Saturday, August 27, 2011

Is Too Much Folic Acid a Bad Thing?

I saw this study earlier today and it definitely gave me pause.  Could it be that the increasing use of folic acid over the past few decades is responsible for part of the rise of conditions like autism?

Folic acid supplementation dysregulates gene expression in lymphoblastoid cells - Implications in nutrition.

Junaid MA, Kuizon S, Cardona J, Azher T, Murakami N, Pullarkat RK, Brown WT.

For over a decade, folic acid (FA) supplementation has been widely prescribed to  pregnant women to prevent neural tube closure defects in newborns. Although neural tube closure occurs within the first trimester, high doses of FA are given throughout pregnancy, the physiological consequences of which are unknown. FA can cause epigenetic modification of the cytosine residues in the CpG dinucleotide, thereby affecting gene expression. Dysregulation of crucial gene expression during gestational development may have lifelong adverse effects or lead to neurodevelopmental defects, such as autism. We have investigated the effect of FA supplementation on gene expression in lymphoblastoid cells by whole-genome expression microarrays. The results showed that high FA caused dysregulation by four-fold up or down to more than 1000 genes, including many imprinted genes. The aberrant expression of three genes (FMR1, GPR37L1, TSSK3) was confirmed by Western blot analyses. The level of altered gene expression changed in an FA concentration-dependent manner. We found significant dysregulation in gene expression at concentrations as low as 15ng/ml, a level that is lower than what has been achieved in the blood through FA fortification guidelines. We found evidence of aberrant promoter methylation in the CpG island of the TSSK3 gene. Excessive FA supplementation may require careful monitoring in women who are planning for, or are in the early stages of pregnancy. Aberrant expression of genes during early brain development may have an impact on behavioural characteristics.

PMID: 21867686
DOI: 10.1016/j.bbrc.2011.08.027

Thursday, August 18, 2011

The Curious Autism Science Foundation

It has been two years since Alison Tepper Singer absconded with Autism Speak's seat on the IACC and co-founded the Autism Science Foundation.  The ASF is, of course, a (cough) leading nonprofit dedicated to finding answers to the puzzle of autism.

Or at least they are dedicated to finding all of the answers possible when starting from the assumption that vaccines, anything related to vaccines, and GI issues have nothing to do with autism.

It has been a little bit of a rocky start for the ASF.

On day one, the ASF climbed into bed with prominent members of the neurodiversity and adult "don't speak ill of" autism community.  I'm guessing they felt the need to do that because they annoyed one large part of the autism community by running away with Autism Speak's seat on the IACC and another large part with their absolute "asked and answered" stance on autism "science".

The ND and adult "self-advocate" groups might have been the only vocal group left who would give them the time of day.  But I have to wonder what sort of pact with the devil was required to seal this deal because Ms Singer was definitely not well liked by these people.  Prior to the formation of the foundation, these people were all but burning her in effigy over comments she made years earlier about autism making her want to drive off a bridge.

But whatever promises were made, the ASF gained the acceptance of a large part of the ND and self-advocate movements.  Which is a rather peculiar pairing when you think about it.  On the one side, you have a foundation dedicating to following science and on the other a group of people who don't seem to think that autism is a disorder or that it needs to be treated/cured.  On the one side you have a foundation dedicated to finding the genetic "causes" of autism and on the other people who object to almost any genetic research into autism.

I think you get the point, the two groups certainly make strange bed fellows.

And so, with their bed made, the ASF turned to more mundane matters such as where to hang their hats.  And speaking of location, the initial location was none other than the basement of Ms. Singer's home.  Which, all things considered, isn't the worst place to start from.  I just have to wonder how many of the other non-profit public members of the IACC worked out of someone's basement.

So, with their bed made and located in Ms. Singer's basement, the foundation turned to creating its website to share its mission and to provide accurate scientific information about autism to the world.

And promptly got it wrong.

On their website, they included information about PDD-NOS, aka Pervasive Developmental Delay - Not Otherwise Specified.  They also wanted to remind us that "autism is pervasive developmental delay, which means children will continue to develop, learn, gain skills and adapt as they age".

