1. UNITED STATES Click on the red pin for US main menu

2. Methods Main Page (Click here)

3. Methods Data Sources Changepoint Analysis Diagnostic and Statistical Manual Thimerosal Containing Vaccines Home

4. Data Sources For the US, autistic disorder data were obtained from the California Department of Developmental Services (DDS) [1] [2] [3] and from the Individuals with Disabilities Education Act (IDEA) program website of the Department of Education [4].1234 Live birth data were extracted from the CDC’s “Annual reports of Vital Statistics of the United States”, [5] [6] and birth year AD prevalence per 10,000 was then calculated.5] [6 Male population data were obtained from the U.S. Census Bureau website, [7] for data prior to 2000 and from the “factfinder” web site for data after 2000 [8]. Birth rates by age of father were obtained from the National Vital Statistics Reports: “Birth Final Data” [9].789 MMR, Varicella and Hepatitis A immunization coverage for children 19 to 35 months of age was obtained from the CDC National Immunization Survey (NIS) [10].10 Methods

5. Changepoint Analysis Linear regression and R 2 analyses were used to assess correlations between AD prevalence and vaccine coverage or births by paternal age; associations with P<0.05 were considered significant. For CP determination, both the hockey-stick [1] and segmented line fitting [2] methods were employed. The robustness of our algorithm was tested by repeating the algorithm using deliberately chosen poor initial inputs.12 Methods

6. Diagnostic and Statistical Manual Diagnostic and Statistical Manual (DSM) editions were checked for printing dates, found on the copyright page. This information was used as an indication of the rapidity with which changes in diagnostic criteria were embraced by the professional community. To determine whether DSM revisions might be related to changes in AD diagnosis rates, we predicted a range of AD changepoint birth years based on the printing dates for the various DSM revisions. Our assumptions were that the earliest age of autism diagnosis is 3 years and that by 8 years of age diagnosis is stable; therefore, a DSM revision would be predicted to induce a changepoint between 8 years prior to the earliest print date and 3 years prior to the latest print date. [1] [2].1] [2]. Methods

7. Thimerosal Containing Vaccines A historical analysis of TCVs was conducted to determine the years in which changes to the thimerosal load received by vaccinated children occurred. Assuming that increased thimerosal load is related to AD we predicted AD changepoints based on FDA approval of new vaccines or new dosing schedules of TCVs and compared these predicted changepoint ranges to the actual calculated changepoints for AD. Methods

8. AD Rate AD Changepoints Vaccines Paternal Age Thimerosal Diagnostic Substitution Polio MMRVaricella Hep A 3 yr olds 8 yr olds Individual BYr Combined Data Criteria Schedules Newschaffer All vaccines THE UNITED STATES (Click on the graphs under each topic)

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11. Calculated AD Changepoints US 1973 - 1987, 19 yr olds1980.8 US 1992 – 2003, 8 yr olds1996.5 CA 1970 - 1997, 5 yr olds1980.9 & 1988.4 CA 1991 - 2002, 4 yr olds1995.6 Go Back to Main Page

12. AD Changepoints US 1973 - 1987, 19 yr olds US 1992 – 2003, 8 yr olds CA 1970 - 1997, 5 yr olds CA 1991 - 2002, 4 yr olds 1980.8 1980.9 1996.5 1988.4 1995.6 Go Back to Main Page

13. TABLE OF POLIO VACCINES POLIO VACCINES AND AD CHANGEPOINTS POLIO VACCINES Go Back to Main Page (Click on the graphs under each topic) Go Back to Main Page

14. POLIO VACCINES IN US CellsNotesCompany FDA Approval End yearTrade Name Age of immunization Comments MRC-5 OPVPfizer19721976DIPLOVAX6-12 weeks never caught on among U.S. pediatricians IPVSanofi-Pasteur11/20/19871991POLIOVAX 2,4,6, 15-18 months IPV 2008NowPENTACEL 2,4,6, 15-18 months Vero cell line * IPVSanofi-Pasteur12/21/1990NowIPOL 2, 4, 6 -18 months, and 4-6 years IPVGSK12/13/2002NowPEDIARIX2, 4, 6 months Source * The Vero lineage was isolated from kidney epithelia cells extracted from an African green monkey Polio main page Go Back to Main Page

15. POLIO VACCINES CellsNotesCompany FDA Approval End yearTrade NameAgeComments MRC-5 OPVPfizer19721976DIPLOVAX6-12 weeks never caught on among U.S. pediatricians IPVSanofi-Pasteur11/20/19871991POLIOVAX2,4,6, 15-18 months IPV 2008NowPENTACEL2,4,6, 15-18 months POLIOVAX Polio main page Go Back to Main Page

