THE EPIDEMIOLOGY OF AUTISM IN CALIFORNIA The EpidemiologyofAutisminCalifornia: on thePrincipalFindingsfrom totheLegislature Report October 17,2002 University ofCalifornia,Davis M.I.N.D. Institute A ComprehensivePilotStudy ○○○○○○○○○○○○○○○○○○○○○○ THE EPIDEMIOLOGY OF AUTISM IN CALIFORNIA UC DavisProjectStaff: eaMyroaResearch Assistant/ADI-R Administrator Research Assistant/ADI-R Administrator Research Assistant/ADI-RAdministrator Project Manager/ADI-RAdministrator Co-Investigator Co-Investigator Vera Meyerkova Elizabeth Lizaola Sara Clavell StudentAssistant StudentAssistant Caitlin Beck Michael Bono,Ph.D. StudentAssistant Marian Sigman,Ph.D. StudentAssistant StudentAssistant UCLA SiteProjectStaff: Statistician Denise Wong StatisticalConsultant Lolly Lee Statistical Consultant Anna Elsdon Diana Chavez Chart Abstractor PostGraduateResearcher PostGraduateResearcher/ADI-R Administrator Emma Calvert Chart Abstractor Jingsong He,M.S. PostGraduateResearcher/ADI-R Administrator Chart Abstractor/ADI-RAdministrator Daniel Tancredi, M.S. Steven Samuels,Ph.D. AdministrativeAssistant Bonnie Walbridge, R.N.,M.P.H. Andrea Moore, M.S.W. ClinicalPsychologist Research Assistant Ruth Baron, R.N. Research Assistant/ADI-RAdministrator Tiffany Hughes Kelly Heung,M.S. Nhue Do Jonathan Neufeld,Ph.D. LeadChart Abstractor Kristen Enders ProjectKasie Gee,M.P.H. Manager PrincipalInvestigator Rachel Shefelbine Janet Keyzer, R.N.C.,M.P.A. Allyson C.Sage,R.N.,M.P.H. Robert S.Byrd, M.D.,M.P.H. ○○○○○○○ ○○○○○○○○○○○○○○○○○○○○○○○○○○○○○○ THE EPIDEMIOLOGY OFAUTISMIN CALIFORNIA ○○○○○

THE EPIDEMIOLOGY OF AUTISM IN CALIFORNIA Table ofContents eeecs...... 67 ...... References 66 ...... Acknowledgments 43 Appendices...... 40 ...... Conclusion 39 Study Aim6Results...... 37 Study Aim5Results...... 29 Study Aim4Results...... 28 Study Aim3Results...... 26 Study Aim2Results...... 24 Study Aim1Results...... 23 ...... Recruitment andEnrollment 22 ...... Statistical Analysis 21 ...... Validating StudyMethodsandProcedures 19 ...... Recruitment andEnrollmentProcedures 15 ...... Methods 14 Panel...... Scientific Advisory 14 ...... Aims oftheStudy 10 Review ofresearchonthecausesautismandothercurrentissues...... 6 ...... Background 2 ...... Executive Summary ○○○○○○○○○○○○○○○○○ pcfcpoeue o aiiswt hlrnwt etlrtrain...... 21 ...... Specific proceduresforfamilieswithchildrenmentalretardation 20 ...... Specific proceduresforfamiliesofchildrenwithautism 20 ...... abstraction Chart 19 ...... consenttoparticipate. How wecontactedfamiliesandobtainedinformed ifvaccinationwithMMRincreases Methods forStudyAim6:Determination ofwhatfamilies Methods forStudyAim5:Determination Methods forStudyAim4:Changeincharacteristicsofchildren Methods forStudyAim3:Changeinin-migrationofchildren ofchildren withDSM-IV Methods forStudyAim2:Proportion Methods forStudyAim1:Changeindiagnosticcriteria 12 ...... Context oftheCurrentStudy Implications ofCurrentUnderstandingAboutAutisminthe 10 ...... Epidemiology ofAutism 9 ...... Legislation AuthorizingThisStudy 8 ...... totheStateLegislature The March1999DDSReport 7 ...... Collection ofInformationintheRegionalCenterSystem 7 ...... oftheRegionalCenterSysteminCalifornia History 6 ...... What isautism? h eurnert fats nsbeun yugr ilns ...... 18 ...... the recurrencerateofautisminsubsequent(younger)siblings. 17 ...... this haschangedintwoagecohorts. believe tobethecauseofautismintheirchildandwhether 17 ...... with CDERstatus1autismovertime. 16 ...... CDER status1autism. with autismthataccountsforincreasednumberofcases 15 ...... autism classifiedashavingmentalretardation. 15 ...... associated withCDERstatus1autism. THE EPIDEMIOLOGY OFAUTISMIN CALIFORNIA ■ PAGE1 ○○○○○○○○○

THE EPIDEMIOLOGY OF AUTISM IN CALIFORNIA Executive Summary study camefrom fourmain sources: with adiagnosisofmental retardation withoutfullsyndrome autism. Dataforthe families of375children withadiagnosis offullsyndrome autismand309children birth year cohorts(1983-1985and1993-1995)wassystematically collectedfrom enrolled toparticipate inthisstudy. Information regarding children from twodifferent California-wide sampleof684children from English-orSpanish-speakingfamilies study toexaminefactorsthatmaybeassociatedwith thisincrease. Neurodevelopmental Disorders (M.I.N.D.)Instituteconductacomprehensive pilot State Legislature requested thattheUniversityofCalifornia’s MedicalInvestigationof this timeperiod.Becauseoftheconcernoverapparent increase inautism,the report documentedanincrease of273% inreported over casesof autisminCalifornia Disorders inCalifornia’s DevelopmentalServicesSystem:1987through 1998.” The “Changes inthePopulationofPersonswithAutismandPervasiveDevelopmental citizens are addressed. mechanismthroughunique asaservice whichtheneedsofdevelopmentallydisabled Act in1969,theRegionalCentersare Centers. EstablishedbytheLanterman coordinated byasystemoflocalRegional mental disabilitiesqualifyforservices full syndrome autismandother develop- and childhoodvaccinations. viral exposures; autoimmunedisorders; exposures tosubstancessuchasmercury; autism casesincludeenvironmental increaseto betterexplaintheobserved in prevalence. Othertheoriesthatattempt fully explaintheincreasing autism purely geneticbasisforautismdoesnot another childwithautism.However, a one autisticchildare more likelyhave common inmalesandismore commonincertain medicalconditions.Familieswith been identified,althoughthere isevidenceforgeneticpredisposition. Autismismore tions puttheprevalence ofautismat10-12per10,000persons.Aclearcausehasnot autism wasrelatively rare, occurringin4-5per10,000persons.More recent estima- prevalence ofautisminthepopulationisnotwelldescribed.Itwasoncethoughtthat individuals towholackanymeansofcommunicatingwithothers.The environment. Thoseaffected byautismfallalongaspectrumof“high-functioning” communicate, formrelationships withothers,andrespond appropriately tothe A ○○○○○○○○○○○○○○○○ utism isaneurological orbraindisorder thatprofoundly affects aperson’s abilityto The studymethodsare presented indetailthefullreport totheLegislature. A In March 1999,theDepartmentofDevelopmentalServicesissuedareport titled In California,personsdiagnosedwith THE EPIDEMIOLOGY OFAUTISMIN CALIFORNIA Autism is a neurological or neurological a is Autism brain disorder that profoundly that disorder brain affects a person’s ability to ability person’s a affects communicate, form relation- form communicate, ships with others, and others, with ships respond appropriately to appropriately respond the environment. the ■ PAGE2 THE EPIDEMIOLOGY OF AUTISM IN CALIFORNIA principal aims: ■ findingsofthestudyareThe primary summarizedinthefollowinglistof adetailedstudyquestionnaire. 4) —Revised(ADI-R);and TheAutismDiagnosticInterview 3) RegionalCenterrecords; 2) Datafrom theDepartment ClientDevelopment ofDevelopmentalServices 1) ■ Study Aim1: Evaluation Report (CDERform); is 87%ofthe1983-85group and93%ofthe1993-95 group. Thus, autistic Study Aim3: spectrum disorder. likely toagree toenroll iftheirmentallyretarded childalsohadanautism rate byfamilieswithmentallyretarded children, and2)familieswere more counted (andnotbeingtreated), because 1)wehadarelatively low response make reliable estimates ofthenumberchildren withautismnotbeing children inthe1993-95cohort. However, thesenumberscannotbeusedto Of the1983-85cohort,18%metcriteriaforautism, compared to19%of retardation withoutfullsyndrome autismdidmeetDSM-IVcriteriaforautism. ■ bytheRegionalCenters. number ofautismclientsserved contributed toincreased in thediagnosticcriteriahas no evidence thataloosening nents oftheADI-R.There is met withinspecificcompo- sons ofthenumbercriteria time were foundincompari- addition, nodifferences over the 1993-95cohort.) In criteria compared to 89% of 85 cohort metDSM-IV over time.(88%ofthe1983- autism, closelymatchedDSM-IVcriteriaforandthisdidnotchange to diagnosis CDER status 1 autism account for a significant proportion of the of proportion significant a for account autism 1 status CDER diagnosis to autism moving into California for services accounts for a significant propor- significant a for accounts services for California into moving autism of autism as mental retardation in the past has contributed to an apparent an to contributed has past the in retardation mental as autism of increased number of cases of autism. of cases of number increased tion of the increased cases of autism reported to DDS. to reported autism of cases increased the of tion increase in the number of children with autism. with children of number the in increase The proportion ofthestudychildren withautismwhoare California-born A portion ofchildren reported bytheRegionalCentersashavingmental Study Aim2: The RegionalCenterdesignationoffullsyndrome autism,CDERstatus1 THE EPIDEMIOLOGY OFAUTISMIN CALIFORNIA

To investigate whether changes over time in the criteria used criteria the in time over changes whether investigate To To investigate whether temporal changes in children with children in changes temporal whether investigate To

To investigate whether the misclassification of some cases some of misclassification the whether investigate To There is no evidence that evidence no is There loosening in diagnostic criteria diagnostic in loosening contributed to an increase in the in increase an to contributed number of children with autism. with children of number ■ PAGE3 THE EPIDEMIOLOGY OF AUTISM IN CALIFORNIA ■ ■ Study Aim4: not comingdisproportionately from outside California. children in the RegionalCenterSystemare largely nativetotheStateandare attributed toenvironmental exposures byabout11%ofthestudyfamilies. Birth eventswere citedbyabout15%ofparents inbothgroups. Autismwas contributing factorby18%oftheoldercohort and33%ofthe younger cohort. sponse forbothgroups (31% and27%).Immunizationswere reported as a “Don’t know”(46%and48%).Geneticswasthesecondmostcommonre- Study Aim5: explain theincrease inautismcasesCalifornia. the youngergroup than theoldergroup (4%).Noneofthesedifferences fully than theoldercohort. Wheatallergy wassignificantlymore frequent (12%)for commonly reported duringthefirst15monthsoflifefor1993-95cohort factors associatedwiththepregnancy. Gastrointestinal symptomswere more effect ratherthanacohort effect.There were fewdifferences overtimein disorders, depression, andbipolardisorder, butthismaybeduetoanage more likelytobereported ashavingticdisorders, obsessive-compulsive child’s conditionovertime(81%vs.93%). Olderchildren withautismwere to report improvement intheir younger group were more likely older group, parents ofthe (28% vs.34%).Compared tothe significantly changeovertime the ADI-Rinterview, didnot milestones, asdeterminedfrom Regression ofdevelopmental 22% inthe1993-95group). (50% inthe1983-85group vs. retardation intheyoungergroup review ofRegionalCenterrecords thatfoundadecrease indiagnosedmental child alsohadmentalretardation (41%vs. 21%).Thisisconsistentwiththe group). Parents oftheoldergroup were more likelytoreport thattheirautistic the youngerautisticgroup (28%inthe1983-85group and39%inthe1993-95 nal andpaternaleducation.Hispanicchildren are more likelytobeincludedin some differences. There are nosignificantdifferences insex,race,andmater- caused their child’s autism, and to determine if this has changed over time. over changed has this if determine to and autism, child’s their caused children with autism have changed over time. over changed have autism with children The mostcommonparental response inbothgroups wasnoresponse or Comparisons betweenthetwoagegroups showmanysimilaritiesand THE EPIDEMIOLOGY OFAUTISMIN CALIFORNIA

