and also stressed how the association remained when other potentially confounding variables were taken into account. And when it comes to ADHD, there are a few (see here for example).

How much weight can we give these results? Well, this is probably the first time that someone has looked at actual paracetamol metabolites in mums rather than just relying on maternal or doctor records of paracetamol usage during pregnancy, and that's a good thing. Authors also mention that their study was "further strengthened by the diagnosis of ADHD by both general pediatricians and developmental specialists." Add in the prospective design of the study, and you have some potentially important evidence for a *relationship* between paracetamol use and subsequent offspring development.

But... "this study only included a one-time measurement of maternal acetaminophen metabolite levels within 1–3 days postpartum." The authors rightly acknowledge that paracetamol is pretty quickly metabolised in the body so, at best, their study really only looked at recent paracetamol use immediately during or after birth. Maybe further study of archived samples during pregnancy (at multiple points during pregnancy) would provide some further information? And comments from the authors like "women with detectable levels of acetaminophen biomarkers are likely to be more regular users" really don't have any place in a scientific paper without supporting evidence. Particularly when pain relief is going to be pretty important when it comes to the process of childbirth.

Also: "our metabolite measurement method did not include acetaminophen sulfate, which accounts for 30–44% of the total metabolites of acetaminophen under the normal dosage." I don't want to go into the nitty-gritty of paracetamol metabolism, but just going back to the research looking at sulphation (sulfation) in the context of autism (see here), it would have been useful to examine both paracetamol sulphate and paracetamol glucuronide at the same time. Certainly it would have provided a more complete picture of typical paracetamol metabolism.

Don't get me wrong, I am interested in the Ji findings and their addition to the literature on paracetamol use and offspring outcomes. This still remains an important area of investigation. I'm not however completely convinced that the evidence presented by Ji and colleagues counts as particularly strong evidence despite the important measurement of paracetamol metabolites in this context...

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[1] Ji Y. et al. Maternal Biomarkers of Acetaminophen Use and Offspring Attention Deficit Hyperactivity Disorder. Brain Sci. 2018 Jul 3;8(7). pii: E127.

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The International Classification of Diseases version 11 (ICD-11) has arrived...

Although peer-reviewed science research is the typical fodder for this blog, I am inclined to post about other important papers and/or events as they emerge. Today is such an occasion, as I draw your attention to an important announcement from the World Health Organization (WHO) recently titled: "WHO releases new International Classification of Diseases (ICD 11)."

Yes, this announcement covers the release of the the much anticipated ICD-11 system "for identifying health trends and statistics worldwide" also including "around 55 000 unique codes for injuries, diseases and causes of death." The ICD-11 schedule as it currently stands can be accessed here.

I might add that the release of ICD-11 is not the same as the 'roll out' of ICD-11, which are we informed "will come into effect on 1 January 2022." This 'advance preview' is basically a way of introducing the new schedule to the world and helping to facilitate a smooth transition from the version currently in use to this new system.

The ICD-11 has not been without some controversy as for example, a new condition known as 'gaming disorder' has been picked up by some media outlets (see here). Others have opined about the inclusion of "Traditional Medicine conditions - Module I" (see here) (where "disorders and patterns which originated in ancient Chinese Medicine and are commonly used in China, Japan, Korea, and elsewhere around the world" have been added in).

Relevant also to this blog - being a blog predominantly about autism research - is the entry on autism, and how the term 'Asperger syndrome' doesn't seem to figure (same as in the DSM-5). Instead, there is the umbrella term 'Autism Spectrum Disorder', complete with various sub-categorisation of diagnosis on the basis of intellectual development 'level' and functional language 'level'. The waning of the term Asperger syndrome is seemingly coincidental to the recent revelations about Hans Asperger (see here) but perhaps reflects long-standing 'doubts' about it's inclusion in previous versions of the diagnostic manual used (see here). There are other changes noted in ICD-11 which are also pertinent to autism (see here) including those relevant to the idea that a diagnosis of autism rarely exists in some sort of diagnostic vacuum (see here).

