Thursday, March 02, 2006

CDDS Data 101

Recently there have been many reports indicating that the number of autism cases is dropping [ref]. I will show that this conclusion results from a haphazard interpretation of the data and misleading terminology.

I will base this simple non-technical analysis on the California DDS (CDDS) data, readily available online. The reader is encouraged to download the data and verify my claims. The numbers are quite clear and you don't need to be a mathematician to interpret them.

Caveat: The CDDS does not recommend using this data to determine prevalence trends, but I will use it to point out flaws in interpretations that have used this data for such a purpose in the past.

Let's agree on some terminology first:

Number of autistic clients.- This is the number of persons with a diagnosis of autism in the CDDS system in any given quarter. It could be taken as a very rough indication of the autistic population in the state of California below the age of 18. [Errata: The CDDS does keep clients older than 18, so this could be taken as a reflection of the autistic population in the state].

Rate of increase.- This is obtained by subtracting the number of autistic clients in one quarter minus the number of autistic clients in the previous quarter. This is equivalent to the number of autistic clients who enter the CDDS system minus the number of autistic clients who leave the CDDS system in any given quarter. (I also sometimes refer to the annual rate of increase).

New cases.- This is the number of autistic clients who enter the CDDS system in any given quarter. Note that the CDDS does not provide data on new cases as defined here. The term "new cases" has often been used to describe "rate of increase" (defined above) and this is where much of the confusion stems from.

So has there been a drop in cases of autism based on CDDS data? Let's see. There were 28,724 autistic clients in Sep. 2005 and 29,424 autistic clients in Dec. 2005. Does it look like a drop? There were even less a year before (Dec. 2004): 26,576. That is, in the last year, the autistic population in the CDDS has increased by 2,848. This is an increase of 10.72%.

Is 10.72% a big increase in the autistic population? Absolutely. Annual population growth in the state of California is roughly 1%. Any growth in number of clients above that level is indicative of an increase in prevalence.

Don't buy that? Let's see if it works with epilepsy. There were 37,301 clients with epilepsy in Dec. 2005, and 37,076 clients with epilepsy in Dec. 2004. That's a rate of increase of 225 clients, or 0.6%. This is even somewhat lower than annual population growth. (BTW, a true increase in autism prevalence would be expected to be matched by an increase in the prevalence of epilepsy).

Can the rate of increase remain at 10.72% indefinitely? This is impossible. If it did, the autistic population would double every 7 years and would reach 20 million (the total population of the state) in about a century and a half. This rate needs to go down to about 1% eventually, and there are indications that it is already starting to go down. It will be obvious when it reaches this level, as you will hear many reports to the effect that autism prevalence has finally leveled off.

So what do people mean when they say that the number of new cases is dropping? What they mean is precisely this: The rate of increase is dropping, which is totally unremarkable as explained above. The problem is that they say "new cases" instead of "rate of increase" and this is completely misleading. But don't take my word for it. Go and check the data against this common claim: "The number of new cases of professionally diagnosed full syndrome DSM IV autism entering California's developmental services system declined from 734 new cases during the second quarter of 2005 (April through June) to 678 new cases during the just completed third quarter of 2005 (July through September), a 7 1/2% decline in one quarter" [ref].

Predictions of Thimerosal Theory

Some proponents of the Thimerosal Theory of Autism maintain that autism did not exist before the 1930s. If their theory is correct, when thimerosal is completely removed from vaccines the quarterly rate of increase should become negative immediately. And in about 18 years, the number of autistic clients in the CDDS should become zero. [Errata: Only the number of autistic minors in the system should become zero after that time. A quicker prediction is that the number of autistic clients in the 3-5 age range should become zero within 4 years of thimerosal removal. It is clear this is not happening.].

Even those who are not so forceful about this theory do maintain that the "autism epidemic" is largely attributable to Thimerosal. Still, the quarterly rate of increase should become negative, and the number of autistic clients in the CDDS should drop to early 90s or 80s levels in about 18 years.

Predictions of the Broader Criteria Theory

This theory says that our conception of what autism is has been broadening and that parent and pediatrician awareness about autism is increasing. Awareness and criteria will have to stop broadening at some point, since clearly not everyone is autistic. So according to this theory, the quarterly rate of increase should gradually drop until it matches population growth in the state of California. And the number of autistic clients should remain at high levels but only grow slowly.

Based on the trend I can see on graphs now, I would predict the autistic population in California will level off in about 2016.

Evidence in favor of the Broader Criteria Theory

In the movie Rain Man (1988), Raymond Bobbit is referred to as "high functioning" a couple times. Today, it's common for Rain Man to be referred to as a "relatively severe case". It is clear that our conception of what autism is has changed.

If a movie doesn't do it for you, consider twin studies. In twin studies, it's obvious that higher concordance will be found the broader the definition of autism is. (That is, the more identical you expect twins to be, the less concordance you will report). In the first twin study on autism by Folstein-Rutter (1977), concordance for autism was found to be 36% for identical twins (0% for fraternal). But they also found that concordance for "cognitive disorder" was 82% in identical twins (10% for fraternal). Now consider that at least 3 modern studies have found a "classic autism" concordance of 60%-95.7% for identical twins. This is fairly good evidence that researchers' conceptions of what autism is have broadened - never mind parent and pediatrician awareness.

Isn't it also remarkable that as the dosage of thimerosal has increased, autism has become more and more heritable?

Further evidence can be found in the California data itself. As I noted, the rate of increase in epilepsy is 0.6% whereas the current rate of increase in autism is 10.7%. It is known that a certain portion of autistics suffer from epilepsy. (Epilepsy is also a favorite of the Thimerosal camp when they argue that autism is pathological). So if there is a real increase in the prevalence of autism, you would expect to see a matching increase in the prevalence of epilepsy.