To ascertain what parents of children with autism believe autism with children of parents what ascertain To To describe how characteristics of characteristics how describe To Parent-reported regression of regression Parent-reported developmental milestones developmental did not change over time. over change not did ■ PAGE4 THE EPIDEMIOLOGY OF AUTISM IN CALIFORNIA T Major Findings overestimation ofthenumberchildren withautisminCalifornia. California, andthenumberofcasespresenting to theRegionalCentersystemisnotan if notall,oftheobservedincrease represents atrueincrease incasesofautism in he majorfindingsofthisstudyare that: Without evidenceforanartificialincrease inautismcases,weconcludethatsome, ■ ■ ■ ■ ■ ■ ■ reported byparents intheyoungergroup. Gastrointestinal symptoms inthefirst15monthsoflifewere more commonly stones) didnotdiffer betweenthetwoagegroups. The percentage ofparent-reported regression (lossofdevelopmentalmile- cantly betweenthetwoagegroups. A diagnosisofmentalretardation associated withautismhaddeclinedsignifi- explain theincrease inautism.␣ there hasbeennomajormigrationofchildren intoCaliforniathatwould Children bytheState'sRegionalCentersare served largely nativebornand appear tohavechangedovertime. not autismdidmeetcriteriaforautism,butthismisclassificationdoes Some children reported bytheRegionalCenterswithmentalretardation and the criteriausedtomakediagnosis. increaseThe observed inautismcasescannotbeexplainedbyaloosening Study Aim6: size canbedone,thisstudyaimwillremain unanswered. excess ofthesizethisstudy(approximately 7,000).Untilastudyofthat number ofchildren toanswerthisstudyaimquestionisfarin necessary vaccine avoidanceislesscommonthanhadbeensuggested.Asaresult, the avoiding immunizationintheiryoungerchildren, butourresults showthat prior tothisstudysuggestedthat50%offamilieswithautisticchildren were ing vaccinationofanyyoungersiblings(10%vs.21%).Anecdotalinformation cohort parents. Similarpatternswere reported withregard toavoiding/delay- this studywasreported by8%ofoldercohort parents and22%ofyounger with an increase in the recurrence rate of autism in subsequent siblings. subsequent in autism of rate recurrence the in increase an with Avoidance ordelayofatleastonevaccinefortheautisticchildenrolled in THE EPIDEMIOLOGY OFAUTISMIN CALIFORNIA

To determine if vaccination with MMR vaccine is associated is vaccine MMR with vaccination if determine To ■ PAGE5 THE EPIDEMIOLOGY OF AUTISM IN CALIFORNIA Background diagnosis ofautismasearly aspossible. diagnosed earlyandtreated intensively haveincreased attentiontoward makingthe local RegionalCenter(described below).Treatment successes forsomechildren In California,thediagnosis isoftenmadefollowinganevaluationofthechild atthe psychologists), neurologists, orspeciallytrainedsocialworkersregistered nurses. developmental specialists(suchaspediatricians ordevelopmental process ofgettingadiagnosismaystart withaprimarycare doctor, thenofteninvolves after aparent oranothercaretaker raisesconcerns aboutthechild’s development. The tion, pleaseseeAppendix1.Thediagnosiscanbedifficult tomake,butusuallyresults Manual-IV (DSM-IV)oftheAmericanPsychiatricAssociation. Foradetaileddefini- be present insomecases. problems, suchasmentalretardation. Aggressive and/orself-injuriousbehaviormay They maylackeyecontactorregard for faces.Theycanhaveadditionaldevelopmental of communicatingwithothers,orcommunicateonlybyrepeating words orphrases. other endofthespectrumare severely affected personswhomaynothaveanymeans maintain employment.Atthe college, andsomefind school classrooms, someattend mainstreamed intoregular “high-functioning”; manycanbe with autismare considered the spectrum,somepersons its effect ondevelopment.Along before theageof3andrangesin tastes. Autismhasanonset sounds, textures, smells,and sensitive tocertain sights, concern. Theymayalsobemore which attractnoticeandcause ing, bodyrocking orspinning, hand flapping,fingerflicker- may havebehaviors,suchas look perfectlynormal, butthey ment. Mostautisticchildren appropriately totheenviron- ships withothers,andrespond communicate, form relation- affects aperson’s abilityto brain disorder thatprofoundly A What isautism? ○○○○○○○○○○○○○○○ utism isaneurological or The diagnosticcriteriaforautismare listed intheDiagnosticandStatistical THE EPIDEMIOLOGY OFAUTISMIN CALIFORNIA Treatment successes for successes Treatment some children diagnosed early diagnosed children some and treated intensively have intensively treated and increased attention toward attention increased making the diagnosis of autism of diagnosis the making as early as possible. as early as ■ PAGE6 THE EPIDEMIOLOGY OF AUTISM IN CALIFORNIA through whichtheneedsofdevelopmentallydisabledcitizensare addressed. Centers.) TheRegionalCentersysteminCaliforniaisuniqueasaservicemechanism psychologists, socialworkers,andnurses).(SeeAppendix2forlocationsofRegional array ofcasemanagers,communityserviceproviders, andprofessional staff (i.e. Regional Centerslocatedthroughout California coordinate theseservicesthrough a chairs; andtheprovision ofrespite care forthefamilyorguardians. Twenty-one planning foreducationalgoals;provision ofnecessarymedicaldevices,suchaswheel- include therapiessuchasphysicaltherapy, occupationaltherapy, andspeechtherapy; Lanterman Act.Typical servicesthatare coordinated through theRegionalCenter is undertaken todetermineifthepersonqualifiesforservices asoutlinedinthe organizations,health orservice orfamiliesmayself-refer theirchildren. Anassessment and adultsare referred totheirlocalRegionalCenterbyhealth-care providers orother forpersonwithdevelopmentaldisabilities.Childrenment andhabilitationservices Actwasamendedtoestablishtherighttreat-Developmental DisabilitiesServices and otherconditionssimilarinseveritytomentalretardation. In1976,theLanterman personswithcerebralIn 1973,thisactwasextendedtoserve palsy, epilepsy, autism managed through anassociationofRegionalCenterslocatedthroughout California. nation ofcare forpersonswithmentalretardation. Thiscare wasoverseenand I oftheRegionalCenterSysteminCalifornia History DSM-IV criteriaforautism, butthisassumptionhasnotbeenvalidatedprior tothis labeled “FullSyndrome” autismandisbelievedtoberoughly equivalenttomeeting CDER Status9. 0isNone(noevidenceofautism).CDERStatus 1is one offourdifferent codes— CDERStatus0,1,2and autism.” Thepresence orabsenceofautismisrecorded onpage3oftheCDERwith that “thediagnosisinthissectionmustbeprovided byapersonqualifiedtodiagnose across time.Thewrittenguidelinesfordeterminingwhetherachildhas autismare criteria inestablishingadiagnosisofautismacross theState’s RegionalCenters and data fortrackingchangesinautismovertimeisthe lackofspecificanduniform in usingthesedataformore purpose.Themajor drawbackofthese thantheirprimary has beenprimarilyusedforadministrativepurposes. Manypotentialproblems exist skills. AcopyoftheCDERformisincludedinAppendix 3. of muscles,independentliving,social,emotional,cognitive,andcommunication chronic majormedicalconditions,medications,andcategorizationofdeficitsinuse retardation, cerebral palsy, autism,seizure disorder, and/orother),mentaldisorders, prepared theform,developmentaldiagnosticinformation(documentationofmental The typesofinformationcollectedontheCDERform includereporting date,who at intake,andyearlythereafter, todetermine developmentalandfunctionalstatus. tion Report (CDER)istheassessmentinstrumentthatadministered toeachclient TheClientDevelopmentEvalua- assessments ofindividualswhoqualifyforservice. C Collection ofInformationintheRegionalCenterSystem n 1969,theLantermanMentalRetardation Actestablishedregional Services coordi- alifornia’s RegionalCenterSystemhascompiledover20yearsofdatafrom annual The CDERdatabase,apotentiallyrichsource ofstatewidedataregarding autism, THE EPIDEMIOLOGY OFAUTISMIN CALIFORNIA ■ PAGE7 THE EPIDEMIOLOGY OF AUTISM IN CALIFORNIA tions changeovertime,buttheextentofthisproblem isunknown. Byanecdotal report,services. thedatabaseisnotalwaysupdated,evenwhenevalua- assessed butdidnotqualifyfor no record ofchildren whowere for developmentalservices,buthas database trackschildren whoqualify over timeinautism.TheCDER using CDERdatatotrackchanges additional potentialproblems with Report discussedbelow. There are der. Thesedatawere usedintheDDS and ChildhoodDisintegrativeDisor- Asperger’s Disorder; Rett’s Disorder; specified(PDD-NOS); otherwise Disorders (PDD),includingPDD,not Developmental such asPervasive tions alongtheautismspectrum, the CDERthatcaptures othercondi- based ondiagnosticcodingmade coded inthedata,CDERStatus4, additional categoryforautismwas tism suspected,notdiagnosed.”An lent. CDERStatus9islabeled“Au- designation lacksaDSM-IVequiva- “Autism, residual state,”butthis study. CDERStatus2islabeled tion hadincreased to9.4%.Thesenumberspointed toincreases inthetotalnumberof 4.9% ofallconsumersRegional Centerservicesinthestate.In1997,thispropor- 72,987 to108,563(49%). In1988,consumerswithautisminallformsaccounted for 22,683 to29,645(31%),and consumerswithmentalretardation increased from palsy increased from 19,972to28,529(43%), consumerswithepilepsyincreased from 11,995, anincrease of210%.Incomparison,thenumberconsumerswithcerebral with anydesignationofautism(CDERstatus1,2,4, and9)increased from 3,864to 80,483 to136,383duringthesameperiod.Thenumber ofRegionalCenterconsumers also documenteda69%increase inthetotalRegionalCenterconsumerpopulationof population increase ofapproximately 20%fortheStateduringthisperiod.Thereport autism (CDERstatus1and2)from 2,778to10,360.Thisisfarinexcessofthe covered inthereport there wasasubstantial(273%) increase inreported casesof (this report willbereferenced as“theDDSReport”). mental Disorders in California’s DevelopmentalServicesSystem:1987through 1998” entitled “ChangesinthePopulationofPersonswithAutismandPervasiveDevelop- I totheStateLegislature The March1999DDSReport n March 1999,theCalifornia Department issuedareport ofDevelopmentalServices THE EPIDEMIOLOGY OFAUTISMIN CALIFORNIA A 273% increase in reported in increase 273% A cases of autism from 1987 from autism of cases through 1998 is far in excess in far is 1998 through of population changes of changes population of approximately 20% for the for 20% approximately State during the same time. same the during State 1 Duringthe12-yearperiod ■ PAGE8 THE EPIDEMIOLOGY OF AUTISM IN CALIFORNIA after whichtimethenumberofconsumerswithautismsteadilyincreased. shows relatively stablenumbersofRegionalCenterconsumerswithautismuntil1981, are duetoautisminCalifornia. children with autismandincreases intheproportion ofdevelopmentaldisorders that Angeles. University ofCalifornia,Davis,andtheircolleagues attheUniversityofCalifornia,Los findings from thestatewidecomprehensive pilotstudyconductedbyresearchers atthe trum disorders inCaliforniafrom 1977to1999.”(SB 160)Thisdocumentreports the factors surrounding theincreased numberofpersons withautismandspec- Disorders (M.I.N.D.)Institutetoprepare acomprehensive pilotstudytoexamineall with theUniversityofCalifornia’s MedicalInvestigationofNeurodevelopmental the DepartmentofDevelopmentalServicesto“enterintoaninteragencyagreement ofincreasesdent observations inautism,theStateLegislature allocated$1,000,000for to answermanyofthequestionsthatwere raisedbythatreport, aswellindepen- T Legislation AuthorizingThisStudy California’s System:1987through DevelopmentalServices 1998”) (from DevelopmentalDisorders “ChangesinthePopulationofPersonswithAutismandPervasive in Figure 1. he findingsfrom theDDSReport generatedmuchconcernandcontroversy. Inorder Number of Enrolled Persons with Autism The numberofcasesautismperbirth yearisshowninFigure 1.Thisfigure 100 200 300 400 500 600 9016 9616 9217 9818 9418 1990 1987 1984 1981 1978 1975 1972 1969 1966 1963 1960 Distribution of birth dates of regional center eligible persons with autism with persons eligible center regional of dates birth of Distribution THE EPIDEMIOLOGY OFAUTISMIN CALIFORNIA Year ofBirth ■ PAGE9 THE EPIDEMIOLOGY OF AUTISM IN CALIFORNIA○○○○○○○○○○○○○○○○○○○○○○○○○○○○○○○○○○○○○○○○○ rates. United Stateshaveshownlower prevalence studiesdoneinthe the rangeof10-12per10,000,but prevalence estimateshavebeenin identical twinscompared toalessthan1% concordance rateinfraternaltwins. in children withautism.Twin studieshavefoundaconcordance of36% to91%in many chromosomes thatare highlyassociatedwithautism,butnotuniversallyfound from 1.8per1,000to51,000. of autism,withestimatesranging disorders ismuchhigherthanthat prevalence ofotherautismspectrum of autismandothercurrentissues Review ofresearchonthecauses It should benotedthatthechangeindiagnostic criteriafromtheKannerdefinitiontoDSMorICD criteria predatestheincre † Asperger’s Disorder. estimate of1in175fortheprevalence ofautismspectrumdisorders, including An investigationofchildren aged5to11yearsinCambridgeshire (UK)provided an define autismmore broadly. DSM-IV, orICD-9criteria,which studies are basedonDSMIII-R, 50 to70.Mostrecent prevalence affects children withanIQrangeof prototype, where autismusually description oftheclassicautism the pastwere basedon Kanner’s The lowerprevalence estimatesin changes inhowautismisdiagnosed. changes inratesare dueinpart to 4-5 per10,000. to 1985,autismwasbelievedbearare conditionwithanestimatedprevalence of the prevalence ofautismvary, withhigherratesreported inmore recent studies.Prior to belearnedaboutwhatcausesautismorevenhowcommonis.Estimatesof A Epidemiology ofAutism than females. general populationof0.05-0.1%.)Autismoccursin males3to4timesmore frequently to youngsiblingsofchildren with autismis4.5%compared totheoccurrence inthe According toprevious data,themajorityof children withautism(about75%) have sibling recurrence riskis45-90timesthatofthegeneralpopulation. ○○○○ spans 1987to1998. utism affectsneurodevelopment inmultipleandprofound ways,yetmuchremains Many children withautismalsohaveothermedical anddevelopmentalconditions. Epidemiological studiesdemonstrateastrong genetic component.Therelative 3 Itissuggestedthatthe 2-4 Studiesoffamilieswithmultiplyaffected membershaveidentified 2 Sincethattime, THE EPIDEMIOLOGY OFAUTISMIN CALIFORNIA 5 † The 3,4 Autism produces profound effects profound produces Autism in neurodevelopment in multiple in neurodevelopment in ways, yet much remains to be to remains much yet ways, learned about what causes autism causes what about learned or even how common autism is. autism common how even or ases noted in the DDS Report, which ases notedintheDDSReport, 6 (Recurrence risk ■ PAGE10 7,8 THE EPIDEMIOLOGY OF AUTISM IN CALIFORNIA of developmentalmilestones)isreported in30%to35%ofcases, regression ofdevelopment(i.e.aperiodnormalthenanapparent loss food allergies. mental insultshasalsobeensuggested. this association. mental retardation. gastrointestinal disorders, viral exposures, vaccinations, children. suspect postnatalfactorscontributetothedevelopmentofautismforatleastsome autism. that occuratleastbythefirstmonthofgestationforalarge numberofchildren with ears, whichwouldsuggestchanges with autismhadposteriorlyrotated at birth foundthat42%ofchildren study ofmorphologicchangesnoted and neurotrophins. elevated levelsoffourneuropeptides sample ofchildren withautismhave autism showedthat95%ofasmall from children laterdiagnosedwith ses ofneonatalbloodspotstaken origin forautism.Datafrom analy- support foraprenatal orperinatal answered. Somestudiesprovide begins inanychildremains tobe However, mostchildren withautismdonothavearecognizable geneticsyndrome. sclerosis, Angelman'ssyndrome, epilepsy, sensoryimpairments,neurofibromatosis, visualandauditory tuberous nuclear cellswasdetected inthree ofninechildren withautisminonestudy. scrutiny followingthecase seriespresented byWakefield, tion betweenmonthofbirth andautism, ders without“full”autismdonot. children withcerebral palsy. with mentalretardation, butnotin and were alsofoundinchildren findings were notspecifictoautism concluded thattheattributableriskassociatedwith theseexposures issmall. chickenpox, measles,mumpsorrubellawasassociated withautism,butfurther association oftheMMRvaccination. previously normalchildren, developmentofautism andenterocolitis, andtemporal Many otherassociationshavebeensuggestedbypriorstudiesofautism,including The questionastowhenautism The possibleassociationofautismwithvaccinations hasreceived increased Viral causeshavebeensuggestedduetoearlyfindingsthatanassocia- 12 Whilemostchildren with autism displaydelayeddevelopmentfrom birth, 24,25 30,31 Theinteractionbetweenageneticpredisposition andearlyenviron- THE EPIDEMIOLOGY OFAUTISMIN CALIFORNIA 9 11 Onestudyfoundthatprenatal orneonatalexposure to (Whereas, themajorityofchildren withautismspectrumdisor- However, these 21 prenatal exposure tothalidomide, 11 17 A immunologicfactors, 10 untreated phenylketonuria,andfragile-Xsyndrome. 2 ) Otherconditionsassociatedwithautisminclude 21 Vaccine strainmeasles inperipheralmono- 26 27-29 The question as to when to as question The butotherstudieshavefailedtoconfirm autism begins in any child any in begins autism remains to be answered. be to remains 18 autoimmunedisorders, et al 22 describingregression in anticonvulsants, 13-16 leadingsometo ■ PAGE11 32 33 19,20 How- 23 and THE EPIDEMIOLOGY OF AUTISM IN CALIFORNIA especially forthoseconsideringimmunizationstheirlater-born children. tion andautism. ever, populationstudieshavenotfoundacausalassociationbetweenMMRvaccina- was DSM-IIIandDSM-IIIR duringthestudyperiodforDDSReport. Priortothis standard atthetimeofdiagnosis.Thecurrent standard isDSM-IV, butthestandard CDER status1autismhas beenassumedtomatchthecriteriafrom therecognized autism. Furthermore, the RegionalCenterthreshold forestablishing adiagnosisof CDER Status9autism.Thisprocess wouldartificially inflatethenumberofcases order thatwouldnotbeavailabletothoseclassifiedas to qualifythemforservices (meeting DSM-IVcriteria)maybegiventheclassification ofCDERstatus1autismin reasoning, children withautisticfeatures thatdonothave“fullsyndrome autism” affected, thenumber ofcaseswillbeartificially increased. Followingthisline of of casesidentified.Ifthecriterialoosentoincludemore children whoare lessseverely ent increase inautismcasescanbeexplainedbytheincrease intheState’s population. bytheState’sserved RegionalCentersystem.Thus,onlyasmallportion oftheappar- an order ofmagnitudelessthanthetwo-tothree-fold increase inpersonswithautism from 1985to1995,whichis creased byapproximately 20% California’s populationin- over thetimeofstudy. address populationgrowth and improved casefinding. moving infrom out-of-state, of children withautism tion, increases inthenumber of autismasmentalretarda- autism, priormisclassification establish thediagnosisof loosening thecriteriausedto overall populationofchildren, include increases in the Thesefactors ing forservices. children with autismpresent- increases thenumberof of factors)thatartificially other factor(orcombination rates ofautismortosome increase innumbersofRegionalCenterindividualswithautismisdue toincreased O in theContextofCurrentStudy Implications ofCurrentUnderstandingAboutAutism ne ofthemostcontroversial aspectsoftheDDSReport iswhetherthesignificant Changes inthediagnosticcriteriaforaspectrum disorder canchangethe number The DDSReportdidnot 13, 34 THE EPIDEMIOLOGY OFAUTISMIN CALIFORNIA Theissueisfarfrom resolved forparents ofchildren withautism, Only a small portion of the of portion small a Only apparent increase in autism cases autism in increase apparent can be explained by the increase the by explained be can in the State’s population. State’s the in ■ PAGE12 THE EPIDEMIOLOGY OF AUTISM IN CALIFORNIA of mentalretardation. autism casesinCaliforniawasunknown. study, increase theextenttowhichmisclassificationcontributedobserved in the uncertainty about theincreasing prevalence ratesofautismraisesdoubtsthat the result of anewexposure. Whilegeneticfactorsare strongly associatedwithautism, etiology ofautismisunknown and2)theincrease inreported casesofautismcould be present totheRegionalCenters. finding overtimehaveresulted inanychangesthenumberofautisticchildren who young children. Thisstudydoesnotexaminetheextenttowhichdifferences incase have increased thediagnosisandtreatment ofdevelopmentaldisorders ininfantsand have beenfurther increased bytheimplementationofearlyinterventionprograms that directed totheRegionalCentersforservices.AutismcasefindinginCalifornia could by bothparents andprofessionals mayresult in more children withautismbeing forchildrenand financingservices withautism.Still,improved recognition ofautism virtually everycaseofautism,becausetheRegional Centersare pivotalincoordinating not countedinCDERdata.SomeassumethattheRegionalCentersystemcaptures outside theRegionalCentersystemare State’s RegionalCenterSystem.Children only describechildren includedinthe cases ofautisminCalifornia.CDERdata an apparent increase inthenumberof study. migration wasnotknownpriortothis increase inautismcanbeexplainedbyin- nia. Theextenttowhichtheobserved state provides thanCalifor- fewerservices may movetoCaliforniaiftheirhome children withautismfrom anotherstate in California.Onemightpostulatethat incidence ratesofautismamongchildren autism, butnotbeduetoincreased real increase inthenumberofcases intensive therapieswasnotasgreat. diagnosis ofautismtoallowforearly past, whentheimperativeforearly misclassification occurred more inthe data asautistic(CDERstatus1autism)withmentalretardation. Presumably, this CDER Status1inthepast,butnowsimilarlyaffected children maybeentered intothe tion withautisticfeatures. Thismighthavebeenrecorded assomethingotherthan with bothmentalretardation andautismcouldbeclassifiedashavingmentalretarda- classified couldcauseanartificial increase inautismcases.Itispossiblethatchildren Recent datasuggestthattheincrease incasesofautismmatchesadecrease incases One ofthereasons thattheDDSReport generated somuchconcernisthat1)the Improved casefindingcouldresult in In-migration couldcontributetoa THE EPIDEMIOLOGY OFAUTISMIN CALIFORNIA 35 Changesinhowbothautismandmentalretardation are Only a small portion of the of portion small a Only apparent increase in autism in increase apparent cases can be explained by explained be can cases an increase in the State’s the in increase an population. ■ PAGE13 ○○○○○○○○

