1. Age at First MMR Vaccination and Autism

2. Vaccines and Autism Two main arguments in support of association
Prevalence of autism has been increasing at the same time that childhood vaccination coverage has increased
Temporal associations in which autistic characteristics become apparent shortly (weeks to months) after vaccination

3. Studies Reporting Possible Association Between Vaccines and Autism
Wakefield:
12 cases with Inflammatory Bowel Disease and Autism
9 of 12 cases had reports of MMR contributed to onset of symptoms
No evidence of measles virus in IBD
Review of UK expert Medical Research Council: No association

4. Studies Reporting Possible Association Between Vaccines and Autism
Serologic evidence:
Zecca: Increased measles antibody in children with autism
Singh: Children with autism and brain autoantibodies (MBP) had higher measles IgG titers than children with autism with no brain antibodies
Gupta: Increased rubella antibody titers in mothers of some patients with autism

5. Recent Studies Not Supporting Association
Between MMR Vaccine and Autism
Taylor:
Population-based: 498 known autism cases in one region
Link with immunization registry
No association found
Gillberg:
No difference in autism prevalence for children born before or after introduction of MMR vaccinations (1982)
Fombonne:
Utilized two large databases, 9000 clinical records and a second survey of autism in school aged children.
No cases that had co-occurrence of ulcerative colitis or Crohn’s disease.

6. Recent Studies Not Supporting Association Between MMR Vaccine and Autism
Working Party of UK’s Medicines Control Agency:
Reviewed all cases of autism and GI disease, GI disease only and autism only
Information available did not support an association between vaccines and autism
Peltola et al:
Examined 1.8 million individuals with ~ 3 million MMR vaccine doses from
Of the 173 potentially adverse events claimed to be causally associated with MMR, 45% had evidence suggesting other causes (i.e., infectious agents, viruses).
No cases of autism were associated with MMR vaccination

7. Recent Studies Not Supporting Association Between MMR Vaccine and Autism
Kaye et al:
Examined children 12 years or younger for the UK diagnosed with autism between
While there was significant increased rates in autism, no temporal association was found between MMR vaccination prevalence rates and risk for autism.
Dales et al:
Retrospective analyses of children from kindergartens born in
( children each year) and of autism cases from California Department of Developmental Services.
Results showed no correlation between the trend in MMR vaccine coverage and the occurrence of autism.

8. Limitations of Previous Investigations
Incomplete ascertainment
Small sample sizes
Lack of standard case definitions
Lack individual-specific vaccine histories

9. Statement from the Institute of Medicine, 2001
Rejects causal relationship at the population level between MMR vaccine and ASD
Committee based this conclusion on: consistent body of evidence showing no association, original case series of children with ASD is uninformative with respect to causality, biologic models linking MMR with ASD are fragmentary, and there are no animal models linking MMR vaccine and ASD
Strongly encouraged additional studies to examine possible associations between MMR and subgroups of autistic children

10. CDC Autism and MMR Vaccine History: Case-Control Study
Main Objective
To evaluate the association between autism and age of receipt of the MMR vaccine
Secondary objectives
To compare MMR vaccination histories between certain autism subgroups and controls

11. Study Methods
The Metropolitan Atlanta Developmental Disabilities Surveillance Program (MADDSP)
Active, ongoing (since 1991)
Population-based: 3-10 year old children in five counties of Metropolitan Atlanta
Multiple source ascertainment of select DDs including: mental retardation,cerebral palsy, hearing impairment and vision impairment, and autism (from 1996)

12. MADDSP Autism Surveillance Approach
Identify potential cases at multiple educational and clinical sources
Schools: pyschoeducational assessments, special education files
Clinical sources: ASD as discharge diagnosis, billing code, or referral reason
Screen source files for autism indicators (“triggers”)
Abstract source files with autism “triggers”
Expert review of abstracted data to determine case status:
Autism Case
Suspected Case
Not a case

13. Study methods: Autism Case Definition
A child 3-10 years old during the study year
Whose parent (s) or legal guardian(s) resided in the five-county metropolitan Atlanta area during the study year
And who displayed behaviors (as described by a qualified professional) consistent with the DSM-IV criteria for autistic disorder, PDD-NOS (including atypical autism), or Asperger’s disorder on evaluations conducted through the end of the year.