It's still very early days for the ICD-11 and so we'll have to wait and see what else emerges as physicians and the like across the globe come to terms with the revised schedule. I don't doubt that the evolving diagnostic nature of autism will also create discussions (and arguments) aplenty...

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(Partly) explaining the increase in the prevalence of autism

"Changes in reporting practices can account for most (60%) of the increase in the observed prevalence of ASDs [autism spectrum disorders] in children born from 1980 through 1991 in Denmark."

Prince of Denmark @ Wikipedia 

That was the headline conclusion reported by Stefan Nygaard Hansen and colleagues [1] based on an analysis of births in Denmark between 1st January 1980 and 31st December 1991 (N=677,915) followed up until 31st December 2011 (or "until ASD diagnosis, death, emigration"). The suggestion being that an update to the ICD (International Classification of Diseases) criteria in 1994 - ICD-8 replaced by ICD-10 - played a significant role alongside "the inclusion of outpatient contacts" and voilà: "the apparent increase in ASDs in recent years is in large part attributable to changes in reporting practices". Some associated media coverage of this study can be found here.

This is certainly interesting data which again taps into those oh-so valuable Scandinavian health registries which are producing all-manner of interesting correlations and results (see here for another example). The question of what factor(s) might be driving the quite astounding increase in cases of autism worldwide (see here) has been a constant source of discussion and argument in certain circles. I have covered some of those debates before on this blog (see here).

Changes to the various diagnostic schedules as being a factor behind the alterations to the autism prevalence rate is by no means a new idea as per discussions about the the rival DSM (Diagnostic and Statistical Manual of Mental Disorders) criteria down the years. Indeed, looking at how the DSM-IV revision (which also came into play in 1994) might have influenced the autism numbers compared against the previous DSM-III criteria tells a similar tale (see here). The most recent DSM-5 revision also looks like it will be playing its own part on the epidemiology of autism at some point (see here) but we wait to see how that eventually pans out.

As per the press release for the Hansen study, there is still a question about the remaining percentage (~40%) of cases of autism not readily attributed to the changes in reporting practices.  A quick trawl through some of the other peer-reviewed work produced by Erik Parner, one of the co-authors on the Hansen paper, provides a few clues as to where researchers have been looking. I've covered some of these variables previously including: shifts in age at diagnosis (see here), the sibling recurrence rate (see here), maternal infection requiring hospitalisation (see here), etc. I might add that this list is not exhaustive as the words 'better autism awareness' are also likely to be banded around (see here for some recent interesting data on this).

I note also one sentence in the press release: "Environmental factors like using certain medications during pregnancy might also contribute, but more research is required to quantify the contribution of hypothesized risk factors" which I suspect ties into some work looking, for example, at prenatal valproate exposure and offspring neurodevelopmental outcomes [2]. Again, this is a topic which has been covered on this blog on more than one occasion (see here and see here) with no medical advice given or intended. I might add that valporate is not the only pharmaceutic which has come under the research spotlight (see here).

The Hansen results make a valuable contribution to the discussions about what might have been driving the increase in autism cases at least in Denmark [3]. Given their focus on participants with birth dates between 1980 and 1991 and the reporting changes included between 1994 and 1995, I'd be interested to see how future work from this group following up subsequent birth cohorts goes, assuming no significant changes in diagnostic schedules or other important adjustments to reporting procedures. I'd also rather hope to see a little more data about possible tie-ins with comorbidity for example, given the input of another Scandinavian team on the ESSENCE of autism...

To close: given that today is 'Remember, remember the 5th of November', I'm inclined to provide you yet again with a link to the rousing speech by 'V' from a favourite film of mine bearing in mind I'm not advocating such revolution. Oh, and please do be careful this Bonfire night...

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[1] Hansen SM. et al. Explaining the Increase in the Prevalence of Autism Spectrum Disorders. JAMA Pediatr. 2014. November 3.

