For those who needed more information on Autism diagnosis specificity

For those who requested information on the fact that autism incidence is not increasing, but rather diagnostic specificity is, here are one magazine and two journal citations:

Time magazine article, "Is the autism epidemic a myth?"

The changing prevalence of autism in California

Croen LA, Grether JK, Hoogstrate J, Selvin S.; J Autism Dev Disord 2002 Jun; 32(2):207-15

We conducted a population-based study of eight successive California births cohorts to examine the degree to which improvements in detection and changes in diagnosis contribute to the observed increase in autism prevalence.  Children born in 1987-1994 who had autism were identified from the statewide agency responsible for coordinating services for individuals with developmental disabilities.  To evaluate the role of diagnostic sustitution, trends in prevalence of mental retardation without autism were also investigated.  A total of 5038 children with full syndrome autism were identified from 4,590,333 California births, a prevalence of 11.0 per 10,000.  During the study period, prevalence increased from 5.8 to 14.9 per 10,000, for an absolute change of 9.1 per 10,000.  The pattern of increase was not influenced by maternal age, race/ethnicity, education, child gender, or plurality.  During the same period, the prevalence of mental retardation without autism decreased from 28.8 to 19.5 per 10,000 for an absolute change of 9.3 per 10,000.  These data suggest that improvements in detection and changes in diagnosis account for the observed increase in autism; whether there has also been a true increase of incidence is not known.

The epidemiology of autistic spectrum disorders:  is the prevalence rising?

Wing, L, Potter D.; Ment Retard Dev Disabil Res Rev 2002;8(3):151-61

For decades after Kanner's original paper on the subject was published in 1943, autism was generally considered to be a rare condition with a prevalence of around 2-4 per 10,000 children.  Then, studies carried out in the late 1990s and the present century reported annual rises in incidence of autism in pre-school children, based on age of diagnosis, and increases in the age-specific prevalence rates in children.  Prevalence rates of up to 60 per 10,000 for autism and even more for the whole autistic spectrum were reported.  Reasons for these increases include changes in diagnostic criteria, development of the concept of a wide autistic spectrum, different methods used in studies, growing awareness and knowledge among parents and professional workers and the development of specialist services, as well as the possibility of a true increase in numbers.

Remember, please, that it is not possible to prove a negative.  The research above pretty conclusively shows where the numbers are coming from, though.  I'm not trying to spur debate, just provide the information which was requested.  Just call me your friendly neighborhood medical librarian.