Which while it might be true that some children with autism will continue to grow and learn on their own, you can't really say that for all children.  And last time I checked, the "scientific" definition of autism is that it is a development disorder, not a "delay", and PDD-NOS stands for Pervasive Developmental Disorder - Not Otherwise Specified, again not a "delay".

I find it highly curious that an organization with the word "science" in their name and a gaggle of scientific advisers would get the name and basic concept of the disorder they are targeting wrong.  Maybe it had something to do with getting into bed with the ND movement?

The foundation also has some questionable information about the gluten-free, casein-free diet on site, saying that "children on the GFCF diet have been found to have lower bone density than controls, which could lead to osteoporosis."

There has been no study (that I am aware of) that has provided strong evidence that children with autism on the GFCF diet are more likely that children with autism who aren't on the diet to have lower bone density.  Or for that matter any study whatsoever that attempts to sort out whether the GFCF diet could cause lower bone density or whether lower bone density could be caused by another condition (such as malabsorption) that the GFCF diet is used to treat.

The best (and worst) you can say about the GFCF diet is that the available evidence is inconclusive.  There is some evidence that suggests it can help some children with autism but there certainly isn't any evidence that suggests that it would help all children or that it could magically cure every person with autism.

But moving along, with the ASF firmly in bed with the advocates in Ms. Singer's basement and their version of science nestled in its crib, the foundation secured funding in the form of proceeds from Dr. Offit's autism book  started operations.

Or something like that, my memory of the exact sequence and timing of events is a little bit blurry.  It is about this time that I finally found something better to do with my time and stopped paying attention to what the ASF was doing.

Fast forward to the present day and most of the original rough start has been erased.

Autism Speaks managed to get another seat on the IACC so that one of the largest private sources of funding for autism research could once again participate in the discussion of the future of autism research.

The ASF appears to have moved out of the basement and into New York City.

Unfortunately, the ASF is still calling autism a developmental delay instead of a disorder and they haven't updated their web site to reflect the data from the most recent twin studies or sibling study.  And the GFCF diet still can lead to osteoporosis.

At least they got the science part, oh wait.  Two out of three isn't bad, right?

Moving right along...

As I think back over the past two years, I can't really put my finger on anything major the ASF has done.  Perhaps it was because I wasn't paying attention but you would think that anything of any major importance would have appeared in the headlines.

I do seem to remember something about them occasionally passing out sandwiches to scientists, possibly to help them think better (it is hard to think on an empty stomach).  I also seem to remember something about them paying for ND bloggers, such as Sullivan and DoC, to attend autism conferences and write about it on their blogs.

Oh, and I think they did fund some research too.

A few months ago, I noticed that the ASF announced the imminent arrival of the first annual report.  Since I hadn't really been following the what the foundation was up to, I thought it would be interesting to see what exactly the ASF had done in the first two years.

For their part, the ASF appeared to be very excited to release their first annual report, calling it "doing BIG things" and going so far as to create a special web site to release the report.  This special site provided little snippets of information from the report and promised that the full report will would available in June.

But then June came and went and the report was not published.  And then July passed and still no report.  Here it is, the middle of August and the special site is still claiming that the report is going to be published in June.  Maybe they mean June 2012?

I know the ASF wants to be taken seriously but I have to wonder.  I can't imagine Autism Speaks or any other large autism non-profit making a big to-do about releasing its annual report and then simply failing to do so.  The ASF says that it survives on donations but who would be willing to donate to an organization that won't even tell you how it uses the money you give it?

Very curious.

Monday, August 15, 2011

Study: Recurrence Risk for Autism Spectrum Disorders: A Baby Siblings Research Consortium Study

The risk of a sibling developing autism is almost double what it was thought to be?


Recurrence Risk for Autism Spectrum Disorders: A Baby Siblings Research Consortium Study

Objective: The recurrence risk of autism spectrum disorders (ASD) is estimated to be between 3% and 10%, but previous research was limited by small sample sizes and biases related to ascertainment, reporting, and stoppage factors. This study used prospective methods to obtain an updated estimate of sibling recurrence risk for ASD.