The CDDS does provide data on autistics with epilepsy. There were 1,886 in Dec. 2004 and 1,979 in Dec. 2005. This is an increase of 93 clients, or 4.9% in the last year. This is a lot lower than the 10.7% rate of increase for autism. (Why isn't it around 1%? Probably because more and more clients with epilepsy are recognized as also being autistic).

The number of autistic clients with no mental retardation was 16,448 in Dec. 2004, and 18,708 in Dec. 2005. So the annual rate of increase of autistics with no MR is 2260 or 13.74%. This is considerably higher than the 10.7% annual rate of increase for all autistic clients.

So there you have it. More and more autistics are not mentally retarded (presumably based on IQ testing - which incidentally is likely flawed). And less and less autistics suffer from a co-morbidity of epilepsy. Need more evidence?

The regional data is also interesting. We would expect to find that in places of high prevalence, awareness and broadening criteria is leveling off more quickly than in the state as a whole. The Westside regional center appears to be a place of high prevalence (over 30% of all clients are autistic). You will find that the annual rate of increase is about 8.3% there, lower than the 10.7% for the state. In contrast, some places (not all) where prevalence hasn't caught up should have a higher rate of increase. You will find that the Inland regional center, for example, has an annual rate of increase of 15.17%, much higher than the 10.7%. It's as if Inland is catching up to Westside - like going back in time. (Professional's conceptions of autism will probably always differ a little from region to region, however).

In conclusion, it's not correct to say that we just don't know whether thimerosal causes autism. The truth is that the weight of the evidence is overwhelmingly on the side of the broadening criteria theory.

Summary


  • The "new cases" terminology is misleading, as it assumes that the rate of increase in the number of clients is the same as the number of clients who enter the system.
  • Current annual increase in the number of autistic clients in the CDDS is 10.7%, which is much higher than population growth in the state of California.
  • The Broadening Criteria theory predicts that the rate of increase should drop gradually to around 1%.
  • The Thimerosal theory predicts that the rate of increase should become negative, and the number of autistic clients drop every quarter until it becomes zero (or at least very low).
  • The data is overwhelmingly in favor of the Broadening Criteria theory.

36 comments:

  1. Excellent analyses. Thank you for this.

    ReplyDelete
  2. That was good. What do you make of the Geiers latest offering in the Journal of American Physicians and Surgeons Volume 11 Number 1 Spring 2006 claiming that autism rates have slumped since the remaoval of thimerosal from vaccines?

    ReplyDelete
  3. Hi Joseph,

    I might challenge a couple technical points, but very well said and analyzed all the same.

    -Jonathan Semetko

    ReplyDelete
  4. I like this analysis. I particularly like your comments about how one would expect a negative rate of increase if thimerosal was largely responsible for autism.

    I'd like to add one more comment. I don't think it's just by chance that Rick Rollens and Dan Olmsted want to discuss the "new cases of professionally diagnosed full syndrome autism". Their main audience is parents of autistic children. We all know that children are usually diagnosed before age 6, so that means that we automatically assume these new cases are all in the young age range. But, any examination of the data shows that is not true. So Rollens et al are deliberately misleading these parents.

    I hope you've also seen the Interverbal analysis of the data:

    here

    and

    here

    ReplyDelete
  5. I found a letter that Autism Diva got a while ago from DDS which makes a point as to why it's important to distinguish "new cases" from "increase in number of clients":


    Dear (Autism Diva):

    Although the source of information for many reports on autism for California is the Department of Developmental Services (DDS)' "Quarterly Client Characteristics Report", the numbers reported by DDS are often misunderstood and misrepresented by others. Except for Table 2 of the Report, only persons with a Client Development Evaluation Report (CDER) on file who have "active" status in the DDS system are counted in the report tables. So, numbers reported do not represent all persons with developmental disabilities in the State of California. The numbers can not be used to report the incidence of autism, for example. Also, the quarterly report represents the number of persons with various characteristics in the DDS system as of a point in time.


    That's the nail in the coffin of the "new cases" terminology.

    ReplyDelete
  6. What do you make of the Geiers latest offering in the Journal of American Physicians and Surgeons Volume 11 Number 1 Spring 2006 claiming that autism rates have slumped since the remaoval of thimerosal from vaccines?

    That suffers from exactly the same flaw, except the Geirs use "newly diagnosed NDs". Replace that with the right terminology: "Increase in clients with ND".

    I don't think they do it out of malice. It's a common error that comes from the assumption that once someone is a client, they are reported as a client forever, even after they die, move out of the state, grow older or move out of a diagnosis. (The report, as clearly noted in the letter from the DDS to Autism Diva, only shows clients with an active status).

    But the peer review process that approved that paper leaves much to be desired. Any decent journal would retract such a paper once they realize a clear error like this.

    ReplyDelete
  7. So Rollens et al are deliberately misleading these parents.

    Maybe, but it's more likely they just don't understand the problem with the terminology.

    ReplyDelete
  8. This is very good. One small correction. The California DDS provided services for adults up to old age, so that if all thimerosal were removed (from nasal sprays and contact lens cleaners, too, according to some) then in 18 years there should be no more minor autistics, but there would be lots of adults... according to their logic.

    Your point about Rain Man being described as "high functioning" was great.

    Already there should be next to no autistic 2 year olds in California, but there are enough for the MIND insititute to plan a study of some hundred or more of them, and those would just be in the Sacramento area. They aren't expecting that there will be any fewer 2 year olds with autism now than there were 5 years ago, but there should be next to none if thimerosal were the cause of the "autism epidemic" in California.

    Rick Rollens is a major creep. There's no particular reason to think that he's not lying through his teeth, given his personality and track record.