One Autism-linked Gene Identified

Original posting at http://www.eurekalert.org/pub_releases/2008-09/econ-tfa082708.php
Public release date: 1-Sep-2008...
Contact: Sonja Maks.mak@update.europe.at43-140-557-340European College of Neuropsychopharmacology
The first autism disease genes
Presented at the 21st Congress of the European College of Neuropsychopharmacology 2008, Barcelona, Spain
This release is available in Spanish.
The autistic disorder was first described, more than sixty years ago, by Dr. Leo Kanner of the Johns Hopkins Hospital (USA), who created the new label ´early infantile autism´. At the same time an Austrian scientist, Dr. Hans Asperger, described a milder form of the disorder that became known as Asperger Syndrome, characterised by higher cognitive abilities and more normal language function. Today, both disorders are classified in the continuum of ´Pervasive Developmental Disorders´ (PDD), more often referred to as Autism Spectrum Disorders (ASD).
The prevalence of (classic) autism in the general population is about 15-20 in 10.000, while all Autism Spectrum Disorders (ASD) affect about 60 in 10.000 children. Males are affected four times more often than females. In approximately 10% of cases, autism is associated with a recognized cause, such as Fragile X Syndrome, Tuberous Sclerosis or diverse chromosomal abnormalities (mean observed rates between 5-10%), but in a vast majority of cases, no known causes are associated with autism (see figure).
All of these neurodevelopmental disorders are characterized by varying deficits in communication skills, social interactions, and restricted, repetitive and stereotyped patterns of interests and activities. Problems that may accompany these disorders are sensory distortion, mental retardation or seizures. Disease onset occurs during the first three years of life. Although early intervention has considerable impact on reducing symptoms and increasing a child´s ability to learn new skills, it is estimated that only 50% of children are diagnosed before the age of 3 years.
Most children with ASD respond well to behavioural management and highly structured, specialized programs in educational settings. Other therapeutic interventions comprise medications to treat behavioural problems such as aggression, self-injury, or severe tantrums.
Warning signs for Autism Spectrum Disorders such as social symptoms, communication deficits and repetitive behaviours should be considered sufficient reason to have a child evaluated by specialized professionals. The earlier the disorder is diagnosed, the sooner the child can be helped through treatment interventions.
Advances in autism research: genetic influences
Research into the causes, diagnosis, and the treatment of ASD has advanced interactively. Imaging studies have shown that many major brain structures are implicated in autism. Other research is focusing on the role of neurotransmitters such as serotonin, dopamine, and epinephrine. The past decade has been marked by an increased interest in the genetic basis of autism, and recent developments point to genetic factors playing a prominent role in the causes for ASD.
The role of gene mutations in autism
Twin and family studies have suggested an underlying genetic vulnerability to ASD. The estimated prevalence of autism in siblings is 5-10%. A higher recurrence risk in families with autistic subjects (45-times greater than the prevalence in the general population) and higher concordance for autism among monozygotic (60-90%) than dizygotic (0-10%) twins argue for a genetic predisposition to idiopathic autism. These data are interpreted as showing that liability to autism is in large part due to oligogenic inheritance in which a combination of multiple – possibly interacting – susceptibility alleles results in autism. A series of multiple independent whole genome scans and chromosomal abnormality studies have pointed out several candidate regions on chromosomes 2q, 7q, 6q, 15q and sex chromosomes. These regions possess candidate genes that have been screened for mutations or association with autism. In a European multicentre project called PARIS (Paris Autism Sib-pair International Study; coordinated by C. Gillberg & M. Leboyer) a large number of multiply affected families were identified, and several mutations of genes encoding proteins implicated in the process of synapse formation (synaptogenesis) have been described.
Autism and synapse formation (synaptogenesis)
In 2003 two new highly conserved members of the human neuroligin family – HNL4, located at Xp22.3 – were characterized (Jamain et al, 2003). A crucial factor in synapse formation, neuroligins are cell adhesion molecules that can trigger the formation of presynaptic structures in non-neuronal cells. The rare mutations of the neuroligins (1%) are associated with autism spectrum conditions. Another step forward in this compelling neurobiological story was the identification of a de novo frame-shift mutation in the X-linked HNL4 gene in two brothers, one with autism and the other with Asperger Syndrome. Since autism and Asperger Syndrome are overly represented in males, mutations in these genes may influence the process of synaptogenesis, and consequently may predispose males to Autism Spectrum Disorders.