[2] Christensen J. et al. Prenatal valproate exposure and risk of autism spectrum disorders and childhood autism. JAMA. 2013 Apr 24;309(16):1696-703.

[3] Parner ET. et al. A comparison of autism prevalence trends in Denmark and Western Australia. J Autism Dev Disord. 2011 Dec;41(12):1601-8.

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Hansen, S., Schendel, D., & Parner, E. (2014). Explaining the Increase in the Prevalence of Autism Spectrum Disorders JAMA Pediatrics DOI: 10.1001/jamapediatrics.2014.1893

Nearly 13% of children with a DSM-IV diagnosis?

I had tweeted about the paper by Sandra Petresco and colleagues [1] (open-access here) a while back as being the source of the sentence: "Nearly 13 % of the children presented a psychiatric diagnosis according to DSM-IV" based on their analysis of the Pelotas Birth Cohort [2] in Brazil.

Aleijadinho: Angel of the Passion @ Wikipedia 

The crux of the Petresco paper was that by looking at all the children, or at least the majority of children, born during 2004 in the city of Pelotas in Brazil and following them up when aged 6 years using the Developmental and Wellbeing Assessment (DAWBA) schedule [3], the rates of various developmental and/or psychiatric conditions according to ICD-10 and DSM-IV criteria were estimated.

The results (bearing in mind the paper is open-access)...

• Out of 4231 live births, 3,585 children were available for investigation at the age of 6. Trained interviewers delivered the DAWBA to parents, mostly in the clinical setting but about a fifth delivered in the family home. Data was analysed taking into account demographic information such as gender and socioeconomic status and various diagnoses assessed.
• Results: "It was found that 13.2% (N=475) and 12.8% (N=458) of the children fulfilled criteria for at least one diagnosis of psychiatric disorder according to DSM-IV and ICD-10, respectively". Boys were more likely to present with "any diagnosis". Top of the diagnostic pops was "any anxiety disorder" reported in nearly 9% of both boys and girls across both DSM and ICD definitions and then other diagnoses like ADHD (attention deficit hyperactivity disorder) and conduct disorder figured less frequently (both hovering around the 2-3% mark) which is interesting. Children from lower income families also seemed to have more risk of diagnosis.
• Another interesting figure here: autism was only picked up in 0.3% (n=10, 8 boys and 2 girls) of cases for both DSM-IV and ICD-10 criteria. Certainly spot on the mark for the 4:1 sex ratio but frequency-wise, quite a lot less than has been quoted in other parts of the world accepting some differences in the numbers included for study. That being said the authors do note that they only administered the screening questions from the "developmental section" of the DAWBA so might not have caught every case of autism. Other studies looking at DAWBA as a screening instrument for autism have also tended to suggest under-diagnosis as potentially being an issue [4].
• When it came to presenting with symptoms reflective of more than one condition, about 16-17% of children fitted this bill across the diagnostic schedules. An ADHD / conduct disorder came out as the most common combination (29%). More than two comorbid conditions was a rare event (n=3) but when present, all were boys.

I'm sure you'll agree that there is some rather interesting data to be had there. I can't help but wonder if similar cohorts using the same DAWBA tool and screening method sited at other areas of the globe would provide a rather interesting comparison to the Brazil data. Not least covering any relationship between different ethnicities in different environments and the frequency of reported DSM-IV and ICD-10 diagnoses?

That headline figure of 13% of children fitting some kind of diagnostic bill when it comes to DSM-IV and ICD-10 also merits a lot more examination. Again, with my head full of wonder, I'd be asking about whether further genetic / biochemical / other inspection might be revealing for this cohort, particularly when one takes into account the discussions about ESSENCE (see here) and the introduction of RDoC (see here) to research proceedings. How this figure might ebb and flow would also be a good idea for future study, bearing in mind the changing diagnostic times that we live in (see here).

Music to close. Grenade by Bruno Mars.

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[1] Petresco S. et al. Prevalence and comorbidity of psychiatric disorders among 6-year-old children: 2004 Pelotas Birth Cohort. Soc Psychiatry Psychiatr Epidemiol. 2014 Feb 1.