Methods: A prospective longitudinal study of infants at risk for ASD was conducted by a multisite international network, the Baby Siblings Research Consortium. Infants (n = 664) with an older biological sibling with ASD were followed from early in life to 36 months, when they were classified as having or not having ASD. An ASD classification required surpassing the cutoff of the Autism Diagnostic Observation Schedule and receiving a clinical diagnosis from an expert clinician.

Results: A total of 18.7% of the infants developed ASD. Infant gender and the presence of >1 older affected sibling were significant predictors of ASD outcome, and there was an almost threefold increase in risk for male subjects and an additional twofold increase in risk if there was >1 older affected sibling. The age of the infant at study enrollment, the gender and functioning level of the infant's older sibling, and other demographic factors did not predict ASD outcome.

Conclusions: The sibling recurrence rate of ASD is higher than suggested by previous estimates. The size of the current sample and prospective nature of data collection minimized many limitations of previous studies of sibling recurrence. Clinical implications, including genetic counseling, are discussed.


Sunday, August 14, 2011

Ghosts of Autism Studies Past

I have been reading older autism twin studies in an effort to put the latest autism twin studies and the idea that autism is a genetic disorder into a historical context.  And the more I read of these old studies, the more the following line keeps coming to mind -

Those who cannot remember the past are condemned to repeat it.

We all hang on the latest word in autism research but I have to wonder how much of what we read is really new.  As I am reading these old studies, I keep bumping into ideas that are being presented now as new and wonderful "discoveries".  So I find myself wondering just how much is new and how much is simply a regurgitation of an older ideas that simply fell out of scientific fashion.

Lets take a look at some of the new, radical ideas about autism in terms of historical studies.

To start off with, what about the recent idea that a maternal infection during pregnancy might increase the risk of autism?  If you read Steffenburgh et al 1989, you would see infections during pregnancy being mentioned as a possible cause of autism  -
In not a single one of the pairs discordant for AD was there a reversed relationship in this respect. There were no cases of diagnosed rubella infection in pregnancy or of other infections currently thought to be of causative importance in autism.
How about the idea that autism might be a combination of genetic and environment influences?  Folsten & Rutter in 1977 -
In studying genetic factors, it is necessary to bear in mind that autism is probably a behavioural syndrome with multiple aetiologies (Rutter, 1974). Certainly, it is known that the syndrome can develop in association with medical conditions as pathologically diverse as congenital rubella (Chess et al, 1971) and infantile spasms (Taft and Cohen, 1971). Accordingly, the investigation of possible hereditary factors must take account of aetiological heterogeneity.
What about the idea that prenatal/perinatal complications might play a role in autism?  Steffenburgh et al in 1989 had this to say -
Nevertheless, the association with perinatal problems in discordant autism twin pairs shows that sometimes perinatal problems alone can be a major aetiological contributory factor.
How about the idea that identical twins might not both have autism and if they do both have autism the severity might be different? In the granddaddy of all autism twin studies in 1977, Folsten & Rutter found that only 4 out of the 11 pairs of identical twins were concordant for autism and that even if they were concordant they had significant differences -
Two of the concordant MZ pairs (i and 3*) were closely similar in all respects. In each case, the twins were severely retarded and the autism was somewhat atypical in terms of the limited evidence of ritualistic features. However, in both the other two pairs, there were important differences between the twins in spite of concordance for autism. In one (2) there was an 18 point difference in non-verbal I.Q_. and a 24 point difference in Peabody language quotient. The twin with a lower non-verbal I.Q,. but higher verbal I.Q,. made much more progress in both social relationships and use of language. In the fourth pair (4) there was a 39 point I.Q,. difference; in this case, the more intelligent twin was less severely autistic, although the type of behaviour was closely similar in both. It is also notable that the more intelligent twin did not develop autism until 3 years of age, although apart from the late onset the clinical picture was typical of autism. 
But you might reply that that was under an old, strange definition of autism that would be quite different than one in use today.  Nope, here is the definition of autism from that study -
a serious impairment in the development of social relationships of the type characteristic of autism (that is with limited eye to eye gaze, poor social responsiveness, impaired selective bonding, a relative failure to go to parents for comfort, and, when older, a lack of empathy, a lack of personal friendships and little group interaction); together with delayed and deviant language development with some of the specific features associated with autism (namely poor language comprehension, little use of gesture, echolalia, pronominal reversal, limited social usage of language, repetitive utterances, flat or staccato speech and very restricted imaginative play); and also stereotyped, repetitive or ritualistic play and interests (as indicated by an abnormal attachment to objects, marked resistance to change, rituals, repetitive behaviour, unusual preoccupations and restricted interest patterns).
That looks almost like a modern definition of autistic disorder to me.  And as recent results have shown, autistic disorder (i.e. classic autism) makes up somewhere between 30% to 50% of all modern cases.