In 2007, mutations of another gene encoding SHANK3 were reported (Durand et al, 2007). This gene regulates the structural organization of dendritic spines in neurons and is a binding partner of neuroligins, previously found to be mutated in autism and Asperger Syndrome. Surprisingly, a mutation of a single copy of SHANK3 at chromosome 22q13 is sufficient to induce language impairment, learning disabilities and/or social communication disorders associated with Autism Spectrum Disorders. Frequency of SHANK3 variants is very low even among autism patients and nearly absent in the general population. These results have thus shed light on one synaptic pathway sensitive to gene dosage and associated to Autism Spectrum Disorders.
In a large international study with a sample of 1.168 multiplex families, another exciting discovery led to the detection of sub-microscopic chromosomal abnormalities (Autism Genome Project, 2007): Copy Number Variant analysis (CNV) highlighted the role of a gene encoding neurexin, which is a tightly linked protein to neuroligin, implicated in synapse formation for glutamate neurons. This revealed a hemizygous deletion of coding exon for neurexin gene for a pair of affected siblings. Accumulating evidence thus points out that neurexin/neuroligin/Shank3 (NLGN3/4, SHANK3, NRXN1) genes are related to autism risk, establishing a direct proof of the association of autism with synaptic abnormalities. Neurexin induces glutamate postsynaptic differentiation in contacting dendrites, while neuroligins induce presynaptic differentiation in glutamate axons. The neurexin-neuroligin link thus appears to be fundamental for glutamatergic synapse formation. Furthermore, aberrant glutamate function is often cited as a cause for autism.
By influencing the process of synapse formation for glutamate neurons, gene mutations predispose individuals to Autism Spectrum Disorders.
Autism and circadian rhythms
Another approach in research of the genetics of autism implies the melatonin pathway. Melatonin is produced in the dark by the pineal gland and is a key regulator of circadian and seasonal rhythms. A low melatonin level was reported in individuals with Autism Spectrum Disorders, but the underlying cause of this deficit was unknown. In several individuals with Autism Spectrum Disorders, deletions of the ASMT-gene were found. This gene, located on the pseudo-autosomal region 1 of the sex chromosomes, encodes the last enzyme of melatonin synthesis. Biochemical analyses performed on blood platelets and/or cultured cells revealed a highly significant decrease in AMST activity and melatonin level in individuals with Autism Spectrum Disorders (Melke et al., 2008).
Recent research indicates that a low melatonin level, caused by a primary deficit in gene activity (AMST), is a risk factor for Autism Spectrum Disorders, and highlights the crucial role of melatonin in human cognition and behaviour.
Clinical implications
These findings stress the importance of further research into genetic abnormalities in autism to obtain a better understanding of the underlying disease mechanisms. However, several questions such as correlations between genotypes and phenotypes including cognition and brain imaging studies still remain to be investigated.
Research to unravel autism requires multidisciplinary approaches involving psychiatrists, psychologists, geneticists and brain imaging specialists.
Autistic patients require a broad workout taking into account psychiatric, somatic, cognitive, social and professional issues; furthermore they should be invited to participate in various research projects, ranging from fundamental research to more applied projects on the development of new therapeutic strategies. In view of these requirements the French Ministry of Research has established in 2007 the foundation Fondation FondaMental with the aim to intensify research in this field and to offer high-functioning autistic subjects optimal treatment and care in specialized expert centers.
###
References
Jamain S, Quach H, Betancur C, et al. on behalf of the PARIS study investigators. A de novo frameshift mutation of HNL4, an X-linked neuroligin, is associated with autism. Nature Genetics 2003;34:27-29
Durand C, Betancur C, Boeckers T, et al. Mutations in the gene encoding the synaptic scaffolding protein SHANK3 are associated with autism spectrum disorders. Nature Genetics 2007;39:25-27
The Autism Genome Project. Mapping autism risk loci using genetic linkage and chromosomal rearrangement, Nature Genetics 2007;39:319-328
Melke J, Botros H-G, Chaste P, et al. Abnormal Melatonin Synthesis in Autism Spectrum Disorders. Molecular Psychiatry 2008;13:90-98
Correspondence: Professor Marion Leboyer, M.D., Ph.D. University of Paris 12, Head of Psychiatry Department, Head of Psychiatry Genetic team INSERM, Director Fondation FondaMental E-mail: marion.leboyer@inserm.fr