THE EPIDEMIOLOGY OF AUTISM IN CALIFORNIA contracting vaccinepreventable illnesses. will ceasetofollowrecommended vaccinationschedules,placingchildren atriskof especially MMR.Thishasledtoconcernsamongpublichealthofficials that parents Some oftheconcernisfocusedonapotentialassociationautismwithvaccinations, potential causes,hasimplicationsbeyondthechildren withautismandtheirfamilies. typical geneticcondition.Thisuncertainty, alongwithparental concernsaboutother for care totheRegionalCentersystemisfarinexcessofwhatwouldbeexpectedfora genetic factorsaloneare responsible. Theincrease inchildren withautismpresenting Scientific Advisory Panelmembers areScientific Advisory listed inAppendix4. were madefollowing the receipt oftheircomments. Thenamesandaffiliations of the was senttotheScientificAdvisory Panelforreview in April2001,andsomechanges staff madeadjustmentstothefocusandmethodology forthestudy. Afinal proposal recommendations thatcameout ofthatmeeting,thePrincipalInvestigatorandstudy draft research proposal fortheAutismEpidemiologyStudy. T Panel Scientific Advisory T Aims oftheStudy ○○○○○○○○○○○○○○○ ○○○○○○○○○○○○○○○○○○○○○○○○○○○○○○○○ he M.I.N.D.InstituteconvenedaScientificAdvisory Paneltoreview andadvisethe he principalaimsofthisstudyare listedbelow: The panelmetNovember11-12,2000,inSacramento, California.Followingthe ■ ■ ■ ■ ■ ■ Study Aim1: Study Aim6: Study Aim5: Study Aim4: Study Aim3: Study Aim2: to diagnosis CDER status 1 autism account for a significant proportion of the of proportion significant a for account autism 1 status CDER diagnosis to with an increase in the recurrence rate of autism in subsequent siblings. subsequent in autism of rate recurrence the in time. over increase an changed with has this if determine to and autism, child’s their caused time. over changed autism moving into California for services account for a significant proportion significant a for account services for California into moving autism autism as mental retardation in the past has contributed to an apparent an to contributed has past the in retardation mental as autism increased numbers of cases of autism. of cases of numbers increased of the increased cases of autism reported to DDS. to reported autism of cases increased the of increase in the number of children with autism. with children of number the in increase THE EPIDEMIOLOGY OFAUTISMIN CALIFORNIA