    ReplyDelete
  9. Even better confirmation comes from a DDS document itself: Data Interpretation Considerations and Limitations. It says:

    Differences in the numbers from quarter to quarter reflect the net changes between individuals who are newly reported and those who dropped out.

    Ok, this is the final nail. If this isn't enough to retract the Greirs paper, I don't know what will.

    ReplyDelete
  10. This is very good. One small correction. The California DDS provided services for adults up to old age, so that if all thimerosal were removed (from nasal sprays and contact lens cleaners, too, according to some) then in 18 years there should be no more minor autistics, but there would be lots of adults... according to their logic.

    True. I wasn't sure if they kept people over 18. They certainly only admit people 18 or under (or diagnosed before 18). The analysis still holds. The number of clients would drop to zero in 60 years or something, but after 18 years it would be minimal.

    ReplyDelete
  11. Great analysis Joseph - just for completeness, I'd like to add blogger Citizen Cain's set of posts on the subject starting in July of last year:

    The original post.
    David Kirby's response.
    Citizen Cain's rebuttal.
    Kirby's next response.

    ReplyDelete

  12. The original post.
    David Kirby's response.
    Citizen Cain's rebuttal.
    Kirby's next response.


    Those are good, and Citizen Cain addresses the most important point: "new cases" is a misleading terminology.

    The analysis of the 3-5 y/olds is notable now that I see it. It doesn't matter if there's a decrease in the rate of increase in that range. But if the total caseload in that rage is not declining at all, the removal of thimerosal is not having any effect whatsoever, unless you believe that the dosage received 1-3 years ago is the same as usual.

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  13. Hi Joseph
    Recently in Kev´s blog you propose a very interesting line -for me- of orientation of the exchange of ideas. I added my personal ideas after the prompts from you.

    Explain to me what thimerosal has to do with autism, and refute the arguments which show (1) that the cognitive and neuroanatomical characteristics of autism can’t possibly be caused by thimerosal;

    Not conclussive and confounding published evidence for HM poisoning as comorbility. Terms of causation seem not adequate, but comorbility seems more adequate, following published clues.

    (2) that the genetic profile of autism can’t possibly be related to thimerosal;

    Not enough studied to have a conclussion. Some clues available.

    (3) that prevalence trends of autism and other NDs can’t possibly be consistent with the thimerosal theory;

    Not conclussive and confounding published evidence in terms of comorbility more than causation

    (4) that many symptoms of mercury poisoning are not characteristic of autism, and many symptoms of autism are not characteristic of mercury poisoning.

    Not enough studied in terms of confounding variables to have a conclussion.

    If you are interested in a further analysis considering the published literature and why I think the way I do you can contact me by e-mail.If you are not, sorry if I disturbed you.

    María Luján

    ReplyDelete
  14. María,

    I see you've made it here. NVM my post at notautism. I prefer to keep the discussion in blogs.

    On (1) I assume you mean that neuroanatomical and cognitive differences are not conclussive. Certainly I understand autism is very heterogeneous and we can't really make generalizations. But if you compare autistics and NTs as groups, you will find distinct differences in average and this is undeniable. Recent research by Mottron-Dawson is remarkable. How does an environmental theory explain a expanding gap in the Raven vs. Wechsler IQ tests the "more autistic" the person is?

    On (2) it's quite clear a single allele cannot account for autism. You need 3 or 4. Some estimate up to 15. Thimerosal theory expects us to believe that there need to be 3 or 4 alleles that interact with each other in order to produce a single mercury excretion liability. As far fetched as this is, the impossibility of this becomes clearer once you examine alleles that have been linked to autism: The SERT gene (causes hyperserotonemia), GABA genes (neurotransmitter inhibition, savant skills), Engrailed 2 (cerebellar development), REELIN (memory formation), PRKCB1, etc.

    On (3) I'd like a rebuttal on the points of this blog posting.

    On (4) I could give you two relevant examples: Kidney damage in mercury poisoning, and savant skills in autism.

    I think the case against it is quite conclussive.

    ReplyDelete
  15. Hi Joseph,
    I think your analysis is very good. I do indeed believe there is a broader criteria, however I am not sure that can attribute entirely for the increase in autsim numbers (of course, this is based on observation, not a report and I'm not going put my money on it, I just think there are several factors). What I find interesting is the Regional differences. I happen to have experience dealing with several different regional centers and can say that they all handle things differently...also each RC seems to have it's own criteria for diagnosing "autism". In addition, many parents need to wait between 3 to 6 months to get assessed by the RC due to availability of psychologists, so I can see that bandwidth for assesments may play a factor in DDS's number's. I'm just curious as to weather or not you have experience dealing with the Regional Center's in California?

    ReplyDelete
  16. Hi Joseph
    I will try to answer you point by point in different posts
    You said
    On (1) I assume you mean that neuroanatomical and cognitive differences are not conclussive. Certainly I understand autism is very heterogeneous and we can't really make generalizations. But if you compare autistics and NTs as groups, you will find distinct differences in average and this is undeniable.

    I posted before

    Not conclussive and confounding published evidence for HM poisoning as comorbility. Terms of causation seem not adequate, but comorbility seems more adequate, following published clues. Therefore, this does not exclude what you mentioned. Being different from birth, I will expect differences with NT in brain structure and many other functions.