AAP looking for parents of autistic children

From: Susan Martin
Sent: Wednesday, February 13, 2008 2:29 PM
To: SPOKESPERSONS@LISTSERV.AAP.ORG
Subject: parent spokespersons

Hello,

As part of our ongoing response to media stories regarding autism and vaccines, the AAP communications department is compiling a list of parents who support the AAP and are available for interviews. We are looking for two types of parents who could serve as spokespersons:

Parents of children with autism spectrum disorders who support immunization and who do not believe there is any link between their child's vaccines and his or her autism.

Parents of children who suffered a vaccine-preventable illness. This could be a parent who declined immunization, whose child became ill before a vaccine was available, or whose child was ineligible for immunization.

We are asking for your help identifying parents who would be good spokespersons. They do not need to be expert public speakers. They just need to be open with their story and interested in speaking out on the issue. We will contact candidates in advance to conduct pre-interviews, to offer guidance on talking to reporters and to obtain a signed waiver giving us permission to release their name.

If a parent were placed on our list, we would offer their name and contact information to select media. We hope to build a list of parents from a wide range of geographical areas.

As the Jenny McCarthy and "Eli Stone" stories illustrate, this issue is likely to recur in the national and local media. The AAP is committed to doing all we can to counter such erroneous reports with factual information supported by scientific evidence and AAP recommendations.

The anti-vaccine groups often have emotional family stories on their side. The ability to offer a reporter an interview with a similarly compelling parent who is sympathetic to the AAP's goals is a powerful tool for our media relations program.

Please contact me if you have any questions or to suggest a parent to interview.

Thank you,
Susan Stevens Martin
Director, Division of Media Relations
American Academy of Pediatrics
847.434.7131

Bear with me--more librarian-type stuff

This is a holding-pen for a bibliography of journal articles disputing the idea that vaccination has any relationship to autism. Just move on by (unless you want the list). As of now (2/8/08) I have just copied and pasted a couple of others' lists; I haven't examined, edited, added to, or verified any of the citations, so do not give me any credit for any of this!
Thanks to Interverbal and Stavros, who have done all the work.

from Stavros:
- Peltola H & Patja A, Leinikki P, Valle M, Davidkin I and Paunio M (1998) No evidence for measles, mumps and rubella vaccine associated inflammatory bowel disease or autism in a 14 year prospective study (Research letters) Lancet 351:1327-8
- Gillberg C & Heijbel H, (1998). MMR and autism [commentary]. Autism, The International Journal of Research and Practice; 2:423-424.
- Taylor B et al (1999) Autism and measles, mumps and rubella vaccine: no epidemiological evidence for a causal association. The Lancet; 353: 2026-29.
- Kaye J et al (2001). Mumps, measles and rubella vaccine and the incidence of autism recorded by general practitioners: A time trend analysis. British Medical Journal 322 :460-3.
- Farrington P et al (2001). MMR and autism: Further evidence against a causal association Vaccine 19:3632-5 Volume 19, Issue 27, 14 June 2001, Pages 3632-3635
- Black C (2002) Relation of childhood gastrointestinal disorders to autism: nested case-control study using data from the UK General Practice Research Database. British Medical Journal 325 :419-21.
- Taylor B et al (2002) Measles, mumps and rubella vaccination and bowel problems or development regression in children with autism: population study. British Medical Journal 324 : 393-396.
- Donald A & Muthu V (2002) No evidence that MMR vaccine is associated with autism or bowel disease. Clinical Evidence, 7:331-40