[2] Santos IS. et al. Cohort profile: the 2004 Pelotas (Brazil) birth cohort study. Int J Epidemiol. 2011 Dec;40(6):1461-8.

[3] Goodman R. et al. The Development and Well-Being Assessment: description and initial validation of an integrated assessment of child and adolescent psychopathology. J Child Psychol Psychiatry. 2000 Jul;41(5):645-55.

[4] Posserud M. et al. The prevalence of autism spectrum disorders: impact of diagnostic instrument and non-response bias. Soc Psychiatry Psychiatr Epidemiol. 2010 Mar;45(3):319-27.

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Petresco S, Anselmi L, Santos IS, Barros AJ, Fleitlich-Bilyk B, Barros FC, & Matijasevich A (2014). Prevalence and comorbidity of psychiatric disorders among 6-year-old children: 2004 Pelotas Birth Cohort. Social psychiatry and psychiatric epidemiology PMID: 24488152

The potential impact of DSM-V on autism numbers

I don't really want to get too bogged down with the various discussions which have passed to-and-fro when it came to the expected impact of the introduction of DSM-V on autism prevalence estimates. I couldn't however let the publication of the paper by Matthew Maenner and colleagues* pass by without making some comment on it (or at least directing readers the various comments being made about it: see here and see here).

To summarise the new study: retrospectively apply the new DSM-V criteria for receiving a diagnosis of autism (sorry, autism spectrum disorder) to data pertaining to a cohort of children previously diagnosed with DSM-IV autism and see how much overlap there is. I think back to similar study when it came to comparing even earlier versions of DSM on autism prevalence estimates (see here) and the interesting effects that seemed to have.

The good news from the Maenner study: 81% of those DSM-IV classified as having autism were also DSM-V classified as having autism. Interestingly, also that those with comorbid intellectual disability or with a history of developmental regression were slightly more likely to meet the DSM-V criteria for autism. The not-so-good news: er, what happens to those children who didn't quite reach the DSM-V diagnostic thresholds..? Social communication disorder (SCD)? Well, we don't know yet because SCD wasn't looked at in the current study, and as far as I can ascertain, SCD is still wanting in terms of research into the diagnosis and indeed, outcomes. Just as an aside, I wonder if it might however also cover some of those unusual ICD codes relevant to autism?

Of course, as the various media on this paper point out, this was a study based on case notes or rather "clinician review of coded behaviors documented in children’s medical and educational evaluations" so one has to be a little bit cautious of making too many judgements. According to the Autism Speaks website there is further work coming to publication soon looking at more "in-person diagnostic evaluations" across both DSM-IV and DSM-V (see here). Perhaps some more concrete answers might emerge from that data; hopefully slightly more optimistic than the results from Wilson and colleagues**.

I'm gonna finish with a link to an interesting blog post by Allen Frances, who was previously Chair of the DSM-IV taskforce, titled: "Will the DSM-5 Reduce Rates of Autism?". According to the Maenner results, Dr Frances is correct in his assertion "Yes, by a lot" (or at least by about 20%). The arguments will no doubt rumble on about DSM-V (and don't even mention RDoC).

Update: 27 January 2014. And then came the paper by Kim and colleagues*** and some chatter about their findings. It seems that the SCD diagnostic coding would serve as a catch-all after all, for most of those not fulfilling the DSM-V criteria for ASD. All well and good I suppose but the questions about SCD remain in terms of what a diagnosis will actually mean for access to services and required provisions.

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* Maenner MJ. et al. Potential Impact of DSM-5 Criteria on Autism Spectrum Disorder Prevalence Estimates. JAMA Psychiatry. January 22, 2014. doi:10.1001/jamapsychiatry.2013.3893

** Wilson CE. et al. Comparison of ICD-10R, DSM-IV-TR and DSM-5 in an adult autism spectrum disorder diagnostic clinic. J Autism Dev Disord. 2013 Nov;43(11):2515-25.