    You can not know for sure what is from Genetics and what is adquired when you test- For example, beyond genetics and how affects the Purkinje cells and minicolumns structure (points that have been known and many researchers and Mrs Clark commented) there are many physical conditions that can be adquired
    A)Lessions in hypocampus and cerebellum. There are some published evidence about postnatal insult and affectation of Purkinje cells
    Postnatal insult Purkinje cells
    1-http://www.medscape.com/medline/abstract/12907269
    Brain Dev. 2003; 25(6):377-82 (ISSN: 0387-7604)
    Kern JK
    2-Also gluten ataxia
    Neurology. 2003 Apr 22;60(8):1397; author reply 1397-9.
    The humoral response in the pathogenesis of gluten ataxia.
    Hadjivassiliou M, Boscolo S, Davies-Jones GA, Grunewald RA, Not T, Sanders DS, Simpson JE, Tongiorgi E, Williamson CA, Woodroofe NM.
    CONCLUSIONS: Patients with gluten ataxia have antibodies against Purkinje cells. Antigliadin antibodies cross-react with epitopes on Purkinje cells.
    3- Neurosci Lett. 2006 Mar 27;396(2):91-6.
    Emergence of endoplasmic reticulum stress and activated microglia in Purkinje cell degeneration mice.
    Kyuhou SI, Kato N, Gemba H.
    4- J Neurosci. 2000 Feb 1;20(3):992-1000.
    Target-related and intrinsic neuronal death in Lurcher mutant mice are both mediated by caspase-3 activation.
    Selimi F, Doughty M, Delhaye-Bouchaud N, Mariani J.
    5-It seems that Purkinje cells are affected by caspase 3-actiuvation postanatally and also by gluten ataxia
    http://www.neurology.org/cgi/content/abstract/58/8/1221
    6-Gluten sensitivity as a neurological illness
    http://jnnp.bmjjournals.com/cgi/content/full/72/5/560
    7-Anti-ganglioside antibodies in idiopathic and hereditary cerebellar degeneration
    Full text: http://www.neurology.org/cgi/content/full/60/10/1672

    Shill HA, Alaedini A, Latov N, Hallett M. Human Motor Control Section, Medical

    Well, it seems that conditions that induces caspase-3 and there is some evidence that antibodies related to celiac disease present cerebellar degeneration, including celiac disease but also gluten ataxia and other conditions related to allergies to gluten.

    B)-Recent research by Mottron-Dawson is remarkable. How does an environmental theory explain a expanding gap in the Raven vs. Wechsler IQ tests the "more autistic" the person is?

    I contacted Dr Mottron and he sent me 16 papers from his work I found very interesting. I wonder how the visual perception and the lateral view of things and avoiding of faces is related to these nutritional imbalances, beyond the brain structural differences between NT and autistic children that following recent and previous findings are real since birth. I do not exclude an interaction of genetics with environment to produce a worsening of things. I think we can not reduce to an OR explanation but to an AND explanation. Genetics AND environment (AND ALSO epigenetics)
    1-J Autism Dev Disord. 2006 Feb 2;:1-12 [Epub ahead of print]
    Subjective Perceptual Distortions and Visual Dysfunction in Children with Autism.
    Davis RA, Bockbrader MA, Murphy RR, Hetrick WP, O'donnell BF.
    2-Neuron. 2005 Nov 3;48(3):497-507.
    Vagaries of visual perception in autism.
    Dakin S, Frith U.
    3-Neuroimage. 2005 Aug 1;27(1):247-52. Epub 2005 Apr 21
    Taking an "intentional stance" on eye-gaze shifts: a functional neuroimaging study of social perception in children.
    Mosconi MW, Mack PB, McCarthy G, Pelphrey KA.
    4-Neuropsychologia. 2005;43(7):1044-53. Epub 2004 Dec 8
    Abnormal global processing along the dorsal visual pathway in autism: a possible mechanism for weak visuospatial coherence?
    Pellicano E, Gibson L, Maybery M, Durkin K, Badcock DR.
    5-Med Sci (Paris). 2005 Feb;21(2):216-21.
    Omega-3 fatty acids in psychiatry
    Bourre JM.
    6-Neuroreport. 2004 Feb 9;15(2):267-70.
    Early visual cortex organization in autism: an fMRI study.
    Hadjikhani N, Chabris CF, Joseph RM, Clark J, McGrath L, Aharon I, Feczko E, Tager-Flusberg H, Harris GJ.
    7- Neuropsychologia. 2002;40(12):2039-49
    Deficits in the initiation of eye movements in the absence of a visual target in adolescents with high functioning autism.
    Goldberg MC, Lasker AG, Zee DS, Garth E, Tien A, Landa RJ.
    8-J Fr Ophtalmol. 1997;20(2):103-10
    Opthalmologic signs in children with autism]
    Denis D, Burillon C, Livet MO, Burguiere O.
    9-J Neuroophthalmol. 1996 Sep;16(3):185-7. Related Articles, Links
    Neuro-ophthalmologic findings in the Asperger disorder.
    Brodsky MC, Barber LG, Lam BL, Merin LM, Edelson S.
    10-Neuroreport. 1995 May 30;6(8):1211-4.
    Postural effects of motion vision in young autistic children.
    Gepner B, Mestre D, Masson G, de Schonen S.
    11-J Autism Dev Disord. 1993 Mar;23(1):1-13. Related Articles, Links
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    Wainwright-Sharp JA, Bryson SE.
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    Rincover A, Ducharme JM.
    13-JPEN J Parenter Enteral Nutr. 1993 May-Jun;17(3):284-6. Related Articles, Links
    Symptomatic vitamin A and D deficiencies in an eight-year-old with autism.
    Clark JH, Rhoden DK, Turner DS.

    I wonder
    1- What is the role of the deficiency of vitamin A in the adaptative enhanced perception found in children with ASD?
    2-What is the role of second messengers signaling in the processing of visual images- and protein G and rhodepsin function?
    3- Have markers of physiology of vision measured? In other words, more than the eye structure, the functionality of eyes has been tested?
    Obviously I am not criticizing their findings, only wondering what confounding physical conditions can be related to adquired conditions (gluten sensivity, visual impairments based on malabsorption, etc).
    MAría Luján

    ReplyDelete
  17. You say

    On (2) it's quite clear a single allele cannot account for autism. You need 3 or 4. Some estimate up to 15. Thimerosal theory expects us to believe that there need to be 3 or 4 alleles that interact with each other in order to produce a single mercury excretion liability. As far fetched as this is, the impossibility of this becomes clearer once you examine alleles that have been linked to autism: The SERT gene (causes hyperserotonemia), GABA genes (neurotransmitter inhibition, savant skills), Engrailed 2 (cerebellar development), REELIN (memory formation), PRKCB1, etc.