But it seems like coming into the "modern" era of autism research that we have forgotten some of these ideas. By the time Bailey et al in 1995 was published, much of these ideas were put put out to pasture and autism was declared a genetic disorder.  It is only now, in modern times, that we have rediscovered some of the ideas about autism that were common over 35 years ago.

In closing, let me leave you with two little fun facts about these old twin studies.  

The following twin studies make up the bulk of historical twin studies that looked at actual co-morbidity in twins - Folsten & Rutter 1977, Steffenburgh et al 1989, and Bailey et al 1995 - and all three of these studies have one very important thing in common.

All three of these studies excluded opposite sex twins, otherwise know as half of the fraternal twin population.

Second, even though the numbers of children with a label has increased by a factor of 25 (2400%) over the years, one thing has not changed - the 4 to 1 ratio of boys to girls.  That ratio is noted all the way back in Folsten & Rutter in 1977 and the reference in there is to an older study from 1966.  

So ask yourself just one question, if the definition of autism has changed so radically over the years and we are now calling things "autism" that would never have been called autism in the past, why hasn't this ratio of boys to girls changed?


Folstein, S, and M Rutter. 1977. “Infantile autism: a genetic study of 21 twin pairs.” Journal of child psychology and psychiatry, and allied disciplines 18(4):297-321.

Ritvo, E R, B J Freeman, A Mason-Brothers, A Mo, and A M Ritvo. 1985. “Concordance for the syndrome of autism in 40 pairs of afflicted twins.” The American journal of psychiatry 142(1):74-7.

Steffenburg, S et al. 1989. “A twin study of autism in Denmark, Finland, Iceland, Norway and Sweden.” Journal of child psychology and psychiatry, and allied disciplines 30(3):405-16.

Bailey, A et al. 1995. “Autism as a strongly genetic disorder: evidence from a British twin study.” Psychological medicine 25(1):63-77.

Saturday, August 13, 2011

Safety in Developmental Disabilities

As I have talked about just a few times before, safety is real concern for parents whose children have autism.  Many of these children lack a basic awareness of their environment and will unknowingly put themselves in situations where there is a very real chance of harm or death.

So parents like me worry and take extra precautions to keep their children safe.  We talk about these concerns openly so that other parents - perhaps parents new to autism - will know enough to take appropriate precautions and keep their children safe.  The penalty for a lack of awareness in this area can be very severe.

But since this is autism we are talking about, there are always the "don't speak ill of autism" crowd how want to deny that these concerns are valid.  One of their complaints against this idea is that there is no "evidence" that safety is a systemic issue in autism.

Well, here is a recent study that takes a look at a relatively simple task that involves safety - crossing the street.  The developmental disability here is one of the forms of ADHD, but I have no doubt that the findings would apply to autism.  There are many children with autism who would also lack the ability "to process perceived information adequately to permit crossing safely."

Mediating factors associated with pedestrian injury in children with attention-deficit/hyperactivity disorder.

Unintentional injury is the leading cause of pediatric mortality. One leading cause of unintentional injury is pedestrian injury. Children with developmental disabilities, particularly those with attention-deficit/hyperactivity disorder-combined type (ADHD-C) seem to have increased pedestrian injury risk. This study examined (1) the differences in pedestrian behavior between children with ADHD-C and normally developing comparison children and (2) the mediating factors that might link ADHD-C with pedestrian injury risk.

A total of 78 children aged 7 to 10 years (39 children with ADHD-C diagnoses and 39 age- and gender-matched typically developing children) participated. The main outcome measure was pedestrian behavior, as measured in a semi-immersive, interactive, virtual pedestrian environment. Key pedestrian variables related to different aspects of the crossing process were identified: (1) before the cross (ie, evaluating aspects of the crossing environment); (2) making the cross (ie, deciding to cross and initiating movement); and (3) safety of the cross (ie, safety within the pedestrian environment after the decision to cross was made).