*** Kim YS. et al. A Comparison of DSM-IV PDD and DSM-5 ASD Prevalence in an Epidemiologic Sample. Journal of the American Academy of Child & Adolescent Psychiatry. 2014. 23 Jan.

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Matthew J. Maenner, Catherine E. Rice, Carrie L. Arneson, Christopher Cunniff, Laura A. Schieve, Laura A. Carpenter, Kim Van Naarden Braun, Russell S. Kirby, Amanda V. Bakian, & Maureen S. Durkin (2014). Potential Impact of DSM-5 Criteria on Autism Spectrum Disorder Prevalence Estimates JAMA Psychiatry : 10.1001/jamapsychiatry.2013.3893

A bottom-up approach to autism research?

If anything else, the recent discussions on the principles of RDoC - Research Domain Criteria (see here) - being applied to psychiatry have prompted many to question whether our current diagnostic labels are actually fit for purpose when it comes to answering the big research questions of how and why.

Bottoms up? @ Wikipedia 

RDoC, for those of you who might not know, is described by the US National Institute of Mental Health (NIMH) as an attempt to: "define basic dimensions of functioning (such as fear circuitry or working memory) to be studied across multiple units of analysis, from genes to neural circuits to behaviors, cutting across disorders as traditionally defined".

In other words, by all means use the DSM or ICD as your diagnostic key, but don't necessarily expect the genes (and epigenetics), biochemistry and brain / body physiology to also fit neatly into those categories that you diagnose with. The proof for this disparity is laid out in front of us all as labels such as autism or schizophrenia or ADHD remain in the most part a mystery when it comes to aetiology, common biological signatures (including replicative work) and consequently generalised intervention options to improve quality of life and functioning.

Even before RDoC I, like quite a few others, often thought that the reliance on something like the label of autism or autism spectrum as a research starting point offered little when it came to autism science. In a previous post, I did talk about the possibility of overcoming this issue as per the discussions on focusing on phenotypes - smaller subgroups on the autism spectrum - characterised by something like response to intervention for example (see here). Indeed, my recent droning on the area of dietary intervention for autism (see here) exemplified how such a shift in focus might yet yield some testable results.

Enter then another modified example of this approach with the paper by Lisa Unwin and colleagues* (open-access version here) and their discussions on a bottom-up approach to autism research. I admit that I was always going to be interested in this paper because of (a) the presence of Andrew Whitehouse on the authorship list (see previous posts here and here) and (b) mention of the 'autisms' over the more 'unitary' label of autism (see here).

As Unwin et al describe, the bottom-up approach used in the paper refers to "known aetiological risk factors, and whether individuals exposed to these risk factors have a more homogenous phenotype". In this case, low birth weight and independently maternal use of SSRIs during pregnancy (see here) were the starting points and then "examining the homogeneity within the groups based on medical complaints such as sleep problems and gastrointestinal complaints in addition to core features of ASD such as social behavior, language characteristics, and severity". Actually on the point of anti-depressant use during pregnancy and autism risk, I'm minded to bring in other, more recent evidence that suggests risk may have been over-inflated?

The first part of the Unwin paper looked at those children with an ASD where maternal SSRI use was reported during pregnancy and suggested that "children with ASD whose mothers took SSRIs during pregnancy were significantly more likely to experience gastrointestinal complaints during childhood" compared with no maternal SSRI history. The second study included in the paper examined children with ASD with a low birth weight compared against those with a normal range birth weight. They suggested "greater sleep disturbances" to be present in the former group.

Whilst the participant numbers included in this paper were low and the results are crying out for replication, I find this approach to be a breath of fresh air when it comes to autism research. Not only because of the realisation that there may be different phenotypes within the autism spectrum as a function of suggested risk factors - of which there may several (see here and here for example) - but also because the authors expanded their horizons outside of just looking at the core behavioural symptoms associated with autism. Indeed the focus on bowel issues (see here) and sleep issues (see here) reflect how frequently these variables crop up and how, for some people, they can so significantly affect quality of life.