    Some additional evidence, beyond the common genes related to ASD
    1-http://www.cmaj.ca/cgi/reprint/174/3/341

    [....]some preliminary evidence supports a
    model that incorporates both genetic and epigenetic contributions
    in the causation of autism.102 Autism has been linked
    to the region on chromosome 15 that is responsible for
    Prader–Willi syndrome and Angelman syndrome. Findings at
    autopsy of brain tissue from patients with autism have revealed
    deficiency in MECP2 expression that appears to account
    for reduced expression of several relevant genes.103
    These results suggest that MECP2 deficiency plays a role in
    chromosome organization in the developing brain in autism,
    Rett syndrome and several other neurodevelopmental disorders

    2-Toxicol Lett. 2006 Feb 20;161(2):159-66. Epub 2005 Oct 7.
    A cascade analysis of the interaction of mercury and coproporphyrinogen oxidase (CPOX) polymorphism on the heme biosynthetic pathway and porphyrin production.

    Heyer NJ, Bittner AC Jr, Echeverria D, Woods JS.

    3-Toxicol Appl Pharmacol. 2005 Aug 7;206(2):113-20.
    The association between genetic polymorphisms of coproporphyrinogen oxidase and an atypical porphyrinogenic response to mercury exposure in humans.
    Woods JS, Echeverria D, Heyer NJ, Simmonds PL, Wilkerson J, Farin FM.
    http://toxsci.oxfordjournals.org/cgi/content/full/81/2/354

    4-Biol Psychiatry. 2005 Sep 19; [Epub ahead of print]
    Brain-Derived Neurotrophic Factor and Autoantibodies to Neural Antigens in Sera of Children with Autistic Spectrum Disorders, Landau-Kleffner Syndrome, and Epilepsy.
    Connolly AM, Chez M, Streif EM, Keeling RM, Golumbek PT, Kwon JM, Riviello JJ, Robinson RG, Neuman RJ, Deuel RM.

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    Nelson PG, Kuddo T, Song EY, Dambrosia JM, Kohler S, Satyanarayana G, Vandunk C, Grether JK, Nelson KB.

    6-J Neurosci. 2004 May 5;24(18):4401-11.
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    Chen ZY, Patel PD, Sant G, Meng CX, Teng KK, Hempstead BL, Lee FS.

    7-Neuron. 2003 Aug 28;39(5):735-8.
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    Lu B.

    8-Cell. 2003 Jan 24;112(2):257-69
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    9-J Biol Chem. 2002 Oct 25;277(43):40901-10. Epub 2002 Jul 18.
    Brain-derived neurotrophic factor regulates surface expression of alpha-amino-3-hydroxy-5-methyl-4-isoxazoleproprionic acid receptors by enhancing the N-ethylmaleimide-sensitive factor/GluR2 interaction in developing neocortical neurons.
    Narisawa-Saito M, Iwakura Y, Kawamura M, Araki K, Kozaki S, Takei N, Nawa H.

    10-Nature. 2001 May 3;411(6833):86-9.
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    Guillin O, Diaz J, Carroll P, Griffon N, Schwartz JC, Sokoloff P.

    11-Brain Res. 2000 Feb 28;857(1-2):141-50.
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    Itami C, Mizuno K, Kohno T, Nakamura S.

    12-Ann Neurol. 2003 Jun;53(6):801-4.
    Mitochondrial dysfunction in autistic patients with 15q inverted duplication.
    Filipek PA, Juranek J, Smith M, Mays LZ, Ramos ER, Bocian M, Masser-Frye D, Laulhere TM, Modahl C, Spence MA, Gargus JJ.

    13-J Child Neurol. 2004 Jun;19(6):413-7.
    Polymorphisms in xenobiotic metabolism genes and autism.
    Serajee FJ, Nabi R, Zhong H, Huq M.

    Department of Pediatrics, Wayne State University, Detroit, MI, USA.

    Autism is a neurodevelopmental syndrome defined by deficits in social reciprocity and communication and by unusual repetitive behaviors. Although there is an underlying genetic predisposition, the etiology of autism is currently unknown. A recent increase in prevalence suggests that genetically determined vulnerability to environmental exposure might contribute to the causation of autism. We performed family-based association studies of polymorphisms in metal-regulatory transcription factor 1(MTF1), a multispecific organic anion transporter (ABCC1), proton-coupled divalent metal ion transporters (SLC11A3 and SLC11A2), paraoxonase 1 (PON1), and glutathione S-transferase (GSTP1) genes in 196 autistic disorder families. There was deviation from the expected pattern of transmission for polymorphisms in MTF1 (Single nucleotide polymorphism database reference identification number, dbSNP rs3790625, P = .02) and divalent metal ion transporter SLC11A3 (dbSNP rs2304704, P = .07) genes. Although these results might represent chance finding, further investigations of genetic variations of metal metabolism in autism are warranted.
    You can see here

    http://www.kevinleitch.co.uk/forum/viewforum.php?id=18
    more about the topic

    ReplyDelete
  18. On (3) I'd like a rebuttal on the points of this blog posting.

    As I comment to you, I prefer the word comment, not rebuttal. My intention is not convince you or anybody of nothing, but to learn about the situation.