Children with ADHD-C chose riskier pedestrian environments to cross within (F(1,72) = 4.83; P <; .05). No significant differences emerged in other aspects of the crossing process. Executive function played a mediating role in the relationship between ADHD-C and the safety of the cross.

Children with ADHD-C seem to display appropriate curbside pedestrian behavior but fail to process perceived information adequately to permit crossing safely.


Stavrinos D, Biasini FJ, Fine PR, Hodgens JB, Khatri S, Mrug S, Schwebel DC. Mediating factors associated with pedestrian injury in children with attention-deficit/hyperactivity disorder. Pediatrics. 2011 Aug;128(2):296-302. Epub 2011 Jul 25.
PMID: 21788213
DOI: 10.1542/peds.2010-3829

Thursday, August 11, 2011

Quality Research

Every now and then I read the abstract for a study and just have to laugh at the absurdity.  The following is one of those -

Characteristics and Quality of Autism Websites.
J Autism Dev Disord. 2011 Aug 6. [Epub ahead of print]

Reichow B, Halpern JI, Steinhoff TB, Letsinger N, Naples A, Volkmar FR.
Yale Child Study Center, 230 South Frontage Road, New Haven, CT, 06519, USA.

The World Wide Web is a common method for obtaining information on autism spectrum disorders, however, there are no guidelines for finding websites with high quality. We conducted two studies examining the characteristics and/or quality of autism websites in 2009 and 2010. We found websites with a .gov top-level domain had a statistically significant association with high quality websites and websites offering a product or service and websites promoting a non-evidence-based practice had a statistically significant association with poor quality websites. Based on our work we concluded that online information should not replace the information consumers obtain from professionals. Further implications for practice, overview of study limitations and future directions are provided.

PMID: 21822761

I don't think I have ever seen anyone try to say that a top-level domain name is statistically significant of anything before let alone say that it determines whether the site is "high quality" or not.

Seriously, how exactly do you define "high quality" so that it isn't just an arbitrary standard that you made up and how on earth do you get away with claiming that this arbitrary definition can have a statistically significant association with anything.  What does that even mean?

You might as well just spell it out and say that you liked what these sites said better than others and don't pretend that there is some sort of science behind it.

And don't even get me started in the idea that "consumers" should give more credence to information dispensed from professionals.  There are many "professionals" out there that don't know the first thing about autism let alone have any clue about how to deal with it.

I would even go so far as to say that the majority of medical professionals that deal with young children don't have a clue when it comes to autism.  If I had a dollar for every time I have heard of a pediatrician using a line like "he's just being a boy" or "they will grow out of it", well, I would be several hundred dollars richer at the very least.

OK, I guess I did get started.  But really, we have been extremely fortunate in having an excellent team of knowledgeable professionals working with our children, but we still have to do our own research to separate out fact from fiction.  We have had "professionals" tell us all sorts of garbage and completely miss things that we managed to catch because we know enough to do our own research.

I know that there is a serious and important point here.  It is important to make sure that what you are looking at is a knowledgeable and reputable source.  But according to this paper we should assume that the information provided by professionals, many of whom are completely clueless, is the more reliable source and disregard the vast amount of reliable and accurate information that the internet can provide?

Yeah, right.

Wednesday, August 10, 2011

Ancestry of Pink Disease and Autism

A study was published a few weeks ago that took a look at whether having a family history of pink disease (Infantile Acrondynia) leads to an increased risk of autism.  Pink disease is, as most of you probably know, a form of mercury poising linked to use of teething powders that used to be commonly seen in infants and toddlers.  And so, as would be expected when someone mentions the words "autism" and "mercury" together in the same sentence, this study has produced some rather strong opinions from all corners of the autism world.

I didn't want to write anything about this one until I had the chance to read what the study did and did not say (unlike some other people).  But after reading it, I don't really understand what the big deal is.  The data contained in the paper is interesting, if very limited, but outside of the typical theories that fill the introduction and conclusion sections of almost every paper, there is no direct link made between mercury and autism.