To investigate whether changes over time in the criteria used criteria the in time over changes whether investigate To To determine if vaccination with MMR vaccine is associated is vaccine MMR with vaccination if determine To believe autism with children of parents what ascertain have To autism with children of characteristics how describe To To investigate whether the misclassification of some cases of cases some of misclassification the whether investigate To To investigate whether temporal changes in children with children in changes temporal whether investigate To ■ PAGE14 THE EPIDEMIOLOGY OF AUTISM IN CALIFORNIA past, allowingforonestandard to beappliedchildren ofdifferent ages. for features ofautismthatmaynotcurrently applytothechild,butdidoccurin whether thechildmeetsDSM-IVcriteriaforautism. Thisstudyinstrument alsoprobes Methods * Autism Diagnostic Interview-Revised (ADI-R)andSocialCommunicationQuestionnaire (SCQ),copyright2001,Western AutismDiagnosticInterview-Revised Psychologica * Methods forStudyAim2: Methods forStudyAim1: D study aimbelow, followedbyadescriptionofrecruitment andenrollment procedures. family orahealth-care provider. Detailsoftheresearch methodsare presented byeach Vaccination Study),andimmunizationrecords provided byeithertheparticipating sion Validation Interview(adaptedfrom aquestionnaire from theAutismRegression/ tion Questionnaire (SCQ)*,theChecklistforAutisminToddlers (CHAT), theRegres- study questionnaire. Additionalsources ofinformationwere theSocialCommunica- charts; —Revised(ADI-R)*;and4)adetailed 3)TheAutismDiagnosticInterview autism isthatsomechildren withautismmay havebeenmisclassifiedashaving developmental disorders including autism. view ofparents orcare providers ofchildren oradultswithsuspectedpervasive child withautism.TheADI-Risaninstrument thatprovides asemi-structured inter- diagnosis; and2)conductinganADI-Rinterviewwiththeparents orguardians ofthe documentation ofdiagnosticcriteriaappliedatthetimechildreceived theautism Regional Centerrecord todetermine criteria were assessedby1)reviewing the Regional CenterinCalifornia.DSM-IV systematically selectedtorepresent each of children from thesetwogroups was 1993-1995 (Cohort 2).Arandomsample (Cohort 1)andchildren between born were children between1983-1985 born Center system.Thetwobirth cohorts full syndrome autisminthe Regional cohorts ofchildren withadiagnosisof for autismwere assessed intwobirth CDER status1autism,DSM-IVcriteria may havechanged.To studytemporalchangesindiagnosticcriteriaassociatedwith status 1autismisthatthecriteriafordeterminingifachildhasfullsyndrome autism ○○○○○○○○○○○ classified as having mental retardation. mental having as classified autism. 1 status CDER with associated CA. TheU.C.DavisM.I.N.D.Institutewasprovided licenseandauthorizationtoreprint forspecific researc theseinstruments ata forthestudycamefrom fourmainsources: 1)CDERdata;2)RegionalCenter Another potentialexplanation fortheobservedincrease inthenumberof casesof increaseOne possibleexplanationfortheobserved innumberofcasesCDER THE EPIDEMIOLOGY OFAUTISMIN CALIFORNIA Change in diagnostic criteria diagnostic in Change Proportion of children with DSM-IV autism DSM-IV with children of Proportion 36 TheADI-Rcanbescored todetermine Uncertainty about the about Uncertainty increasing prevalence increasing rates of autism raises autism of rates doubts that genetic factors genetic that doubts alone are responsible. are alone h use. l Services, LosAngeles, l Services, ■ PAGE15 THE EPIDEMIOLOGY OF AUTISM IN CALIFORNIA criteria are thestandard forcomparisoninthisstudy. many ofthechildren inCohort 1were diagnosedwithmentalretardation, butthese recognized thatDSM-IVcriteriaisastandard thatwasnotestablishedatthetime Study Aim1,results oftheADI-RhavebeenequatedwithDSM-IVcriteria.Itis diagnosis. PositiveSCQscores were followedupwithaconfirmatory ADI-R.Aswith that achildmayhaveanautismspectrumdisorder, anautism butdoesnotconfirm tionnaire) canbeusedtoscreen forautistic-likebehaviors.Apositive score indicates Questionnaire (SCQ).Theshort SCQ(previously named theAutismScreening Ques- For eachparticipatingchild,parents orguardians completedaSocialCommunication between 1983-1985andCohort 2iscomprisedofchildren between1993-1995. born Cohort 1iscomprisedofchildren born criteria forautism.AswithStudyAim1, dren whomeetorhavemetDSM-IV determine theproportion ofthesechil- CDER status1autismwere studiedto mined tohavementalretardation without the present. (without autism)inthepastcompared to misclassified ashavingmentalretardation children who meetautismcriteriawere tively doubletheautismrate. having mentalretardation couldeffec- misclassification ofchildren reported as a smallchangeintherateof children with CDERstatus1autism,and is significantlygreater thanthenumberof retardation servedbytheRegionalCenters The numberofchildren withmental misclassifications occurred inthepast. mental retardation, andthatmore ofthese Methods forStudyAim3: increase. increase incasesofautism,butitcouldaccount forsomeportion oftheobserved California. Itisnotexpected thatin-migrationwillaccountfor100%oftheobserved Regional Centersystemthatisnotduetoincreased autismratesamongthechildren of then there couldbeanincrease inthenumberofchildren bythe withautismserved born out-of-stateandmovedtoCaliforniafordevelopmental oreducationalservices, there has beenatemporalincrease intheproportion ofchildren withautismwhowere autism isthatchildren withautism from other statesmovetoCalifornia forcare. If that accounts for increased number of cases of CDER status 1 autism. 1 status CDER of cases of number increased for accounts that Two birth cohorts ofchildren deter- We investigatedwhetherornotmore A third increase possibleexplanationforanobserved incasesofCDERstatus1 THE EPIDEMIOLOGY OFAUTISMIN CALIFORNIA Change in in-migration of children with autism with children of in-migration in Change A possible explanation for an for explanation possible A observed increase in cases of cases in increase observed autism is that children with children that is autism autism from other states move states other from autism to California for care. for California to ■ PAGE16 THE EPIDEMIOLOGY OF AUTISM IN CALIFORNIA Methods forStudyAim4: Methods forStudyAim5: sion) inthechildwasalsoascertained. Alistofquestionsisprovided inAppendix5. A historyofgastrointestinal symptomsorlossofdevelopmental milestones(regres- exposures duringthepregnancy. and problems orenvironmental associated medicalconditions, mental retardation, seizures, graphic information,presence of viewed todeterminedemo- questionnaire orwere inter- completed adetailedstudy teristics overtime.Families demographic andothercharac- 1 toassessanyoverallchangesin autism constructedforStudyAim of children withCDERstatus1 Aim 4,weevaluatedthesample previously verified.ForStudy tion. Thisfindinghasnotbeen less likelytohavementalretarda- with CDERstatus1autismare children more recently reported The DDSReportsuggeststhat nosed inthemore distantpast. symptoms thanchildren diag- higher cognitivefunctionandtohaveexperiencedregression andgastrointestinal that thoseautisticchildren whowere more recently diagnosedare more likelytohave horts. Study Aim4.Responsestothisquestionwere compared betweenthetwobirth co- included aspart ofthe detailed studyquestionnaire orinterviewthatwasusedfor developmental problem?” toparents ofchildren withautism.This questionwas families believe to be the cause of autism in their child and child their in autism of cause the be to believe families time. over autism 1 status CDER with children of whether this has changed in two age cohorts. age two in changed has this whether Some havesuggestedthattheprofile ofchildren withautismhaschangedsuch We askedthequestion, “Whatdoyouthinkcausedyourchild’s autismorother THE EPIDEMIOLOGY OFAUTISMIN CALIFORNIA Change in characteristics in Change Determination of what of Determination Some have suggested that the that suggested have Some profile of children with autism with children of profile has changed. has ■ PAGE17 THE EPIDEMIOLOGY OF AUTISM IN CALIFORNIA Methods forStudyAim6: siblings). nated siblingstotherateamongunvaccinated (andtopartially vaccinated an adequatesample,wewouldcompare therateofautismand/orPDDamongvacci- have acopy).Amongfamilieswithatleastonechild affected withautism,assuming immunization records from thefamilyorhealth-care provider (ifthefamilydidnot (e.g. vaccinationwithMMR)were gathered byrequesting acopy ofthesiblings’ CHAT forsiblings18monthsofagethrough 23monthsofage.Vaccine exposures family tocompleteeithertheSCQforsiblings24monthsofageandolder, orthe siblings wasascertained byasking the autism andPDDamongsubsequent autism inthesesiblings.Theincidenceof B vaccines,andthedevelopmentof choices, specificallyMMRandHepatitis gated theassociationofvaccination who haveyoungersiblings,weinvesti- the sub-sampleofchildren withautism to answerStudyAims1,3,4and5.For were askedoftheentire sample selected subsequent siblings.Thesequestions vaccination choicesmadebyparents with including questionsaboutsiblingsand MMR. subsequent siblingsvaccinatedwith autistic children whochoosenottohave with MMR,compared tofamilieswith who electtohavesiblingsvaccinated siblings ishigheramongthosefamilies not therateofautisminsubsequent experiment” toinvestigatewhetheror mately 5%),allowingfora“natural autism amongfamilieswithatleastoneaffected siblingisrelatively high(approxi- opting outofvaccinatingsubsequentsiblingswithMMR.Therecurrence rateof many —uptohalfoffamilieswithonechildaffected withautismorPDDare the CentersforDiseaseControl inAtlanta,Georgia, anecdotalreports suggestthat increases the recurrence rate of autism in subsequent (younger) siblings. (younger) subsequent in autism of rate recurrence the increases This studyaimwasinvestigatedby Based ondiscussionswiththeCalifornia Birth DefectsMonitoringProgram and THE EPIDEMIOLOGY OFAUTISMIN CALIFORNIA Determination if vaccination with MMR with vaccination if Determination The recurrence rate of rate recurrence The autism among families with families among autism at least one affected sibling affected one least at is relatively high allowing high relatively is for a “natural experiment” “natural a for to investigate whether or whether investigate to not the rate of autism in autism of rate the not subsequent siblings is siblings subsequent higher among those families those among higher who elect to have siblings have to elect who vaccinated with MMR. with vaccinated ■ PAGE18 ○○○○○○○○○○○○○