    I do think that there is an increase of ASD of multicausal in nature, but I am pretty clear that it is very difficult (IF IT IS, because I can be wrong) to prove it because there are many things involved in the reported increase using educational data. For me one thing is the true number of ASD, other the diagnosed ones and different these two numbers from reported from educational data , that can be different from statistical ones. So, it is really a mess when you want to analyze these data. However, I think your analysis is interesting.
    I have some questions about for example
    What is the incidence of home-schooled children with ASD that are not under any educational data, reported?
    What is the incidence of home schooled children WITH A DIAGNOSIS of ASD, but no treatment?
    What is the incidence of home schooled children with a diagnosis of ASD and under treatment- so perhaps they are counted?
    What is the incidence of home-schooled children without a Diagnosis of ASD- so mild forms that can be confused with language delay or other such as mental retardation?
    What is the incidence of this in terms of parental resources? As you know, in EEUU you need 250 to 400 dollars to get ONE appointment with a doctor. So I wonder how many children do not have a diagnosis because the parents can not pay for a consult, because they have not Medicare or another health system What is the change from state to state of all these? Mrs Clark posted a comment of a manuscript about.
    So I wonder how many children is the statistics/educational/other sources missing because of SOCIAL problems and this kind of situations?
    I only want to point that this kind of situation is important to get into consideration. Perhaps you have some additional information about you can share so I can complete the view.
    I reach then my final question
    What is the impact in these numbers , even of the considered as the basis for epidemiology of
    2-Population movement and increase of global populations
    3-Changes in the assignation of services or in the procedures to get services
    4-Changes in the vaccination schedule, introduction of new variants of the same vaccine or a new one , such as Prevnar?
    What about compensatory effects?

    I do think that from one
    state to another- and mainly from one country to another-, there must be changes because of the different genetic pool, different environmental insult, different management of the antibiotics, different medical approach to childhood infections, different food quality, air quality, water quality. What if we have also a compensatory effect for example no HepB at birth but more potent antibiotics or a strain of DPT vaccine more strong?
    How can all these issues , without considering the mother implication in the child health ( environmental insult during pregnancy), only since birth, affect the epidemiological and educational data? A LOT for me so my conclussion is that

    I can´t assure if we have or not an epidemics of ASD. I wonder who can´assure if we have or not with the quality of the information available? Epidemiological studies also rest on diagnosis, with the same problems than above.
    The reported values of this 2005 year for the educational data can be meaningless because we do not know all the other issues that can be collaborating in the decrease, that can be apparent or in the increase, that we can not assign for sure quantitatively to different components. I think that the increase of the last years can have a TRUE component of increase of the numbers of children with autism but it is very difficult to prove this and to separate it from inflation to get services, changes in diagnosis, population changes or unknown effects..
    Probably the remotion of thimerosal was benefitial but I wonder if compensatory effect would not mask a true effect. I do not think that the decrease will be so big and your theory surely can be part of the explanation. What about ALL the other things we have been discussing (other preservants, viruses and toxids in vaccines, antibiotics in vaccines , Hep B vaccine , etc etc etc ).

    NOBODY has analyzed the possibility of a subgroup of the population under risk because of different genetics than “neurotypical” fron birth. Nobody has addressed the changes autistic children potentially have after environmental insult FOR THEM (vaccines, infections, antibiotics,exposure to chemicals) at a big population level because there are no biomarkers at birth to test.

    How we can know the effect on ASD children of vaccines if there are no data about them of a biomarker at birth?

    Sorry by the long posts
    I will be glad to hear (read :) ) your comments.
    María Luján

    ReplyDelete
  19. You say
    Kidney damage in mercury poisoning, and savant skills in autism.

    There are reports of kidney damage in certain autistic patients that can be related to a detectable genetic problem (such as tuberous sclerosis) or another source.
    Why can not we think in the combination of genetics plus oversensibility to for example heavy metals and air contamination, that can be different in an individual basis so one or the other- or both- can be present?
    I wonder, how many of autistic children are tested adequately for heavy metals when they have kidney damage? How many are carefully tested for kidney damage if it is minor/subclinic?
    Savant skills for me are related to genetics. ASD people is supposed to have from birth more glutamate receptors and some conditions have higher incidence of savant skills –Prader Willi.
    For me, kidney damage can be or not be present in autism as a combination of environmental insults, whereas intellingence would be more related to genetics and brain structure.
    Under the proposal of a combination of factors, this is not incompatible, because of the importance of the individual presentation.
    About kidney damage

    1-Eur J Paediatr Neurol. 2004;8(6):327-32.
    Autism in tuberous sclerosis.
    Curatolo P, Porfirio MC, Manzi B, Seri S.

    2-Pharm World Sci. 1994 Apr 15;16(2):139-48.
    When and how does one search for inborn errors of purine and pyrimidine metabolism?
    Simmonds HA.

    3-J Inherit Metab Dis. 1997 Jun;20(2):214-26.
    When to investigate for purine and pyrimidine disorders. Introduction and review of clinical and laboratory indications.
    Simmonds HA, Duley JA, Fairbanks LD, McBride MB.

    HGPRT is an enzyme involved in purine/pirimidine metabolism.

    4-J Environ Pathol Toxicol Oncol. 1995;14(3-4):165-71.
    Somatic cell mutation in workers occupationally exposed to mercury vapors.
    Shamy MY, El-Gazzar RM, Taleb AN, Christie NT, El Said KF.
    High Institute of Public Health, Alexandria University, Egypt.

    The exposed group showed higher levels of MN (32.0 +/- 1.7), SCE (7.3 +/- 0.2),and HGPRT mutations (0.94 +/- 0.01) then the nonexposed controls. ..