There are some other nuggets of research gold to come out of this paper which are worthy of comment. So, "it seems reasonable that environmental factors may be related to the expression of non-core ASD symptoms among these children rather than to any variance in core symptomatology". In other words, autism might actually be greater than the sum of its triadic (sorry dyadic) parts. As per my chatter about the 'autisms' previously, the authors also note: "A key question facing the field is whether the long-held view that autism is a unitary disorder with a single causal pathway is correct, or whether autism may best be conceptualized as an umbrella term for a collection of behavioral disorders resulting from a range of causal pathways, analogous to cerebral palsy". Not surprisingly the authors conclude that the plural autism might be "a more accurate representation".

Tom Insel of the NIMH is quoted along similar lines with his phrase: "Clearly autism is many disorders". I'd have to say that I agree and that 'range' of conditions falling under the autism umbrella seems to be growing all the time.

Music maestro.... Common People by Pulp?

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* Unwin LM. et al. A "bottom-up" approach to aetiological research in autism spectrum disorders. Front Hum Neurosci. 2013 Sep 19;7:606. doi: 10.3389/fnhum.2013.00606.

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Unwin LM, Maybery MT, Wray JA, Whitehouse AJ. (2013). A "bottom-up" approach to aetiological research in autism spectrum disorders. Front Hum Neurosci. DOI: 10.3389/fnhum.2013.00606

The strange case of ICD code F84.8

We all make mistakes. I do however consider myself to be quite a consientious person; checking and re-checking various things in my life (I am one of those people who has to make sure that the gas cooker is turned off every evening before bed, even though I have no history of ever leaving it on).

I did however make a recent mistake on a reply post I made over at autism.about.com run by Lisa Jo Rudy on the topic of 'Atypical autism or PDD-NOS'. The discussion thread was all about labels and diagnoses; to which I posted, what I thought was an interesting point; a reply which mentioned the ICD-10 criteria for autism spectrum conditions which contained a typo. I was corrected, I might add, by someone with sharper eyes than I.

Getting back to my post: I mentioned those peculiar codes of the ICD-10 autism criteria: F84.8 Other Pervasive Developmental Disorder and F84.9 Pervasive Developmental Disorder, unspecified. It has always been a little bit of a mystery to me as to why ICD-10 contains both these two codings. Maybe I should back up a little and show readers what codings are available in ICD-10 pertient to pervasive developmental disorders:

• F84.0 = childhood autism. 
• F84.1 = atypical autism (including some sub-categories for areas of atypicaility). 
• F84.2 = Rett syndrome. 
• F84.3 = other childhood disintegrative disorder. 
• F84.4 = overactive disorder(?). 
• F84.5 = Asperger syndrome.

Then our mystery F84.8 and F84.9.

F84.9 PDD unspecified has a description saying that it is a residual category for PDD where there is either inadequate information or contradictory findings regarding diagnosis. F84.8 has no description at all. No description but present - the strange case of F84.8.

If we assume that F84.1 (atypical autism) is equivalent to PDD-NOS (or Autism Spectrum Disorder in the UK) and F84.9 is a catch-all for autism or PDD-NOS where some issue/s are present which do not make diagnosis as clear-cut, we are still left questioning what fits into F84.8.

Looking at the research where F84.8 is mentioned I'm afraid I am none the wiser. This paper, published in BMC Pediatrics on the early detection of autism spectrum conditions in the UK makes reference to the coding. The authors imply that F84.1 is correctly used to determine atypical autism but then go on to say that semantic pragmatic language disorder is also covered under either F84.1 or F84.8 or F84.9. This paper also makes reference to the F84.8 and F84.9 codings but again I don't see the distinction.

I assume that, at the time of the ICD-10 planning, there was some logic as to how these codings would be used. Was F84.8 the 'overspill of the overspill' coding?

To quote from Sir Arthur's greatest invention: "when you have eliminated the impossible, whatever remains, however improbable must be the truth".