THE EPIDEMIOLOGY OF AUTISM IN CALIFORNIA Enrollment Procedures and Recruitment response withinthree weeksofthefirst mailing. staff tothepotentialstudysubjects.We conductedonefollow-upmailingif wehadno asan“introduction”English andSpanish.These packetsserved oftheUC Davis study anonymous response form andpostagepaidenvelope.Allitemswere printedinboth one-page descriptionofthe studyprocedures, informedconsentdocuments, and an randomly ordered list.Thepacketincluded aletterfrom DDSdescribingthestudy, a ceeded bymailingarecruitment packettofamiliesaccording totheirpositiononthe Center, yearofbirth, anddiagnosistoproduce asamplingframe.Recruitmentpro- tion (MRcohorts 1and2).Thesegroups were thenrandomlysorted byRegional have fullsyndrome autism(inthecaseof cohorts 1 and2)ormentalretarda- cohort andbytheRegionalCenter where theywere firstassessedanddetermined to the yearofbirth (1983-85and1993-95).Potentialstudysubjectswere separated by CDER (fullsyndrome autismormentalretardation withoutfullsyndrome autism)and A obtained informedconsenttoparticipate. How wecontactedfamiliesand study, aswellwhatfamiliesdidiftheyagreed toenroll, are describedbelow. The specificprocedures thatweemployedtocontactandinform familiesaboutthe describe ourapproach toinitialandfollow-upcontactotherstudyprocedures. families intheleastinvasivemannerpossible.“LowImpact”wastermweusedto licited invitationtoparticipate. Itwasourintentionforthisstudytorecruit andenroll Thus,eachfamily thatwasselectedforthestudyreceivedservices. atleastoneunso- pate inthisstudybasedonarandomsampleofchildren whoreceived RegionalCenter included intheRegionalCenters’administrativedata.Familieswere askedtopartici- calculations canbefoundinAppendix6. 2). Further detailsoftheselectiontarget samplebyRegionalCenterandsize dren witheachcondition(ADandMR)within agegroup (Cohort 1andCohort numbers were determinedforeachRegionalCenterbasedontheproportion ofchil- which there were only991children. Within the4studygroups, target enrollment or approximately 1500,ineachgroup, exceptfor theolderautismgroup (AD1)for and MR2).Thesamplingframewasconstructed toinclude6timesthetarget number, number ofchildren withmentalretardation overthissameperiod. birth cohorts thatare separatedby10yearsandreduction byapproximately 25%the These changesreflect atriplingofthenumberchildren withautismbetweenthese In the1993-95cohort, theMRnumberswere only3-foldthatoftheautismnumbers. status 1autism)was12timesgreater thanthatofchildren withCDERstatus1autism. 1983-85 cohort, thenumberofchildren withmentalretardation (withoutCDER T ○○○○○○○○○○○○○○○○ he CDERrecords formedthebasisforidentifyingstudysubjectsthisstudy. Inthe s describedpreviously, wehadfourstudygroups basedonthechild’s diagnosisin The studypopulationwaslimitedtothosechildren whoseCDERreports were The target samplewasapproximately 250children ineachgroup (AD1,AD2,MR1 THE EPIDEMIOLOGY OFAUTISMIN CALIFORNIA ■ PAGE19 THE EPIDEMIOLOGY OF AUTISM IN CALIFORNIA Evaluation of younger siblings younger of Evaluation questionnaire study the Completing interview ADI-R the Scheduling Specific procedures forfamiliesofchildren withautism staff) orbyRegionalCenterstaff themselves. made eitherbyacontractedcompany(afterthechart waspulledbyRegionalCenter informed consent(whichauthorizedtherelease oftheserecords). Photocopieswere W abstraction Chart viewed withthemthestudyprocedures. lope. Uponhearingfrom afamilythattheywere interested inparticipating were- contact ususingatoll-free numberorreturn aresponse forminapostage-paidenve- subjects basedontheagegroup, diagnosis,andtheRegionalCenter. Familiescould who didn’t respond, were replaced bythenextchildonrandomlistofstudy months oldtoassessvaccinationstatusanddevelopmental outcomes. 18 months,werequested permissiontocontactthefamilywhenchildturns 24 sibling, basedontheageofsibling.Foryounger siblingswhowere youngerthan the parent/guardian complete oneoftwoautism-screening testsforeachyounger received theconsentdocument. tocompletethestudyquestionnairetelephone interview thiswassetupwhenwe envelope inwhichtoreturn thecompletedquestionnaire. Ifthefamilyrequested a receipt ofthesignedconsentdocument.We provided apre-addressed, postage-paid Excellence inAutism(CPEA)Regression/Vaccination Study. view wasadaptedfrom aquestionnaire developedfortheCollaborativePrograms of view overthetelephonewithaparent orguardian. TheRegression Validation Inter- detailed assessmentwasconductedbyadministeringtheRegression Validation Inter- to compensatethemfortheirtime. speaking families.Parents/guardians were paid$35attheconclusionofinterview tered theADI-R.Theinstrument wastranslatedinto SpanishforusewithSpanish- branch office thatwasclosesttothefamily. Atrained,certifiedstaff personadminis- interview. Inmostinstances,theseinterviewswere conductedattheRegionalCenter e requested aphotocopyoftheRegionalCenterrecord afterreceiving thewritten Participation inthestudywasvoluntary. Familieswhodeclinedtoparticipate, or For siblingsatleast18months ofagebutlessthan24monthsage: If there were youngerhalf-orfull siblings oftheautisticsubject,werequested that A copyofthestudyquestionnaire wasmailedtothefamilyforcompletionupon If thefamilyreported ahistoryofregression duringtheADI-Rinterview, amore After agreeing toparticipate inthestudy, familieswere scheduledforanADI-R scored usingstandard documentationandentered intoasiblingdatabase. Toddlers (CHAT) form foranysiblingwithinthisagegroup. Resultswere The parents/guardians were askedtocomplete aChecklistforAutismin THE EPIDEMIOLOGY OFAUTISMIN CALIFORNIA ■ PAGE20 ○○○○○○○○○○○○○○○○○○○○

THE EPIDEMIOLOGY OF AUTISM IN CALIFORNIA participation inthestudywere sentto100familiesofchildren withautism(50ineach (Cohort A)compared tochildren in1991or1992(Cohort born B).Letters inviting pilot differed from thestatewidestudy, withchildren ineither1986or1987 born their proximity totheM.I.N.D.Institute.Theyear ofbirth forsubjects selectedinthe This studyinvolvedtwoRegionalCenters,AltaCalifornia andValley Mountain, dueto the ADI-RandSCQ,RegionalCenterchart abstraction,andconductoftheinterview.). in twoagecohorts withautismandchildren withmentalretardation, performance of A Methods andProcedures Validating Study enrollment of Completion ADI-R the using autism for Assessment questionnaire study and SCQ the Completing with childrenmentalretardation Specific procedures forfamilies enrollment of Completion compensated $35fortheirtimeattheinterview. the twoquestionnaires. Ifthefamilyparticipated theywere inanADI-Rinterview also study subjectswithmentalretardation whoseSCQscores were positive(score that appeared inadvertently omitted. contacted familiesbytelephonetoclarifyinconsistenciesorcompleteresponses we received theconsentdocument.Studystaff reviewed returned questionnaires and requested tocompletetheseinstrumentsthiswassetupwhen atelephoneinterview postage-paid envelopeinwhichtoreturn thecompleted questionnaire. Ifthefamily tion uponreceipt ofthesignedconsentdocument.We provided apre-addressed, pleting thequestionnaires. omitted. We sentacheckintheamountof$30tofamilythankthemforcom- phone toclarifyinconsistenciesorcompleteresponses thatappeared inadvertently ○○○○○○○○○○○○ smallstudywasconductedtotestallaspectsofthe study(identificationofchildren For siblingsatleast24monthsofage: We sentacheckintheamountof$35tofamilythankthemfor completing wasscheduledatthelocalRegionalCenterforfamiliesof ADI-Rinterview An A copyofthestudyquestionnaire andSCQwere mailedtothefamilyforcomple- Study staff reviewed thereturned questionnaires andcontactedfamiliesbytele- entered intoasiblingdatabase. months ofageorolder. Resultswere scored usingstandard documentationand The parents/guardians were askedtocompleteaSCQforeachsibling24 THE EPIDEMIOLOGY OFAUTISMIN CALIFORNIA ■ PAGE21 ≥ 22). ○○○○○○○○

THE EPIDEMIOLOGY OF AUTISM IN CALIFORNIA additional dataonvaccinationpracticesinfamilieswithchildren withautism. the laststudyaim.Thisaimwasincludedinstatewidetoprovide answered bythestatewidestudy. Theteststudysamplesizewasinsufficient toanswer but pilottestingdemonstratedthatfiveofsixthestudyaimswouldlikelybe group. Thesampleintheteststudywastoosmalltodrawanydefinitive conclusions, record forautismandADI-Rresults. Also,casesofautismwere foundintheMR The teststudysuggestedthatthere wassomedegree ofdiscrepancy betweentheCDER low response rateintheMRgroup, incentiveswere increased in thestatewidestudy. in thepilot,16%ofthoseCohort Aand10%ofthoseinCohort B.Asaresult ofthe 44% forCohort B.Fewerfamilieswhosechildren hadmentalretardation participated cohort). Responserateswere higheramongtheautism group, 38%forCohort Aand age cohort) and100familiesofchildren withmentalretardation (50ineachage MR). strategy bynestingtheanalysisRegionalCenter, agecohort,andcondition(ADvs was exhausted.AnalysiswithSUDAANsoftware accountedforthiscomplexsampling ment proceeded ineachcelluntilthetarget numberwasachievedortherandomlist cohort asdrawnfrom CDERrecords were randomlyordered withina“cell.”Recruit- P Statistical Analysis statistically significantiftheywere factoring inthelikelihoodofmailingwithinagiven cell.P-valueswere considered enrollment foreachsubjectwhowassentamailingrequesting participation and 2, 4,or9).Weighting factorswere determinedusingthecalculatedprobability of any CDERrecord withthedesignationofan autismspectrum disorder (CDERStatus group, anadditional variablewasincludedthatspecifiedwhetherornotachildhad status 1autismdiagnosissubsequentlylosesthat designation.FortheMR additional dichotomousvariablewasincludedforwhetherornotachildwithCDER dichotomous variableforaprimarylanguageofSpanish.Fortheautismgroups, an parent(s), (4)adichotomousvariableforprimarylanguageofEnglish,and(5) dichotomous variableforwhetherornotachildwaslivingathomewiththeir with theRegionalCentersmightbemore inclinedtoparticipate), (2)sex,(3)a individual hadmultipleCDERrecords (assumingthatchildren withlongercontact both groups, thesemodelsincluded(1)adichotomousvariableforwhetherornotan likelihood ofresponse orenrollment were determinedintheseenhancedmodels. For condition, aswellfactorsrecorded intheCDERdatathatmightinfluence rates withincells. ○○○○○○○○○○○○○○○○ otential research subjectsbasedondiagnosticgroup, RegionalCenter, andage 37 PosthocanalysesusedsomeoftheCDERdatatoadjustfordiffering response THE EPIDEMIOLOGY OFAUTISMIN CALIFORNIA 38 Theprobability ofenrollment byRegionalCenter, agecohort, and ≤ 0.05. ■ PAGE22 ○○○○○○○○○○○○○○○○○○○○○○

THE EPIDEMIOLOGY OF AUTISM IN CALIFORNIA for the Autism Epidemiology Study. Epidemiology Autism the for Recruitment andEnrollment Recruitment Table 1. with autism(93%)andlowestfortheoldergroup with MR(50%). proportion oftheenrolled tothe target enrollment washighestfortheyoungergroup No response wasobtainedfor63%ofthoserecruited despitetwomailings.The did nothaveautism.About15%ofourmailingswere returned marked“badaddress.” sponded thatseizures were herchild’s mainproblem, andtworeported thattheirchild privacy concerns.Oneparent notedthatherdaughterhadRett’s Disorder, onere- in otherstudies,somewere dealingwithacutemedicalproblems, andsomecited busy, ortheydidnotwanttosubjecttheirchildanymore tests.Somewere already sponded thattheydidnotwanttoparticipate, mostlycitingreasons thattheywere too late tocompletethecomponentsofstudy. About5%ofrecruited familiesre- willing toparticipate, buteitherfailedtoreturn asignedconsentform ordidsotoo sponse ratebyRegionalCenter(notshown).Asmallnumberofrespondents were AD1=18%, MR1=10%,AD2=24%,MR2=15%).There were alsodifferences inre- ences inresponse ratesbasedontheconditionandagegroup (response rate: T ○○○○○○○○○○○○○○ able 1summarizestherecruitment andenrollment forthestudy. There were differ- ee epne 4 5 1 920 717 859 48 185 540 232 48 9 1 8 3 124 76 1548 143 9 10 10 3 1384 7 44 1554 9275 1161 1572 4 5 7 2 20 3209 1388 991 12139 13 892 3 4 0 1 991 Other Never responded Responded —notwillingtoenroll 0 Initially enrolledbutlaterwithdrewfromstudy Willing, butnotEnglish-orSpanish-speaking Wait listed(willingbutRegionalCentergroupfull) Willing consenttoolate butreturned Willing, butdidn’t consent return Enrolled Total mailed(recruited): Sampling frame Total CDERrecords erimn akt o ald2 5 69 29 353 193 15 1 2 0 46 101 8 64 23 18 1 292 0 1 38 8 138 23 12 2 71 8 36 4 11 0 Recruitment packetsnotmailed 3 23 undeliverable Bad address,returned, Bad addressinfile,notmailed Residing inanotherstate,responded orreturned Residing inanotherstate,file,notmailed Unmatched IDNumber, notmailed Deceased, respondedorreturned Deceased, infile,notmailed Status of recruitment and enrollment efforts as of September 30, 2002 30, September of as efforts enrollment and recruitment of Status THE EPIDEMIOLOGY OFAUTISMIN CALIFORNIA Autism (AD1) CDER Birth YearBirth 1983-85 (MR1) CDER MR Autism (AD2) CDER Birth YearBirth 1993-95 ■ PAGE23 (MR2) CDER MR ○○○○○○○○○