    About Savant skills
    5-Linkage and association of the glutamate receptor 6 gene with autism.
    Jamain S, Betancur C, Quach H, Philippe A, Fellous M, Giros B, Gillberg C, Leboyer M, Bourgeron T; Paris Autism Research International Sibpair (PARIS) Study.
    6-J Child Psychol Psychiatry. 2004 Jul;45(5):899-911.
    Annotation: the savant syndrome.
    Heaton P, Wallace GL.
    7-J Am Acad Child Adolesc Psychiatry. 2003 Jul;42(7):856-63.
    Exploratory subsetting of autism families based on savant skills improves evidence of genetic linkage to 15q11-q13.
    Nurmi EL, Dowd M, Tadevosyan-Leyfer O, Haines JL, Folstein SE, Sutcliffe JS.


    This is part of the information. Sorry by the long posts (again).
    You say
    I think the case against it is quite conclussive

    Thinking in heavy metal poisoning as a comorbility and because of the genetic susceptibility I am not so sure.

    María Luján

    ReplyDelete
  20. SquareGirl says:

    I'm just curious as to weather or not you have experience dealing with the Regional Center's in California?

    No, not at all. I used to live in California, though, so I have some idea of where those centers are.

    ReplyDelete
  21. Wow, that's a lot of stuff María. A couple points for now:

    On (1) you seem to accept that autistics are different from birth, so neuroanatomical differences are not surprising. So then you must be of the opinion that these differences are not enough to cause autistic behavior; that there must be additional environmental pathology. I don't see a reason for this, and would invoke Occam's Razor at this point.

    On (4) you mention kidney damage in Tuberous Sclerosis. I wasn't aware of that, but it is clearly not relevant to autism. Tuberous Sclerosis, BTW, totally genetic.

    ReplyDelete
  22. What is the incidence of home-schooled children with ASD that are not under any educational data, reported? (Etc.)

    Right, CDDS specifically says that their numbers cannot be taken to be a report of the total autistic population of the state. Obviously, not everyone is in the CDDS. And that's why they don't recommend using that data as an indication of prevalence trends.

    ReplyDelete
  23. So I wonder how many children do not have a diagnosis because the parents can not pay for a consult, because they have not Medicare or another health system What is the change from state to state of all these?

    Right, this might account for some of the regional differences. Did you also see the latest Autism Diva post on differences across states?

    ReplyDelete
  24. I can´t assure if we have or not an epidemics of ASD.

    What about my argument on the incidence of epilepsy? Don't you think that's a very good indication that there's no such epidemic?

    ReplyDelete
  25. Changes in the vaccination schedule, introduction of new variants of the same vaccine or a new one , such as Prevnar?

    The graph of rate of increase looks very smooth to me. It's what you'd expect to see in any population that grows exponentially initially and then levels off. (I bet you'd see basically the same thing in human population growth). If prevalence were to be affected by quick policy changes, you'd see some sharp changes in that graph. There's no such thing.

    ReplyDelete
  26. Hi Joseph
    You say
    So then you must be of the opinion that these differences are not enough to cause autistic behavior; that there must be additional environmental pathology. I don't see a reason for this, and would invoke Occam's Razor at this point.

    For me, depends on the child, at an individual level if , with the knowledge TODAY we have, another things can be detected as problems because of the impact of epigenetics/clinical impact of stressor in susceptible children. With the knowlege TODAY we have for me there are environmental impact that are evident in SOME children with ASD. The key here is what to search. You will never find a comorbility if you do not search for the correct test first.So, in this point, we think different.

    On 4), again, where are the studies about subclinical kidney damage in an enough big population of autistics. Because there is no information, I would not discard it. The information I mentioned was related to purely genetic ones. In the case of purine /pirimidine imbalances there are clues about kidney damage with these problems. There are published evidence about problems with folate/methionine/BH4 cycles, that are closely related to purine/pirimidine synthesis in ASD- If you are interested you can go to Kev´s forum (General).

    You say
    What about my argument on the incidence of epilepsy? Don't you think that's a very good indication that there's no such epidemic?
    The problem I see is that there is a high incidence of epileptiform acitvity in the EEG, beyond myoclonic/declared epilepsy. Again I wonder if with this numbers , ONLY, you can discard that mild/subclinical forms are not counted or considered and depends on diagnosis.
    Joseph, I think your analysis was well done and it is very interesting. Ony that I think that only with clinical evidence- and knowledge about what to test- we can construct a real picture and this will be very difficult to have at an ASD population level.
    You say
    If prevalence were to be affected by quick policy changes, you'd see some sharp changes in that graph. There's no such thing.

    Looking at certain graphs, that I will be happy to hear criticisms, there is increase at 4-5 years and 11 years in the diagnosis, when vaccine boosters are included in the schedule.
    You can see here
    http://www.nomercury.org/science.htm
    the graph-provided by Dr Deth- on the incidence of the diagnosis at ages when vaccines boosters are given. For me, at my personal interpretation, this increase is a combination of factors, one of them the environmental insult for susceptible children.

    Sincerely
    María Luján

    ReplyDelete
  27. Hi Joseph
    About Occam´s Razor
    Multiples should not be considered without necessity
    I agree totally. Personally in science we say that the best explanation is always the most simple, but there are so much heterogeneity in ASD that unfortunately I think that here the prompt does not apply.
    I am saying that for SOME ASD children the presentation is due to genetics ONLY, but also I am saying that for other subgroups there are combinations, multiple, depending on individual susceptibility and epigenetics.
    María Luján

    ReplyDelete
  28. With the knowlege TODAY we have for me there are environmental impact that are evident in SOME children with ASD.

    You mean, based on case reports? The only evidence outside of case reports that exists on environmental factors is that which implicates natal complications. This is one thing which is largely random, though, and will not be affected by policy.

    ReplyDelete
  29. The problem I see is that there is a high incidence of epileptiform acitvity in the EEG, beyond myoclonic/declared epilepsy. Again I wonder if with this numbers , ONLY, you can discard that mild/subclinical forms are not counted or considered and depends on diagnosis.