Or to put it another way, even if every bit of actual data in the study is 100% true and having a parent or grandparent who survived pink disease does increase the risk of having autism, it does not speak to why the relationship is there.  So this is just a simple association study saying that A might be associated with B, and a very tenuous one at that.

The core of the data is quite simple.  The researchers sent out surveys via mail and e-mail to approximately 2,300 survivors of pink disease.  The surveys indicated that they were collecting data on the general health outcomes in the descendants of survivors of pink disease instead of identifying the interest in autism specifically.

The surveys asked questions about the number of biological children and grandchildren that each survivor had that lived until at least their fifth birthday.  It asked how many of the children and grandchildren had one or more of the following conditions : autism, Asperger's, ADHD, epilepsy, fragile X, intellectual disability, or Down syndrome.

Out of all of the surveys sent out, only 522 completed, non-duplicate surveys were received back.  If you are looking for problems with the study, this is one of the first ones.  Only a small fraction of the surveys were returned leading to the very real possibility that people who chose to respond were biased in some way.

The breakdown of the responses is as follows.  I am only going to report the autism and ADHD numbers as those are the interesting ones.

There were a total of 1,103 children who had a mean age of 37.1 years old.  In this group, there were 11 children with any form of autism (3 autism, 8 Asperger) and 38 children with ADHD.

There were a total of 1,366 grandchildren who had a mean age of 11.3 years old.  In this group, there were 34 grandchildren with autism (12 autism, 22 Asperger) and 29 grandchildren with ADHD.

The researchers then compared the rates of autism in the grandchildren against other published estimates of autism prevalence from Australia.  There are some other sites out there (some of which didn't read the paper) that are claiming that this is one of the problems with this paper.  The claim is that there is no accepted autism prevalence number so there is nothing to compare against.

These claims are largely baseless as the prevalence estimates used in the paper are from other published research that specifically looked at autism prevalence in Australia in and around the age of the grandchildren.  Furthermore, the estimates used are in line with other published estimates in other countries during the same time period.

Personally, I don't find these comparisons to other prevalence estimates all that useful or meaningful.  I think the raw numbers speaks for themselves even in terms of the most recent autism prevalence estimates.

The bottom line is that there were far more cases of autism in grandchildren than would be expected in a group of this size.  The total rate in this population would be almost 2.5%, or more than double what would be expected even in the youngest children today.  When the grandchildren are grouped according to age, the autism prevalence are -

1 in 25 for 6-12 year olds (398 kids)
1 in 35 for 13-16 year olds (141 kids)
1 in 60 for 16+ year olds (827 kids)

That last point is my own extrapolation from the data included in the study.  As a point of comparison, the accepted expected rate of autism today is about 1 in 110, or at least it is in the US.

The study doesn't go into details about the children, but simple math would show you that about 1 in 100 of the direct children had a form of autism.  That number is far larger than would be expected considering that the majority of these people were born before 1980.  Back then the expected rate would have been something like 4 in 10,000 - not 100 in 10,000.

But as shocking as these numbers are, you can't read too much into them because they are based on a survey.  No one went out and actually verified that the people had the condition that they said they did.  No one checked for any sort of response bias in the data.  No one even checked that the people who responded did actually survive pink disease.

So the results are interesting but hardly earth-shattering.

There are also two interesting artifacts in the data that give me pause.

First, the proportion of people with autism compared to Asperger's is out of balance.  Normally you find one person with Asperger's for each 9 with classic autism or pdd-nos.  Yet in both the children and grandchildren Asperger's made up almost two thirds of the autism group.

Perhaps the survivors whose children had autism were less likely to have grandchildren or were less likely to be included in the sample.  This could especially be true since the response to autism back them was to stick people in an institution for the rest of their lives.

Second, there is something interesting going on with the total number of autism and ADHD cases.  In the children, the percent with either form of autism or ADHD was about 4.5%.  In the grandchildren, this percent was about almost identical at 4.6%.  The two populations aren't the same size but it looks like about half of the increase in the autism group could have come from the decrease in the ADHD group.

But again, this is just survey data, so we can't read too much into these quirks just like we can't read too much into the autism rates.