THE EPIDEMIOLOGY OF AUTISM IN CALIFORNIA by age group, Autism Epidemiology Study. Epidemiology Autism group, age by Study Aim1Results Table 2. presented inTable 2. comparison betweenthetwoagecohorts ofchildren withCDERstatus1autismare symptoms (age<36months)wasconsistentwithadiagnosisofautism.Theresults of terns) metcriteriamatchingDSM-IVforautism,andtheageofonset tion, CommunicationImpairments,andRepetitiveBehaviorsStereotyped Pat- scores ineachofthree domains(QualitativeImpairmentsinReciprocal SocialInterac- children in the autismgroups. Theresults oftheADI-Rwere considered positiveif A their childas havingautism,onereported PDD,and onereported ChildhoodDisinte- were returned for 20ofthe23children withanegativeADI-R;18parents reported other basedonanswersgiven duringtheADI-R.ForCohort 2,studyquestionnaires meet DSM-IVcriteriaforautism, parents hadreported autisminoneandPDDthe reported Rett’s Disorder. Inthetwo remaining children whoseADI-Rscores didnot their childhadautism,tworeported PDD,onereported Asperger’s Disorder, andone questionnaires were returned for13ofthese15children; nineparents reported that ADI-R despitehavingaCDERstatus1autismdesignation. ForCohort 1,study this report are real andnotjustafabricationbasedoncomplexstatisticalmodeling. presented forthefirstthree studyaimstoassure readers thattheresults presented in both simplecomparisonsandthemore complex, butmore accurate,analysesare closely matchresults from amore precise weightedandadjustedanalysis.Resultsfrom mates asimplerandomsample.Thismeansthat comparisonsoftheresults effect ofnearly1showsthatthecomplexsamplingemployedin the analysisapproxi- and response byRegionalCenterandagecohort (88.2%and88.7%).Thedesign very littlewhenapplyingaweightingfactorandaccountingfordifferences insampling met DSM-IVcriteria,compared to89.4%inthe1993-95group. Theresults change two agecohorts. Usingunadjustednumbers,88.9%ofchildren inthe1983-85group met DSM-IVcriteriaforautismandthatthisclosecorrelation differs little betweenthe ○○○○○○○○○○○○○○○○○ einEfc .80.99 0.0215 1.08 0.0289 193 0.97 232 216 120 89.4% 0.78 0.90 143 88.9% 135 93.1% 88.7% 94.4% 88.2% Design Effect Standard Error for thestagedsamplingdesign) PositiveADI-R(Weighted,Proportion adjusted (Unweighted andunadjusted) PositiveADI-R Proportion Positive ADI-R ADI-RCompleted Proportion ADI-R Completed Enrolled utism Diagnostic Interviews wereutism DiagnosticInterviews conductedonthemajority(94%and93%)of Thirty-eight children (15from Cohort 1and23from Cohort 2)hadanegative The mainfindingisthatthevastmajorityofchildren withCDERstatus1autism Comparison of ADI-R results for children with CDER status 1 autism, 1 status CDER with children for results ADI-R of Comparison THE EPIDEMIOLOGY OFAUTISMIN CALIFORNIA Birth YearBirth 1983-85 Birth YearBirth 1993-95 ■ PAGE24 p-value THE EPIDEMIOLOGY OF AUTISM IN CALIFORNIA autism who were ADI-R positive, by age group, Autism Epidemiology Study. Epidemiology Autism group, age by positive, ADI-R were who autism overall changeinautismdiagnosticthresholds. autism. Furthermore, thesetwodifferences wouldexert anopposinginfluenceonany Section isnotlikelytobeassociatedwithsignificantchangesinthediagnosisof three-quarter pointdifference betweenscores fortheRepetitive/Stereotypic Behaviors and notlikelytoresult inmajorchangesthediagnosisofautism. Likewise,the younger cohort, butthisdifference ofaquarter pointisoflittleclinicalsignificance There wasastatisticallysignificantdifference inthescore foragecriteriawiththe old formakingthediagnosisofautismchangedlittlebetweentwoagecohorts. between thetwoagecohorts. Theresults (showninTable 3)indicatethatthethresh- that thethreshold formakingadesignationofCDERstatus1autismhadchanged diagnosis ofautismdiffers byagecohort. Differences inmeanscores wouldsuggest two agecohorts totestwhetherornotthenumberofcriteriauseddetermine meet DSM-IVcriteriaforautismwere somewhere ontheautismspectrum. of autism.Thus,mostthechildren intheautismgroups whoseADI-Rscore didnot reported attentiondeficitdisorder, butdidnotspecificallyrefute theirchild’s diagnosis responses, twoparents reported theirchild’s diagnosisasautism;theremaining parent grative Disorder. Fortheremaining three children inthiscohort withoutquestionnaire (Results ofweightedandadjustedanalyses) Table 3. D 19-5 91.102 0.88 0.84 0.22 0.25 0.97 12.41 1.03 13.07 0.28 49 0.32 27 0.94 17.33 1.05 17.88 0.26 144 0.98 0.32 93 16.02 1.23 AD2 (1993-95) 16.66 0.16 193 AD1 (1983-85) 0.23 0.87 120 6.07 —Non-VerbalCommunication Impairment Children 1.03 6.84 AD2 (1993-95) 0.31 193 AD1 (1983-85) 0.98 0.34 120 —VerbalCommunication Impairment Children 23.33 1.27 AD2 (1993-95) 22.86 0.07 193 AD1 (1983-85) 0.11 120 3.50 —Overall Communication Impairment 3.26 AD2 (1993-95) 193 AD1 (1983-85) 120 Repetitive/Stereotypic Behaviors AD2 (1993-95) AD1 (1983-85) Social Impairments AD2 (1993-95) AD1 (1983-85) Age criteria Scores onthethree maincomponentsandtheagecriteriawere compared forthe Comparisons of component scores on ADI-R for children with CDER status 1 status CDER with children for ADI-R on scores component of Comparisons THE EPIDEMIOLOGY OFAUTISMIN CALIFORNIA Positive # ADI-R Mean Score Standard Error Design Effect ■ PAGE25 p-value 0.053 0.20 0.12 0.01 0.31 0.03 ○○○○○○○○○

THE EPIDEMIOLOGY OF AUTISM IN CALIFORNIA retardation without CDER status 1 autism, by age group, Autism Epidemiology Study. Epidemiology Autism group, age by autism, 1 status CDER without retardation Study Aim2Results Table 4. misclassification inbothagecohorts. fication ratewouldhavetobegreater fortheoldercohort. We foundsimilarratesof misclassification tocontributeanapparent increase inautismcases,themisclassi- significant difference inmisclassificationbetweenthetwoagecohorts. Forthistypeof for bothgroups. Theseresults, showninTable 4,demonstratethatthere isnota adjusted forthecomplexsamplingdesign,theseproportions are approximately 18% children in the 1993-95cohort. Whentheresults were weightedandtheanalyses autism. Ofthe1983-85cohort, 17%metcriteriaforautism,compared to21%of system metDSM-IVcriteriaforautism,representing anundercounting ofcases A odds rationof 1.0(95%confidenceinterval 0.82-2.75).Thisslight biasofenrollment listing ofanASDcondition was1.50,butthisnotsignificantlydifferent from an ously) weconsidered thisevidenceforASD.Theoddsratio forenrollment givena (ASD). IftheCDERrecord wasmarkedforAutismStatus2,4,or 9(definedprevi- respond iftheCDERrecord indicated the childmayhaveanautismspectrumdisorder dents. We testedwhetherparents ofchildren in the MRgroup were more likelyto increased thelikelihood ofadifferential response (“bias”)among the parental respon- believed theirchildhadautisticfeatures. Thelowresponse rateinthisgroup also dren intheMRgroups might havebeenmore likelytorespond andenroll ifthey for autismislikelytobeanoverestimation oftheactualpercentage. Parents ofchil- ○○○○○○○○○○○○○○○○○ Aayi egtd dutd 84 87 0.96 18.7% 0.64 18.4% 28 75.7% 37 0.56 66.7% 0.93 0.62 16 0.71 185 24 20.6% 33.5% 82.7% 153 35.3% (Analysis weighted,adjusted) 16.7% 124 32.9% (excluding positiveSCQwithoutafollow-upADI-R) 85.5% Rate ofPositiveADI-R’s 32.1% 106 (excluding positiveSCQwithoutafollow-upADI-R) Rate ofPositiveADI-R’s (among thepositiveSCQ’s) Rate ofPositiveADI-R’s Number ofPositiveADI-R’s (among thepositiveSCQ’s) Number ofFollow-upADI-R’s (Analysis weighted,adjusted) ofPositiveSCQ’sProportion (unweighted andunadjusted) ofPositiveSCQ’sProportion SCQ Positive(score Completion Rate SCQ’s Completed Enrolled portionofchildren categorizedashavingmentalretardation bytheRegionalCenter Our estimatethat18%ofchildren withmentalretardation meetDSM-IVcriteria Autism screening and ADI-R results among children determined to have mental have to determined children among results ADI-R and screening Autism THE EPIDEMIOLOGY OFAUTISMIN CALIFORNIA ≥ 2)3 54 34 22) Birth YearBirth 1983-85 Birth YearBirth 1993-95 p-value ■ PAGE26 THE EPIDEMIOLOGY OF AUTISM IN CALIFORNIA palsy andmicrocephaly. disorder diagnosis.The oneremaining studysubjectwasreported tohavecerebral PDD bysevenparents. Theother12parents didnotreport anautismspectrum 28 studysubjects.Autism wasnotedonthestudyquestionnaire byeightparents and during theADI-Rinterview. InCohort 2,questionnaire data were availablefor27of syndrome withautistictendencies(1)andaduplication ontheXchromosome (1) children inCohort 1didnotcomplete thequestionnaire, butdidreport fragileX autism spectrumdisorder, andonehadanunknowncondition.Familiesfortwo reported tohavePDD,onewas reported tohavePrader-Willi syndrome, sixhadno these 11,onechildwasreported tohaveChildhoodDisintegrativeDisorder, twowere positive ADI-R.Autismwasreported bythree parents andwasnotreported by11.Of In Cohort 1,studyquestionnaires were completed on14ofthe16children witha based ontheADI-R,someparents reported anautismdiagnosiswhilemostdidnot. We foundnoevidencethatsuchadifference exists. produce anapparent riseinautism. past andlessfrequently currently to have tooccurmore frequently inthe retardation. Misclassificationwould children reported withmental misclassification ofautismamong produce anaccurateestimateofthe these datawhichlimitourabilityto are manypotentialproblems with criteria forautism.However, there have beenfoundtomeetDSM-IV children intheMRgroup would interview, itislikelythatmore were followedupwithanADI-R mean score was25.30 ADI-R follow-up,the 25.48 score forADI-Rcompleterswas 61 andnoton27.ThemeanSCQ SCQ; anADI-Rwascompletedon MR whoscored positivelyonthe did not.There were 88children with completed anADI-Rwiththosewho total SCQscore forthosewho tested forpotentialbiasinthecompletionofADI-R’s bycomparingtheaverage positive. Unfortunately, notallofthesefamiliescompletedanADI-Rinterview. We 1.44). for children withASDconditionswassimilarinbothcohorts (oddsratiosof1.42and Among the44children intheMRgroup whometDSM-IVcriteriaforautism If allofthepositiveSCQresults There wasahighrateofpositiveADI-R’s amongthechildren whoseSCQwas ± 3.01, andforthoselacking THE EPIDEMIOLOGY OFAUTISMIN CALIFORNIA ± 2.80 (p=.79). Among the 44 children in the in children 44 the Among MR group who met DSM-IV met who group MR criteria for autism based on based autism for criteria the ADI-R, some parents some ADI-R, the reported an autism diagnosis autism an reported while most did not. did most while ■ PAGE27 ○○○○○○○○○

THE EPIDEMIOLOGY OF AUTISM IN CALIFORNIA by age group and ADI-R status, Autism Epidemiology Study. Epidemiology Autism status, ADI-R and group age by Study Aim3Results Table 5. born elsewhere andthenmoveintotheState. would beexpectedwiththeoldergroup havingmore timetobecomprisedofchildren California. Thefindingthatagreater proportion ofolderchildren are born out-of-state increased numbersofautismcasestobeduechildren withautismmovinginto among theyoungerchildren withautismistheoppositethatwouldbenecessaryfor autism were inCalifornia. born Thetrend foragreater proportion ofCaliforniabirths shows theresults oftheseplace-of-birth analyses.Thevastmajority ofchildren with uted inpart tolarge numbersofchildren withautismmovingintoCalifornia.Table 5 autism todeterminewhethertheapparent increase inautismnumberscanbeattrib- P observed increaseobserved inautismtheRegional CenterSystem. ○○○○○○○○○○○○○○○○○ Aayi egtd dutd 73 29 0.22 0.17 161 92.9% 94.4% 87.3% 100 152 89.0% 0.25 89 232 178 0.23 93.0% 143 94.2% 105 88.5% 189 (Analysis weighted,adjusted) ofCABirths Proportion 89.7% (unweighted andunadjusted) ofCABirths Proportion 117 among+ADI-R birth California Positive ADI-R CDER Status1Autismand+ADI-R (Analysis weighted,adjusted) ofCABirths Proportion (unweighted andunadjusted) ofCABirths Proportion birth California completed Study Surveys Enrolled CDER Status1Autism lace ofbirth wascompared foreachagecohort amongchildren withCDERstatus1 In summary, mobilityofchildren withautismdoesnotaccountforanyofthe Place of birth comparisons for children with CDER status 1 autism, 1 status CDER with children for comparisons birth of Place THE EPIDEMIOLOGY OFAUTISMIN CALIFORNIA Birth YearBirth Birth YearBirth 1983-85 1983-85 Birth YearBirth YearBirth 1993-95 1993-95 ■ p-value p-value PAGE28 ○○○○○○○○○