16. A.“SIMIAN VIRUS 40 (SV40): A POSSIBLE HUMAN POLYOMAVIRUS WORKSHOP - MONDAY, 27 JANUARY, 1997” http://www.fda.gov/cber/minutes/sv40012797-2.htmhttp://www.fda.gov/cber/minutes/sv40012797-2.htm B.Immunogenicity Review of Pentacel from FDA BLA STN # 103940 (POLIOVAX), approved November 20, 1987 C.CDC list of Discontinued Vaccine in US ( http://www.cdc.gov/vaccines/pubs/pinkbook/downloads/appendices/b/discontinued_vaccines.pdf ) http://www.cdc.gov/vaccines/pubs/pinkbook/downloads/appendices/b/discontinued_vaccines.pdf Poliovax was used from 1988-1991 D.Procedure of manual school immunization - Department of Health (http://www.dsf.health.state.pa.us/health/lib/health/school_procedure_manual.pdf )http://www.dsf.health.state.pa.us/health/lib/health/school_procedure_manual.pdf Trivalent Oral Polio Vaccine - June 25, 1963 e-IPV - December 22, 1987 IPV - Used from 1959-1989 Poliovax -polio virus vaccine, enhanced, inactivated vaccine (e-IPV), Pasteur-Merieux- Connaught ( discontinued 1991 ) Back Polio main page Go Back to Main Page

18. Measles, Mumps and Rubella MMR vaccine information table MMR and AD changepoints (Click on the graphs under each topic) Go Back to Main Page

19. MEASLES, MUMPS, RUBELLA, VARICELLA 01/1979Meruvax IIA rubella vaccine with the RA 27/3 Merck>=12 monthsLicensed. 1979MMR IICombined measles, mumps and rubella with the RA 27/3 strain Merck>=12 months Licensed 1989MMR IICombined measles, mumps and rubella with the RA 27/3 strain Merck>=12 months2 nd dose Go Back to Main Page MMR main page

20. MEASLES, MUMPS, RUBELLA, VARICELLA 01/1979Meruvax IIA rubella vaccine with the RA 27/3 Merck>=12 monthsLicensed. 1979MMR IICombined measles, mumps and rubella with the RA 27/3 strain Merck>=12 months Licensed 1989MMR IICombined measles, mumps and rubella with the RA 27/3 strain Merck>=12 months2 nd dose Meruvax II MMR II MMR II 2 nd dose Go Back to Main Page MMR main page

21. Varicella Uptake of Varicella for All States for 35 monhs old born between 1992 through 2007 U.S. AD vs Varicella for 8 years old born between 1992-1998 All States AD vs Varicella for 8 years old born between 1993-1998 Normalized Varivax immunizations vs Normalized Autism Disorder cases for 8 year olds for birth year 1993-1998 Varicella vaccine and AD Changepoint Go Back to Main Page (Click on the graphs under each topic)

22. Varicella main page Hep A recommended/ considered in 17 states Go Back to Main Page

23. Varicella main pageGo Back to Main Page

24. Varicella main page Go Back to Main Page

25. Varicella main page Go Back to Main Page

26. VARICELLA 3/17/1995VarivaxVaricella virus vaccine, liveMerck>=12 monthsLicensed Varivax Varicella main page Go Back to Main Page

27. Hepatitis A Table of Hepatitis A vaccines approved in the US. Hepatitis A immunization coverage for 35 months old born between 2003-2008 Hepatitis A immunization case vs AD cases for children born 2003-2008 Go Back to Main Page (Click on the graphs under each topic)

28. History of Hepatitis A vaccines approved for use in the U.S. 2/22/1995HavrixThe first inactivated hepatitis A vaccine SmithKline Beecham >=24 monthsLicensed 3/29/1996 1999 Vaqta A second inactivated hepatitis A vaccine 17 states rec/considered for use Merck>=24 months Licensed 5/11/2001Twinrix A combined hepatitis A inactivated and hepatitis B (recombinant) vaccine SmithKline Beecham >=18 yearsLicensed 8/11/2005 2005 Vaqta A second inactivated hepatitis A vaccine Included in ACIP recommendations Merck>=12 months FDA approved lowering the age limit to 12 months 10/18/2005Havrix The inactivated hepatitis A vaccineGSK>=12 months FDA approved lowering the age limit to 12 months 3/28/2007TwinrixA combined hepatitis A inactivated and hepatitis B (recombinant) vaccine GSK>=18yearsFDA approved an accelerated dosing schedule. Hep A main page Go Back to Main Page