    The problem is that things don't work that way. If you get a large enough group of autistics, you will find that a certain portion only have subclinical seizures. An even smaller portion will have mild seizures, and an even smaller portion will have epilepsy. You can't just have many autistics with subclinical seizures and none with epilepsy. The CDDS data is completely inconsistent with what is known about autism and seizures.

    ReplyDelete
  30. Hi Joseph

    There are some reports about EEG in ASD

    http://dx.doi.org/10.1016/j.yebeh.2005.11.001

    that "shows that 540 of 889 -ASD patients-(60.7%) subjects had abnormal EEG epileptiform activity in sleep"
    I agree with your statement
    The CDDS data is completely inconsistent with what is known about autism and seizures.
    You say
    You mean, based on case reports? The only evidence outside of case reports that exists on environmental factors is that which implicates natal complications. This is one thing which is largely random, though, and will not be affected by policy.
    Well, to answer properly I must present you what I think is environmental insult or postnatal insult in susceptible children and involves vaccines-beyond thimerosal-, antibiotics overuse, herpes and streptococus infections, mentioning the most important but not all (prenatal insult for example CMV, rubella).
    If you are interested in the comment of this please let me know.
    María Luján

    ReplyDelete
  31. that "shows that 540 of 889 -ASD patients-(60.7%) subjects had abnormal EEG epileptiform activity in sleep"
    I agree with your statement
    The CDDS data is completely inconsistent with what is known about autism and seizures.


    So you believe that the CDDS data is flawed or that it's impossible for an epidemic to be occurring? (A middle ground doesn't appear to be mathematically feasible in this case).

    About prevalence of characteristics of autistics, that always has to be taken as a very rough estimate. This is because the definition of autism varies from doctor to doctor, from region to region, and is constantly broadening as I've shown. So without knowing how 'severe' the group you mention is, the statistic is not very helpful.

    ReplyDelete
  32. There are some reports about EEG in ASD

    http://dx.doi.org/10.1016/j.yebeh.2005.11.001

    that "shows that 540 of 889 -ASD patients-(60.7%) subjects had abnormal EEG epileptiform activity in sleep"
    I agree with your statement
    The CDDS data is completely inconsistent with what is known about autism and seizures.


    I should also note that there's something called 'natural variation'. Who's to say that these subclinical epileptic activity is not in the 'natural variation' range - or better yet, the 'natural variation' range for autistics. Doctors like to throw the word 'abnormal' around to describe differences. Sometimes they have non-arbitrary reasons to define something as 'abnormal'. But in this case, it appears unlikely that they have one.

    ReplyDelete
  33. I did not have time to read all of the comments to your post, but I did want to take the time to reply.

    My son is 15 months old and was diagnosed by Early Intervention at the age of 14 months as autistic. I am still uncertain as to whether I agree with this diagnosis. I know that there is something unusual about him and if I was forced to choose, I would say that it is very likely that he is. I also believe that he has petit mahl seizures but this has not yet been addressed.

    My husband suffered from rolandic epilepsy as a child and while I love him dearly, he has many characteristics that led me to believe that he may be very mildly autistic. He is very intelligent and the sweetest most caring man that I have ever known, but he has great difficulties socially. He cannot make eye contact with people he does not know well, and he is not able to work a job that requires a lot of contact with other people. He also did not speak until he was 3 and had many of the other classic childhood indications of autism. Of course they weren't diagnosing autism for people like him at that time.

    In light of these things, I chose not to vaccinate my son when he was born. My son has not had a single vaccination, yet still he has been classified as autistic.

    My belief is that there is a genetic component, that can be worsened by toxins (including vaccines) in the body. I do not know what the outcome would have been had my son been vaccinated, however I think there is a good chance that he would be much worse off than he is now.

    I think the problem when looking for these causes is that there is not just one cause, and so you will never find the evidence to hang in one place. I think the problem has many factors and causes that lead to what we now call autism.

    Forgive me if my reply is simple or not meaningful. I'm new to the world of autism and have actually been quite shocked at what I have discovered in the autistic blogging world.

    Cindy
    www.griffinsjourney.com

    ReplyDelete
  34. My husband suffered from rolandic epilepsy as a child and while I love him dearly, he has many characteristics that led me to believe that he may be very mildly autistic. He is very intelligent and the sweetest most caring man that I have ever known, but he has great difficulties socially. He cannot make eye contact with people he does not know well, and he is not able to work a job that requires a lot of contact with other people. He also did not speak until he was 3 and had many of the other classic childhood indications of autism. Of course they weren't diagnosing autism for people like him at that time.


    Sounds kind of like my dad, who didn't speak until the age of 4. He does not have epilepsy, but I have a cousin on my dad's side who does. (My dad prefers to think of himself as NT, however).

    In light of these things, I chose not to vaccinate my son when he was born. My son has not had a single vaccination, yet still he has been classified as autistic.


    Yes, that's not surprising. There's no reason to believe the rate of diagnosis is higher in vaccinated children than in non-vaccinated children.

    I think the problem when looking for these causes is that there is not just one cause, and so you will never find the evidence to hang in one place. I think the problem has many factors and causes that lead to what we now call autism.

    You're right that autism is not 100% heritable. No behavior is. There must be some influence from the environment. But from the data I conclude that there's no epidemic-causing environmental factor.

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  35. Nicely done. You might check out some of what I've said on this very topic, starting with http://citizencain.blogspot.com/2006/03/autism-mercury-news.html

    ReplyDelete
  36. Citizen Cain,

    That's a good analysis. In particular, I wasn't aware that there's data on drop-outs. This is important, because as the autistic population grows, the number of drop-outs must necessarily grow as well... and this is what causes the numbers to stabilize eventually.

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