I am not going to go into the mercury/autism theories as there isn't too much point.

Any possible relationship between pink disease and autism is purely hypothetical at this point.  If you wanted to prove some sort of relationship you would have to do a much better job with data collection and analysis.

And on the flip side, we know almost nothing about the relationship between the type of mercury associated with pink disease and autism.  It is a different type of mercury delivered in different doses in a different way.  You can't look at the existing data on  intramuscular ethyl mercury exposure and draw conclusions about ingested mercury chloride.


Shandley, Kerrie, and David W Austin. 2011. “Ancestry of pink disease (infantile acrodynia) identified as a risk factor for autism spectrum disorders.” Journal of toxicology and environmental health. Part A 74(18):1185-94.
PMID : 21797771 

Tuesday, August 9, 2011

Revisiting the Flawed 1% Estimate of Adult Autism in the UK

If you remember, a survey results that was first published in 2009 and again in 2010 found that an estimated 1% of the adult population in the UK had some form of autism.  This result was a big deal at the time because it was one of the first results that demonstrated that autism is as common in adults as it is in children.

Unfortunately, it is now very likely that this result is also wrong.  A new study was quietly published this month  that seems to blow the earlier result out of the water.  The problem is something of a technical one but, to put it simply, it turns out that the screening test used in the survey, a modified version of the autism quotient called the AQ-20, is a very poor test for autism.

The basic idea of surveys like this is to give a quick and easy screening test to a large population to identify the people most likely to have a condition.  You then pick a sample out of the screened population and give them a more comprehensive evaluation to determine how many of them actually have the condition.  You can then use that number to estimate how many people would have been found to have the condition if you had evaluated them all.

The survey in the UK did just this - it used the AQ-20 to screen the population and then picked a subset of the population and gave them the ADOS.  It found that out of the an approximate 618 people evaluated using the ADOS that 19 of them had a form of autism.  That 19 was then extrapolated back into the entire population using the AQ-20 score to arrive at the the estimate that there would have 72 total cases of autism found, or about 1% of the population.

This final step is the problem as it turns out that the AQ-20 has two glaring flaws -

First, it is a very poor screen for autism, at least in this population.  The sensitivity was found to be 0.73 and the specificity was 0.62.  That means that it would miss almost 1 in 3 people who had autism while saying that almost 40% of the people who didn't have autism did.

Second, and much more importantly, the actual AQ scores are not a good predictor of whether a person had autism or not.  In the words of the authors in the latest validation study -
The AQ-20 self-report screening questionnaire score was found to have a low correlation (0.24 ; p<;0.0001) with the continuous ADOS-4 total score and unsatisfactory sensitivity and specificity with the ADOS 10+ threshold. It was not possible to predict confidently which of the phase 1 respondents with AQ-20 scores of >= 5 had ASD unless they had been assessed on the ADOS-4 in phase 2.
Pay very close attention to that last sentence - having an AQ-20 score of greater than five could not be used to accurately predict which of the people had autism.  Yet that is exactly what the original survey did to arrive at the 1% estimate.

I think it is safe to say that it is likely that the one percent estimate is wrong.

Thursday, August 4, 2011

Neurodiversity Loses a Follower

It is always a good day when the neurodiversity movement loses a follower -
By choosing to have the neurodiversity symposium encompass and showcase facilitated communication, the key promoters of the construct are signalling their support for a debunked communication form and actively supporting its continued use. And they are obviously, openly anti-cure. Based on the language here, one could argue that if an autistic individual happens to communicate by smearing feces, that this should be celebrated. I hope that's not what they mean.
Perhaps there's a failure to think through here on their part, but regardless, it seems to be an extreme position that I can not, after having worked  for two decades with my son to help him overcome obstacles, to learn to communicate, to function in the wider world, support. I have not sought to make him neurotypical, but I have worked to help him function better, to master new skills, to become more autonomous (the same as I've done for my daughters). Imagine if I'd chosen to celebrate his (and their) autistic forms of communication and self-expression involving feces instead. 
Since I have been somewhat critical of Kim Wombles in the past, I though I should take this opportunity to point out when she gets something right.  As I have been saying for years now, the neurodiversity movement is not a good thing for the majority of people with autism because it ignores the needs of those who are disabled by their autism and creates unrealistic ideas of what it means to have autism.