29. Hep A main page Go Back to Main Page

30. Hep A main page Go Back to Main Page

31. Paternal Age Absolute Live births and AD cases grouped by age of father from 1992-2002 Absolute live births from 1960-2008 grouped by paternal age AD prevalence & live births to fathers aged 40 – 44 from 1960 to 2002 (Click on the graphs under each topic) Go Back to Main Page

32. Paternal age Main topics

33. Go Back to Main Page Paternal age Main topics

34. 0 10 20 30 40 50 60 70 80 90 0 50,000 100,000 150,000 200,000 250,000 300,000 19501960197019801990200020102020 AD prevalence & live births to fathers aged 40 – 44 from 1960 to 2002 # Live Births to 40-44 yr oldsUS Autism DisorderPredicted 1960 AD rate Go Back to Main Page Paternal age Main topics

35. Thimerosal containing vaccines and national vaccination schedule from 0-18 months Go Back to Main Page

36. Table 1- Comparison of diagnostic criteria for autistic disorder (AD) across DSM revisions Go Back to Main Page

37. Table 2 - Printing schedules for DSM revisions/editions Date of printingNumber printedPredicted BYr CP range by DSM printingsCalculated BYr CP DSM III Feb-8040,000 Feb 1972-Sep 19781980.85* May-8025,000 Sep-8025,000 Nov-8030,000 Jan-8130,000 Mar-8135,000 Sep-8125,000 DSM IIIR May-8775,000 May 1979 –Nov 19841988.4 Jun-8780,000 Nov-8775,000 DSM IV May-94 Jul-94 Aug-94 Jan-95 not given May 1986- Jan 1992 1995.6 Go Back to Main Page

38. National Autism Prevalence Trends From United States Special Education Data Craig J. Newschaffer, Matthew D. Falb and James G. Gurney Go Back to Main Page

39. 1. Qian S (2010) Environmental and Ecological Statistics with R. Boca Raton, FL: Chapman & Hall/CRC. 2. Muggeo VM (2008) segmented: an R Package to Fit Regression Models with Broken-Line Relationships. R News. pp. 20-25. Back

40. 1. McDonald ME PJ (2010) Timing of increased autistic disorder cumulative incidence. Environ Sci Technol 44: 2112-2118. 2. Cavagnaro AT. Autistic Spectrum Disorders. Changes in California Caseload. An Update: 1999 through 2002. California Health and Human Services Agency 2003. 3. Schechter R, Grether JK. Continuing increases in autism reported to California's developmental services system: mercury in retrograde. Arch Gen Psychiatry 2008;65:19-24. 4. Individuals with Disabilities Education Act (IDEA) (2012). Child Count Data. Available: https://www.ideadata.org/default.asp. Accessed September 2012. https://www.ideadata.org/default.asp 5. Centers of Disease Control and Prevention. Vital Statistics of the United States. Available: http://www.cdc.gov/nchs/products/vsus.htm. Accessed September 2012. 6. Centers of Disease Control and Prevention (2012). Vital Statistics Data - Births. Available: http://www.cdc.gov/nchs/data_access/Vitalstatsonline.htm#Births. Accessed September 2012. 7. US Census Bureau (2012). Population Estimates. Available: http://www.census.gov/popest/data/historical/index.html. Accessed September 2012 8. US Census Bureau. American Fact Finder. Available: http://factfinder2.census.gov/faces/nav/jsf/pages/searchresults.xhtml?ref=top&refresh=t. Accessed September 2012. http://factfinder2.census.gov/faces/nav/jsf/pages/searchresults.xhtml?ref=top&refresh=t 9. Centers of Disease Control and Prevention (2012). National vital Statistics System. Available: http://www.cdc.gov/nchs/births.htm. Accessed September 2012. 10. Centers of Disease Control and Prevention (2012).U.S. Vaccination Coverage Reported via NIS. Available: http://www.cdc.gov/vaccines/stats-surv/nis/default.htm. Accessed September 2012.http://www.cdc.gov/vaccines/stats-surv/nis/default.htm Back

41. 1. Lord C, Risi S, DiLavore PS, Shulman C, Thurm A, Pickles A. (2006) Autism From 2 to 9 Years of Age. Arch Gen Psychiatry 63: 694-701. 2.Luyster R, Gotham K, Guthrie W, Coffing M, Petrak R, Pierce K, Bishop S, Esler A, Hus V, Oti R, Richler J, Risi S, Lord C. (2009) The Autism Diagnostic Observation Schedule-toddler module: a new module of a standardized diagnostic measure for autism spectrum disorders. J Autism Dev Disord 39:1305-1320. Back