from Interverbal:
1. Bertrand, J., Mars, A., Boyle, C., Bove, F., Yeargin-Allsop, M., & Decoufle, P. (2001). Prevalence of autism in a United States population: the Brick Township, New Jersey, investigation. Pediatrics, 108, 1155-161.
2. Chakrabarti, S., & Fombonne, E. (2001). Pervasive developmental disorders in preschool children. Journal of the American Medical Association, 285,3093-3099.
3. Chakrabarti, S., Fombonne, E., (2005). Pervasive developmental disorders in preschool children: confirmation of high prevalence. American Journal ofPsychiatry, 162(6), 1133-1141.
4. Fombonne, E. (2002). Prevalence of childhood disintegrative disorder (CDD). Autism 6, 2, 147-155.
5. Fombonne, E. (2003). Epidemiological surveys of autism and other pervasive developmental disorders: an update. Journal of Autism and Developmental Disorders. 33, 365-382.
6. Fombonne, E. (2001). Is there an epidemic of autism? Pediatrics.Vol 107 (2), 411-412.
7. Gernsbacher, M.A., Dawson, M, & Goldsmith, H. H. (2005).Three reasons not to believe in an autism epidemic. Current directions in psychological science, 14 (2), 55-58.
8. Gallo C, Volkmar F. Diagnosis of autism. Trends Evidence-BasedNeuropsychiatry 2003;5(1):23– 8.
9. Honda, H., Shimizu, Y., Imai, M., & Nitto, Y. (2005). Cumulative incidence of childhood autism: a total population study of better accuracy and precision. Developmental Medicine And Child Neurology. 47(1), 10-8.
10. Jick H, Beach KJ, Kaye JA. Incidence of autism over time.Epidemiology. (2006). Epidemiology, 17(1), 120-121.
11. Laidler, J. (2005). US Department of Education data on "autism" are not reliable for tracking autism prevalence. Pediatrics, 116 (1), 120-124.
12. Mandall, D. S., Novak, M. M., Zubritsky, C. D. (2005). Factors associated with age of diagnosis among children with autism spectrum disorders. Pediatrics,Vol 116 (6), 1480-6.
13. Spitzer, R., Siegal, B.(1990). The DSM-III R field trial of pervasive developmental disorders. Journal of American Academy of Child and Adolescent Psychiatry. 29, 855–862.
14. Tidmarsh, L., Volkmar, F, R. (2003)Diagnosis and epidemiology of autism spectrum disorders. Canadian Journal of Psychiatry. 48, 517-525.
15. Yeargin-Allsopp, M., Rice, C., Karapurka, T., Doernberg, N., Boyle, C., Murphy, C. (2003). Prevalence of autism in a US metropolitan area. Journal of the American Medical Association, 289, 49-89.For the MMR:
16. Fombonne E. MMR and autistic enterocolitis: a consistent epidemiological failure to find an association. Mol Psychiatry 2003;8:133–4.
17. Honda Shimizu, Y., Rutter, M. (2005). No effect of MMR withdrawal on the incidence of autism: a total population study. Journal of Child Psychology and Psychiatry, vol 46 (6), 572-579.
18. Horton, R., (2004). A statement by the editors of the Lancet. Lancet, 363, 820-1
19. Kaye, J. A., del Melero-Montes, M., & Jick, H. (2001). Mumps, measles, and rubella vaccine and the incidence of autism recorded by general practitioners: A time trend analysis. BritishMedical Journal, 322, 460–463.
20. Madsen KM, Hviid A, Vestergaard M, Schendel D, Wohlfahrt J, Thorsen P, andothers. A population-based study of measles, mumps, and rubella vaccinationand autism. New Engl J Med 2002;347:1477–82.
21. Madsen KM. Measles, mumps and rubella vaccination and autism. N Engl J Med2003;348:951–4.
22. Murch, S., Anthony, A., Casson, D., Malik, M., Berelowitz, M., Dhillon, A., Thomson, P., Valentine, A., Davies, S., & Walker-Smith, J. (2004). Retraction of interpretation, 363, 750.
23. Roberts W, Harford M. Immunization and children at risk for autism. PaediatricChild Health 2002;7:623–32.
24. Spitzer W. Measles, mumps, and rubella vaccination and autism. N Engl J Med2003;348:951–4.
25. Stoto MA, Cleary SD, Foster VB . Epidemiologic studies of MMR vaccine andautism. Washington (DC): Institute of Medicine Immunization Safety ReviewCommittee; 2001.
26. Taylor B, Miller E, Farrington CP, et al. Autism and measles, mumps, and rubella vaccine; no epidemiological evidence for a causal association. Lancet, 353, 2026-2029.For Thimerosal:
27. Andrews, N., Miller, E., Grant, A., Stowe, J., Osborne, V., Taylor, B. (2004). Thimerosal exposure in infants and developmental disorders: a retrospective cohort study in the United kingdom does not support a causal association. Pediatrics. 114(3), 584-591.
28.Meadows, M. (2004). IOM report: no link between vaccines and autism. FDA Consumer. 38(5), 38-9.2
9. Nelson K, Bauman M. Thimerosal and autism? Pediatrics 2003. 111, 674–679.
30. Parker, S, K., Schwartz, B., Todd, J., Pickering, L, K. (2004). Thimerosal-containing vaccines and autistic spectrum disorder: a critical review of published original data. Pediatrics. 114(3), 793-804.
31. Singh, V, K., Hanson, J. (2006). Assessment of metallothionein and antibodies to metallothionein in normal and autistic children having exposure to vaccine-derived thimerosal. Pediatric Allergy and Immunology. 17, 291–296.
32. Stehr-Green, P., Tull, P., Stellfeld, M., Mortenson, P., Simpson. (2003). Autism and thimerosal-containing vaccines lack of consistent evidence for an association. American Journal of Preventative Medicine. 25(2), 101-106.
33. Verstraeten T, Davis RL, DeStefano F, et al. Safety of thimerosal-containing vaccines: a two-phased study of computerized health maintenance organization databases. Pediatrics.2003; 112 :1039 –1048
34. Vertraeten, T. (2004). Thimerosal, the Centers for Disease Control and Prevention, and GlaxoSmithKline. Pediatrics. 113(2), 932.