Don't get me wrong, the basic idea of neurodiversity isn't a bad one.  Every person - disabled or otherwise - is entitled to be treated with respect and dignity, and you should respect a person's right to be different.  But like other grand philosophical systems (i.e. socialism), there is a disconnect between the lofty ideal and what it looks like in practice.

In practice, neurodiversity starts out with a respect for the individual and acceptance of their differences, but quickly degrades into an anti-cure, anti-treatment movement that attacks people who are trying to help their loved ones.

Acceptance is a wonderful thing, but no amount of acceptance is going to give my children the ability to function on their own.  Acceptance can't teach them how to talk or socialize.  Nor will any amount of acceptance give them the ability to take care of themselves or live independently when they are older.

In practice, neurodiversity is a movement that ignores the fact that most people with autism are actually disabled by their autism.  It is a movement that ignores the major challenges that autism creates and instead focuses almost exclusively on the "autistic quirks" of extremely high functioning.

There is a fundamental difference between the "quirks" of someone who doesn't like velvet but can function well enough to serve on the IACC and a child that can't talk, can't socialize, and is almost incapacitated by their rigidities.  The neurodiversity made up of the former but pretends to speak for the needs of the latter while at the same time ignoring their very real needs.

So, I am happy to see that the neurodiversity movement has lost a follower.  Good job Kim.

Monday, August 1, 2011

Study : Lack of association between autism and four heavy metal regulatory genes

This study revisits the older idea that children with autism have an altered mercury (Hg) metabolism that makes them susceptible to even "safe" levels of Hg.  It did this by looking for an association between autism and mutations in four genes involved in Hg metabolism.

Not surprisingly, the study found no association.  I wouldn't make too much out of this result though, as interesting as it is.

For one thing, other larger genetic studies have taught us that most mutations and copy number variations that have a relation to autism only appear in a very small number of cases, typically less than one percent.  If that were the case here then the current study might not have included enough participants to find the association.

Another potential problem is that there is a difference between a genetic susceptibility and what the actual biological pathway is doing.  If you wanted to test the altered metabolism theory then the best way of doing so would be to devise some direct test of the metabolism.  Although I suspect that might be easier said than done.

In general, I think these sorts of genetic association studies are going to be useless until we come up with a way to separate out the different forms of autism.  Right now we are taking everyone with a label of "autism" and looking at them as a group and finding nothing.

That would be like taking anyone with any form of cancer and looking at them as a single group.  You wouldn't get any useful relationships that way either.  It is only when you separate out the different types and look at then individually that you get very useful results.

Lack of association between autism and four heavy metal regulatory genes.
Neurotoxicology. 2011 Jul 20.
Owens SE, Summar ML, Ryckman KK, Haines JL, Reiss S, Summar SR, Aschner M.
Department of Pediatric Toxicology, Vanderbilt University School of Medicine, Nashville, TN, USA.

Autism is a common neurodevelopmental disorder with genetic and environmental components. Though unproven, genetic susceptibility to high mercury (Hg) body burden has been suggested as an autism risk factor in a subset of children. We hypothesized that exposure to "safe" Hg levels could be implicated in the etiology of autism if genetic susceptibility altered Hg's metabolism or intracellular compartmentalization. Genetic sequences of four genes implicated in the transport and response to Hg were screened for variation and association with autism. LAT1 and DMT1 function in Hg transport, and Hg exposure induces MTF1 and MT1a. We identified and characterized 74 variants in MT1a, DMT1, LAT1 and MTF1. Polymorphisms identified through screening 48 unrelated individuals from the general and autistic populations were evaluated for differences in allele frequencies using Fisher's exact test. Three variants with suggestive p-values <0.1 and four variants with significant p-values <0.05 were followed-up with TaqMan genotyping in a larger cohort of 204 patients and 323 control samples. The pedigree disequilibrium test was used to examine linkage and association. Analysis failed to show association with autism for any variant evaluated in both the initial screening set and the expanded cohort, suggesting that variations in the ability of the four genes studied to process and transport Hg may not play a significant role in the etiology of autism.

PMID: 21798283