THE EPIDEMIOLOGY OF AUTISM IN CALIFORNIA younger birth cohorts, Autism Epidemiology Study. Epidemiology Autism cohorts, birth younger Study Aim4Results *Parents couldselect multipleresponses fortherace/ethnicityquestion. All percentages are weightedandadjusted forthestudy’s samplingdesign. Study samplewaslimitedtothosechildren whometDSM-IVcriteriaforautismbasedontheADI-Rinterview. Table 6. to beambidextrous. Just over7%oftheoldercohort andnearly13%oftheyoungercohort were reported (data notshown).About75%ofparents reported theirchildren were right-handed. handed, left-handed,both)were notsignificantlydifferent betweenthetwoagegroups and maternalorpaternaleducation.Patternsofdominanthandedness(i.e.right- Table 6.There were nosignificantdifferences betweentheagegroups forsex,race, California. Basicdemographiccharacteristicsforchildren withautismare shownin demographic characteristicsmayhelpexplaintheobservedincrease inautism age groups asinprevious analyses.We postulatedthatsignificantdifferences incertain on theresults oftheADI-Rinterview. Characteristicswere compared betweenthetwo limited thestudysampletothosechildren whometDSM-IVcriteriaforautismbased W been labeled.Whilemost parents reported thattheirchild’s autismimproved over This findingmaybedueto ashiftovertimeinhowhighfunctioningchildren have proportion ofolderchildren were reported tohaveadiagnosisofAsperger’s Disorder. drome” autism.Table 7showsthe diagnosesthattheparents reported. Agreater ○○○○○○○○○○○○○○○○○ aesx9.%8.%0.08 83.7% 90.4% p-value Percentage Parent educationallevel: Percentage Race/Ethnicity*: Male sex Characteristic e analyzeddemographiccharacteristicsofchildren withCDERstatus1autism.We Parents ofautisticchildren didnotuniversallyreport thediagnosisof“fullsyn- ereo ihr3.%3.%0.70 0.54 33.3% 0.81 89.1% 0.06 0.06 38.7% 35.5% 0.82 77.6% 0.12 86.5% 39.0% 0.68 40.3% 0.40 3.0% 78.3% 87.0% 27.6% 7.4% degree orhigher 14.5% Mother withcollegeassociate’s diploma orhigher 3.5% 68.3% Mother withhighschool degree orhigher 8.9% 19.5% Father withcollegeassociate’s diploma orhigher Father withhighschool Hispanic Native American Asian/Pacific Islander African-American White Demographic characteristics of children with full syndrome autism, by older and older by autism, syndrome full with children of characteristics Demographic THE EPIDEMIOLOGY OFAUTISMIN CALIFORNIA Birth YearBirth 1983-85 (N=100) Birth YearBirth 1993-95 (N=161) ■ PAGE29 THE EPIDEMIOLOGY OF AUTISM IN CALIFORNIA birth cohorts, children with full syndrome autism, Autism Epidemiology Study. Epidemiology Autism autism, syndrome full with children cohorts, birth syndrome full with children cohorts, birth younger and older by parents, by reported autism, Autism Epidemiology Study. Epidemiology Autism autism, Table 9showstheseresults. been diagnosedwithmental retardation?,” andaYes orNoresponse wasrequired. shown inTable 8). time, parents ofchildren intheyoungercohort were more likelytodoso(results All percentages are weightedandadjusted forthestudy’s samplingdesign. Study samplewaslimitedtothosechildren whometDSM-IVcriteriaforautismbasedontheADI-Rinterview. Table 8. developmentaldisorder,*Pervasive nototherwise specified All percentages are weightedandadjustedforthestudy’s samplingdesign. Study samplewaslimitedtothosechildren whometDSM-IVcriteriaforautismbasedonthe ADI-Rinterview. Table 7. or below(IQ and RegionalCenterrecord documentationisthepresence ofmildmentalretardation us onthestudyquestionnaire. Thedefinitionofmentalretardation asusedinCDER the CDERdata,inRegionalCenterdocumentation, andwithwhatparents reported to declined significantlybetweenthetwobirth cohorts. Thisdeclinewasconsistentin nnw .%29 0.72 - 0.21 2.9% 0.0% 14.5% <0.001 2.0% 0.13 0.34 1.7% 0.0% 20.9% 1.1% 88.6% 15.4% 0.0% 84.2% p-value Unknown Percentage Rett’s syndrome PDD-NOS* Childhood disintegrativedisorder Percentage Asperger’s disorder Autism orautisticdisorder (multiple responsesallowed) Autism SpectrumDiagnosis oilitrcin 33 26 0.90 0.30 0.43 82.6% 81.0% 90.9% 0.01 83.3% 93.3% 75.0% 87.7% 80.8% p-value Behavior/interests/activities Language/communication Percentage Social interactions Those whoanswered“yes,autismimproved”notedimprovementsintheseareas: Percentage Child’s autismhasimproved in child’s autism ofimprovement Parent report We foundthatadiagnosis ofmentalretardation associatedwithautism had Improvement in child’s autism as reported by parents, by older and younger and older by parents, by reported as autism child’s in Improvement as disorders autistic other or autism of diagnosis a with children of Percentage ≤ 70).Forthestudyquestionnaire, parents were asked“Hasyourchild THE EPIDEMIOLOGY OFAUTISMIN CALIFORNIA Birth YearBirth Birth YearBirth 1983-85 1983-85 (N=100) (N=100) Birth YearBirth Birth YearBirth 1993-95 1993-95 (N=161) (N=161) ■ PAGE30 THE EPIDEMIOLOGY OF AUTISM IN CALIFORNIA younger birth cohorts, children with full syndrome autism, Autism Epidemiology Study. Epidemiology Autism autism, syndrome full with children cohorts, birth younger record, and parental report, by older and younger birth cohorts, children with full with children cohorts, birth younger and older by report, parental and record, syndrome autism, Autism Epidemiology Study. Epidemiology Autism autism, syndrome Table 9. All percentages are weightedandadjusted forthestudy’s samplingdesign. Study samplewaslimitedtothosechildren whometDSM-IVcriteriaforautismbasedontheADI-Rinterview. Table 10. All percentages are weightedandadjustedforthestudy’s samplingdesign. Study samplewaslimitedtothosechildren whometDSM-IVcriteriaforautismbasedontheADI-Rinterview. history ofmentalretardation.history cohort. Theyoungergroup ofchildren withautismwaslesslikelytohave afamily presents familyhistoriesasreported byparents, andcompares thesehistoriesbybirth develop intheyoungergroup. disorder. Thesedifferences maybeage-related, andovertimethesedisorders may their childwasdiagnosedwithaticdisorder, depression, orobsessive-compulsive ioa iodr07 .%0.95 0.02 <0.001 0.27 0.6% 0.41 0.6% 1.1% 9.8% <0.001 1.4% 0.7% 5.1% 7.4% 15.7% 14.8% 2.6% 20.5% p-value Percentage Bipolar disorder Depressive disorder Percentage Obsessive-compulsive disorder Tic disorder Cerebral palsy Epilepsy (multiple responsesallowed) Associated Conditions <0.001 22.3% <0.001 185 20.8% 49.7% 161 119 41.3% <0.001 100 26.7% 193 60.5% 120 byparents MR reported Center record MR documentedinRegional MR documentedinCDERrecord soitdmna eadto Sample Associated mentalretardation Most children withautismdidnothaveafamilyhistoryofautism. Table 11 Parents oftheyoungergroup ofautisticchildren were lesslikelytoreport that Presence of mental retardation as documented by CDER, Regional Center Regional CDER, by documented as retardation mental of Presence Parent-reported conditions associated with autism diagnoses, by older and older by diagnoses, autism with associated conditions Parent-reported THE EPIDEMIOLOGY OFAUTISMIN CALIFORNIA Sample size Birth YearBirth 1983-85 Birth YearBirth 1983-85 (N=100) % size Birth YearBirth Birth YearBirth 1993-95 1993-95 (N=161) % ■ PAGE31 p-value THE EPIDEMIOLOGY OF AUTISM IN CALIFORNIA by older and younger birth cohorts, children with full syndrome autism, syndrome full with children cohorts, birth younger and older by Autism Epidemiology Study. Epidemiology Autism Table 11. All percentages are weightedandadjustedforthestudy’s samplingdesign. Study samplewaslimitedtothosechildren whometDSM-IVcriteriaforautismbasedonthe ADI-Rinterview. mothers ofautisticchildren inbothcohorts (datanotshown). bleeding, elevatedbloodpressure, orpre-term labor, wasreported byabout15%of prescribing bedrest duringthepregnancy, duetocomplicationssuchasvaginal during pregnancy. Again,there were fewagegroup differences. Ahealth-care provider group (Table 13).About15%ofmothersreported receiving avaccinationorshot to 13%ofpregnancies; mostwere attributedtoflu,andtheydiffered littlebyage these comparisonsare showninTable 12. Seriousviralillnesseswere reported in10% autism cohort. Overallthisinvolvedlessthan10%ofgroup. Additionaldetailsof pies tobecomepregnant wasreported more frequently bytheparents oftheyounger mother wasavailabletoanswerthequestions.Theuseofmedicationsorotherthera- ioa iodr1.%82 0.53 0.82 0.49 0.07 8.2% 0.47 3.3% 0.01 0.89 27.4% 7.3% 0.73 10.5% 16.3% 16.2% 8.7% 3.8% 31.3% 4.7% 2.9% 12.9% 30.5% 9.2% 5.7% p-value Bipolar disorder Depressive disorder Percentage Obsessive-compulsive disorder Tic disorder Percentage Mental retardation PDD-NOS Asperger’s disorder Autism FamilyHistory Reported We askedthefamilytocompletequestionsaboutpregnancy ifthebiological Family history of autism or other conditions/disorders as reported by parents, by reported as conditions/disorders other or autism of history Family THE EPIDEMIOLOGY OFAUTISMIN CALIFORNIA Birth YearBirth 1983-85 (N=100) Birth YearBirth 1993-95 (N=161) ■ PAGE32 THE EPIDEMIOLOGY OF AUTISM IN CALIFORNIA younger birth cohorts, children with full syndrome autism, Autism Epidemiology Study. Epidemiology Autism autism, syndrome full with children cohorts, birth younger autism, syndrome full with children cohorts, birth younger and older by pregnant, Autism Epidemiology Study. Epidemiology Autism Table 12. All percentages are weightedandadjusted forthestudy’s samplingdesign. Study samplewaslimitedtothosechildren whometDSM-IVcriteriaforautismbasedontheADI-Rinterview. Table 13. All percentages are weightedandadjustedforthestudy’s samplingdesign. Study samplewaslimitedtothosechildren whometDSM-IVcriteriaforautismbasedonthe ADI-Rinterview. n r-emlbr1.%86 0.17 0.89 0.73 0.11 8.6% 34.9% 8.3% 0.06 13.4% 14.8% 2.5% 32.7% 8.8% 15.6% p-value Percentage 8.4% or augmentuterinecontractions Received medicinetoinduce Percentage Took labor medicinetostopthepre-term labor Any pre-term during thepregnancy Any shotorvaccination body aches) illnesswithfever,Flu (respiratory Pregnancy event nvtofriiain00 .%0.08 0.87 0.07 4.4% 0.7% 2.9% 0.57 0.0% 0.08 2.7% 0.9% 0.19 0.0% 9.7% 7.9% 1.8% 3.6% In-vitro fertilization 3.6% insemination Artificial fallopian tubes Treatment/surgery forblocked shots Received hormone Took medicine tostimulateovulation Medical treatmentsthatwereused: to helpbecomepregnant Mother usedanymedicaltreatment Percentage of mothers reporting events during pregnancy, by older and older by pregnancy, during events reporting mothers of Percentage become to treatments medical of use reporting mothers of Percentage THE EPIDEMIOLOGY OFAUTISMIN CALIFORNIA ecnaePretg p-value Percentage Percentage Birth YearBirth Birth YearBirth 1983-85 1983-85 (N=100) (N=100) Birth YearBirth Birth YearBirth 1993-95 1993-95 (N=161) (N=161) ■ PAGE33 THE EPIDEMIOLOGY OF AUTISM IN CALIFORNIA younger birth cohorts, children with full syndrome autism, Autism Epidemiology Study. Epidemiology Autism autism, syndrome full with children cohorts, birth younger All percentages are weightedandadjusted forthestudy’s samplingdesign. Study samplewaslimitedtothosechildren whometDSM-IVcriteriaforautismbasedontheADI-Rinterview. Table 14. enough positiveresponses onanyindividualitemtosupport additionalanalyses. barbiturates, orLSDimmediatelypreceding orduringthepregnancy. There were not the useofmarijuana,cocaine,methamphetamines,heroin, methanol,PCP/“angeldust,” cigarette smokingordrug usebetweenbirthcohorts. Fordruguse,wequeriedabout reported forbothbirth cohorts. There were nosignificantdifferences inmaternal cohorts. Adeclineinalcoholuseafterthemotherbecameaware ofherpregnancy was obtained. Maternalalcoholusepriortopregnancy wasabout30%forbothbirth were omittedfrom earlyquestionnaires untilanNIHCertificate ofConfidentiality was about alcoholandcigarette use.Duetothesensitivenature usequestions,they ofdrug and theresults are summarizedinTable 14.Mostrespondents answered thequestions 44.8%, p=.07).Forfamilies withyoungersiblings,parents ofchildren intheyounger expected, theoldergroup wasmore likelytohaveanyyoungersiblings(56.7% vs. older cohort as compared withtheyoungercohort (7.9%vs.21.5%,p<.001).As difference infamilies’decisionstoavoidordelayat leastonevaccinationamongthe differ across birth cohorts(98.4%vs.99.4%,p=.49). There was,however, asubstantial eoecidwsbr .803 0.39 0.28% 0.37 5.4% 3.0% 0.18 0.79 2.45 Had anycigarettes before childwasborn 2.74 ofpregnancyand after learned Average numberofdrinkspermonth was born ofpregnancyandbeforechild learned Had anyalcoholicbeveragesafter ofpregnancy before learned Average numberofdrinkspermonth ≤ Had anyalcoholicbeverages eoecidwsbr 45 .%0.26 0.28 9.7% 6.4% 14.5% 10.3% Used anystreetdrugs pregnancy andbeforechildborn of Had anycigarettesafterlearning before childwasborn eoecidwsbr 02 .%0.37 0.83 6.3% 6.5% 10.2% 7.4% of pregnancyandbeforechildborn Used anystreetdrugsafterlearning before childwasborn 1 otsbfr hl a on3.%2.%0.39 29.2% 34.7% 12monthsbeforechildwasborn Questions aboutmaternalsubstanceusebefore andduringpregnancy were asked Virtually allchildren withautismreceived atleastonevaccinationandthisdid not Prenatal exposure to alcohol, cigarettes, and street drugs by older and older by drugs street and cigarettes, alcohol, to exposure Prenatal THE EPIDEMIOLOGY OFAUTISMIN CALIFORNIA ≤ 12months ≤ 12months v rnsm.Ave #drinks/mo. Ave #drinks/mo. Ave #drinks/mo. Ave #drinks/mo. ecnaePercentage Percentage Percentage Percentage p-value Percentage Percentage Birth YearBirth 1983-85 (N=100) Birth YearBirth 1993-95 (N=161) ■ PAGE34 THE EPIDEMIOLOGY OF AUTISM IN CALIFORNIA by parents, by older and younger birth cohorts, children with full syndrome autism, Autism autism, syndrome full with children cohorts, birth younger and older by parents, by Epidemiology Study. Epidemiology noted beyond15monthsofage. younger cohort duringthistimeperiod.Nodifferences betweenagecohorts were the transitiontotablefoods.Vomiting wasalsomore commonlyreported inthe in thefirstyear, whensolidfoodswere introduced, andwhenthechildwasmaking GI symptomswere more commonamongtheyoungercohort, especiallyconstipation at variousages.Resultsofbirth cohortcomparisonsare showninTable 15.Reported (9.5% vs.20.7%,p=.06). cohort were more likelytoavoidordelayatleastonevaccinationforayoungersibling *Includes gas,bloodydiarrhea, problems swallowing,colic. All percentages are weightedandadjustedforthestudy’s samplingdesign. Study samplewaslimitedtothose children whometDSM-IV criteriaforautismbasedontheADI-Rinterview. Table 15. irha1.%1.%0.42 0.70 0.36 0.72 14.0% 0.47 6.7% 24.0% 7.9% 0.21 5.2% 0.05 10.7% 0.81 <0.001 5.5% 19.3% 15.5% 0.72 6.8% 5.6% 3.4% 19.1% 58.0% 0.12 2.3% 0.06 10.4% 0.01 0.01 1.6% 59.6% 6.4% 11.8% Abdominal painorcramping 0.67 59.3% Vomiting orreflux 9.5% 3.3% 17.9% Diarrhea Constipation 0.047 0.73 Percentage ofspecificgastrointestinalproblemsatorafterage 15months: 5.5% 7.0% age 15monthstothepresent 0.03 73.7% 0.08 4.0% No 8.1% 59.5% Other* 12.5% Vomiting orreflux 20.1% 0.24 7.1% Diarrhea 21.8% Constipation Percentage ofspecificgastrointestinalproblemswhentransitionedtotablefoods: 71.2% 14.0% transitioned totablefoods 52.1% 10.9% No 13.5% Other* Vomiting orreflux Diarrhea 59.7% Constipation Percentage ofspecificgastrointestinalproblemswhenintroducedsolidfoods: introduced solidfoods No Other* Vomiting orreflux Diarrhea Constipation period: Percentage ofspecificgastrointestinalproblemsduringthenewborn period newborn No We askedquestionsaboutthepresence ofspecificgastrointestinal (GI)symptoms gastrointestinalproblemsfrom gastrointestinalproblemswhen gastrointestinalproblemswhen gastrointestinalproblemsinthe Percentage of children with a history of gastrointestinal symptoms as reported as symptoms gastrointestinal of history a with children of Percentage THE EPIDEMIOLOGY OFAUTISMIN CALIFORNIA ecnaePretg p-value Percentage Percentage Birth YearBirth 1983-85 (N=100) Birth YearBirth 1993-95 (N=161) ■ PAGE35 THE EPIDEMIOLOGY OF AUTISM IN CALIFORNIA by older and younger birth cohorts, children with full syndrome autism, Autism autism, syndrome full with children cohorts, birth younger and older by Epidemiology Study. Epidemiology All percentages are weightedandadjustedforthestudy’s samplingdesign. Study samplewaslimitedtothosechildren whometDSM-IVcriteriaforautismbasedonthe ADI-Rinterview. Table 16. vs. 11.5%). Reported wheatallergies hadincreased significantlyintheyoungeragegroup (3.8% were mostcommon,althoughnotsignificantlydifferent betweenthetwoagegroups. parents inbothcohorts reported foodallergies. Allergies tomilkordairyproducts is thechildallergic. Resultsare showninTable 16.Overall,aboutaquarter ofthe before thislossofwords. Theaveragenumberofwords usedpriortoregression was one month.We askedtheparents toreport thenumber ofwords thechildwasusing months, mostparents (>75%)reported thattheirchildstopped usingwords foratleast months ofage(75%vs.80%, p=.86)Forthosechildren withregression priorto36 in Table 16.Mostparents reported thattheonsetofregression occurred before 36 phone andlastedaboutthirty minutes.Theresults oftheseinterviewsare summarized withtheparent.detailed interview were Theseinterviews conductedoverthetele- a historyofregression intheirautisticchild. there were nodifferences basedonbirthcohort ontheproportion ofparents reporting Nonetheless, bothresults from thestudyquestionnaire andADI-Rinterviewshowthat of regression from theADI-Rwere consistentlylessfrequent (approximately 30%). two developmentalissueswasmadeclearduringthe ADI-Rinterview, thusthereports with regression ofamilestonethathadbeenachieved.Thedistinction betweenthese questionnaire. Manyparents were confusingdelayintheacquisitionofamilestone We clarifiedsomeofthesestatementsthrough follow-upphonecallsortheadditional cohort reported onthestudyquestionnaire thattheirchildhadundergone regression. whose ADI-Rindicatedregression. More thanhalfoftheparents from eachbirth questions from theADI-R,andadministeringafollow-upquestionnaire forchildren inclusion ofaseriesquestionsonthestudyquestionnaire, evaluatingregression gs09 .%0.09 0.60 0.01 0.44 3.5% 2.8% 0.07 0.45 11.5% 0.76 1.1% 0.81 1.8% 0.9% 19.3% 1.9% 3.3% 3.8% 2.2% 25.1% 15.6% 0.0% 4.0% 23.8% p-value Shellfish (shrimp,crab,etc.) Vegetables Percentage (includingtomatoes) Fruit orberries Nuts (peanuts,walnuts,etc.) Percentage Eggs Wheat Milk ordairy Any foodallergies FoodAllergies Reported We askedtheparents iftheirchildhadanyfoodallergies, andifyes,towhatfood We followedupreports ofregression from theADI-Rbyadministeringamore Regression ondevelopmentalmilestoneswasassessedbyseveralmethods:the Percentage of children with a history of food allergies as reported by parents, by reported as allergies food of history a with children of Percentage THE EPIDEMIOLOGY OFAUTISMIN CALIFORNIA Birth YearBirth 1983-85 (N=100) Birth YearBirth 1993-95 (N=161) ■ PAGE36 ○○○○○○○○○