Michael E. Pichichero, Angela Gentile, Norberto Giglio, Veronica Umido, Thomas Clarkson, Elsa Cernichiari, Grazyna Zareba, Carlos Gotelli, Mariano Gotelli, Lihan Yan and John Treanor
Mercury Levels in Newborns and Infants After Receipt of Thimerosal-Containing Vaccines
Pediatrics 2008;121;e208-e214 http://pediatrics.aappublications.org/cgi/reprint/121/2/e208.pdf

University of California - Davis - Health System (2008, February 12). Some Cases Of Autism May Be Traced To The Immune System Of Mothers During Pregnancy. ScienceDaily. Retrieved February 15, 2008, from http://www.sciencedaily.com­ /releases/2008/02/080211172535.htm

From David Gorski at Science-Based Medicine:

Schechter R and JK Grether (2008). Continuing Increases in Autism Reported to California’s Developmental Services System. Arch. Gen. Psychiatry 65: 19-24.
Shattuck P (2006). The Contribution of Diagnostic Substitution to the Growing Administrative Prevalence of Autism in US Special Education. Pediatrics 117:1028-1037.
Hviid A, M Stellfeld, J. Wohlfahrt, and M Melbye (2003). Association between thimerosal-containing vaccines and autism. JAMA 290:1763-1766.
Madsen KM, MB Lauritsen, CB Pedersen, P Thorsen, AM Plesner, PH Andersen, PB Mortensen (2003). Thimerosal and the Occurrence of Autism: Negative Ecological Evidence From Danish Population-Based Data. Pediatrics 112:604-6.
Fombonne E, R Zakarian, A Bennett, L Meng, D. McLean-Heywood (2006). Pervasive Developmental Disorders in Montreal, Quebec, Canada: Prevalence and Links With Immunizations. Pediatrics 118:e139-50.
Thompson WW, C Price, B Goodson, DK Shay, P Benson, VL Hinrichsen, E Lewis, E Eriksen, P Ray, SM Marcy, J Dunn, LA Jackson, TA Lieu, S Black, G Stewart, ES Weintraub, RL Davis, F DeStefano; Vaccine Safety Datalink Team (2007). Early Thimerosal Exposure and Neuropsychological Outcomes at 7 to 10 Years. NEJM 357:1281-1292.
Parker SK, B Schwartz, J Todd, and LKPickering (2004). Thimerosal-containing vaccines and autistic spectrum disorder: a critical review of published original data. Pediatrics 114:793-804.
Fombonne E (2008). Thimerosal disappears but autism remains. Arch. Gen. Psychiatry 65: 15-6.

CDC List of Studies (pdf), with results and findings and citations

article on recall bias specifically related to vaccines:
Murphy, D., Hotopf, M., Wessely, S. (2008). Multiple vaccinations, health, and recall bias within UK armed forces deployed to Iraq: cohort study. BMJ, 337(jun30 1), a220-a220. DOI: 10.1136/bmj.a220
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Info pages and statements:
CDC
IOM Report

AAP especially "Autism Facts for Parents" which states:

The higher number of ASD cases is NOT due to vaccines. At one time it was thought
that thimerosal, a mercury-based preservative in vaccines, could contribute to ASD.
However, studies have shown there is no link. Indeed, thimerosal was removed from
childhood vaccines by 2002, and the cases of ASD have still risen.