14. Methods: Types of Data Collected for MADDSP
Demographic
Child and maternal identifying information
Date of birth, race, gender
Educational
Special education eligibility category
Psychometric test results (intelligence, developmental, adaptive, autism-specific)
Medical/Clinical
Physical findings
Associated medical conditions, family history, lab/genetic test results
Other developmental disabilities
Behavioral
Verbatim abstraction of behavioral features

15. Methods: Expert Review Process
Case status determined by systematic review of abstracted information by autism experts
Behavioral coding scheme developed based on DSM-IV criteria for Autistic Disorder and PDD-NOS
Abstracted evaluations from all sources for a child were compiled and behaviors scored individually
Criteria were summarized to arrive at case status
Questionable cases were re-reviewed
20% reliability sample – 96% agreement

16. Study of Autism and MMR Vaccine: Study design and population
Case-control study design
Cases: 624 children with ASD
Identified through MADDSP Autism Surveillance in 1996
Born from
With valid MMR vaccination dates on the immunization form in the school record
Controls: 1,824 children without known DD
3:1 control to case ratio
Selected from regular education programs
Matched to case-children based on age, sex, and school of attendance at the time of abstraction*
* Certain exceptions had to be made for some control children
The exceptions made for the selection of control children are regarding cases that were : 1) in psychoeducational program 2) case-children who were older than there grade-level classmates (we don’t get into this in the paper-it is too confusing)

17. Study of Autism and MMR Vaccine: Flow Chart of Sample Selection
MADDSP
Confirmed
Autism Cases
(N = 987)
Cases With
Immunization records
(N = 660)
Cases with available controls
(N = 647)
Matched
Controls
(N = 1,891)
Cases with valid MMR vaccination dates
(N = 624)
Matched Controls with valid MMR vaccination dates
(N = 1,824)

18. Study of Autism and MMR Vaccine History: Data Collection
Vaccination History: Collected from the standard State of Georgia Immunization Form
Vaccine information consists of vaccines required by school law for entry into the school (i.e., MMR, DTP, OPV, IPV, HepB (1992)).
Other information included location of vaccine administration, name of physician, and administration of vaccines not required by school (i.e., Hib) or additional doses of vaccines that are required.
Vaccine exemption data are also collected when available.

19. Study of Autism and MMR Vaccine History: Data Collection
Child’s School Record and Birth Certificate
Demographic and other information that was collected included child’s birth state, birth certificate number, sex, race, date of birth, parent’s names, adoption status
Cases and controls born in Georgia were linked to State Birth Certificate Files to collect information on key variables (mother’s education and age, birth weight, gestational age, etc.)
MADDSP
Presence of other DDs, co-existing medical conditions, and IQ functioning
MACDP
Information on major congenital malformations

20. Study of Autism and MMR Vaccine History: Exposure Variables
Three specific age cut-offs were chosen:
18 months: indicator of “on-time” vaccination and also median age for the occurrence of regression
24 months: the upper age limit at which onset of regression or parental concern usually occurs
36 months: the age by which autistic characteristics must have developed according to DSM-IV criteria for autism

21. Study of Autism and MMR Vaccine History: Classification of Autism Subgroups
Subgroups based on demographic factors
Gender
Age at ascertainment
Subgroups based on clinical presentation
Children without a pre-existing condition < 1 year of age
No birth defect, diagnosed disability, indication of developmental delay, or neonatal event that is related to onset of autistic behaviors by 1 year of age
Children identified with regression or plateau
Children with and without mental retardation

22. Subgroups based on factors related to case selection
Study of Autism and MMR Vaccine History: Classification of Autism Subgroups
Subgroups based on factors related to case selection
Children with records abstracted at school sources only
Children with records abstracted from multiple sources and/or clinical sources
Children with and without a previous ASD diagnosis

23. Study of Autism and MMR Vaccine Study: Potential Confounding Variables
Age at ascertainment (1996)
Child’s sex
Child’s race
Maternal age
Maternal education
Birth weight
Multiplicity
Parity

24. Study of Autism and MMR Vaccine History: Analytic Approach
Conditional logistic regression analysis stratified by matched case-control sets
Confounding variables included as covariates that had an odds ratio p-value of < .20 when evaluated individually for association with autism case definition
Odds ratios were adjusted for confounding variables in assessing association between age at vaccination and autism

25. Results: Comparison between case-children included in MMR study and case-children not included in the study
Significant findings
Case-children included in the study were more likely to be identified at a school source only (AOR=1.6; 95% CI= 1.1,2.5).
Case-children NOT included in the study were less likely to be from mothers of lower education (AOR=0.4; 95% CI=0.2,0.8).

26. Results: Age of 1st MMR Vaccination by Case Status For Total Sample

27. CDC Autism and MMR Vaccine History: Case-Control Study
Strengths:
Population-based sample of children with autism available from MADDSP
Immunization records of children available from existing records
Case:control study design provides information on children without autism from the same population
Information 700+ children with autism and control children

29. CDC Autism and MMR Vaccine History: Case-Control Study
Limitations:
Record-based review of autism: Difficult to pinpoint earliest onset of disorder for a number of children
Information on other possible contributing factors not always available