THE EPIDEMIOLOGY OF AUTISM IN CALIFORNIA younger birth cohorts, children with full syndrome autism, Autism Epidemiology Study. Epidemiology Autism autism, syndrome full with children cohorts, birth younger two birth cohorts. reports (approximately 30%usingtheADI-R)andthisratediffered little betweenthe developmental milestonesobservedinthisstudyissimilartoprevious published higher fortheyoungercohort (7.8vs.10.9).Insummary, therateofregression of mentioned as causesforautism. Pregnancy related events,birth trauma,andenvironmental exposures were also was nextmostfrequently citedbyparents ofchildren with autism(30.6%vs.26.6%). autism toimmunizations (30.5% vs.49.8%incohorts 1and2respectively). Genetics sion ofdevelopmentalmilestones were muchmore likely to attributetheirchild’s Analysis ofdatafrom theADI-Rinterviewshowed thatparents whoreported regres- of theyoungercohort parents attributingtheirchild’s autismtoimmunizations. response categorywasimmunizations, with18.3%ofoldercohort parents and33.0% quency ofthisresponse didnotdiffer betweenbirth cohorts.Thenextmostfrequent response was“don’t know”orleaving thatpart ofthequestionnaire blank.Thefre- birth cohort andwecompared responses betweenbirth cohorts. Themostfrequent We includedthose thatrepresented atleast1%ofparental responses withineither children withCDERstatus1autismwhometDSM-IVcriteria are showninTable 17. response. Thesewere thenreviewed andcategorized.Theresponses from parents of developmental problem?” We provided alarge blankarea forparents towriteintheir W Study Aim5Results All percentages are weightedandadjustedforthestudy’s samplingdesign. Study samplewaslimitedtothosechildren whometDSM-IVcriteriaforautismbasedonthe ADI-Rinterview. Table 17. ○○○○○○○○○○○○○○○○○ usinar eut 045 0.31 0.28 53.7% 20 63 33.6% 60.2% 27.8% p-value 33 Percentage questionnaire results Total numberwithfollow-up Percentage Total numberwithregressiononADI-R onADI-R Regression reported study questionnaire on Regression reported Evaluation ofRegression e askedtheparents, “Whatdoyouthinkcausedyourchild’s autismand/orother n ot 91 02 0.93 70.2% 69.1% 0.35 7.8 81.9% to regression(mean+/–SE) 71.0% Mean totalnumberofwordsprior one month Stopped usingwordsforatleast regression by36monthsofage Percentage withreported Regression of developmental milestones as reported by parents, by older and older by parents, by reported as milestones developmental of Regression THE EPIDEMIOLOGY OFAUTISMIN CALIFORNIA Birth YearBirth 1983-85 (N=103) ± .510.9 0.75 Birth YearBirth 1993-95 (N=174) ± .30.01 0.93 ■ PAGE37 THE EPIDEMIOLOGY OF AUTISM IN CALIFORNIA child’s autism and/or other developmental problem?” by older and younger and older by problem?” developmental other and/or autism child’s birth cohorts, children with full syndrome autism, Autism Epidemiology Study. Epidemiology Autism autism, syndrome full with children cohorts, birth Table 18. All percentages are weightedandadjusted forthestudy’s samplingdesign. Study samplewaslimitedtothosechildren whometDSM-IVcriteriaforautismbasedontheADI-Rinterview. ihFvr00 .%0.13 0.02 0.06 1.1% 0.18 2.9% 0.51 0.57 1.8% 0.16 3.5% 0.49 0.0% 0.14 2.4% 0.0% 1.1% 2.4% 2.9% 0.0% 0.60 1.3% 5.4% 0.41 1.4% 0.48 2.0% 0.86 1.3% 0.6% 0.81 1.8% 0.31 1.1% 2.3% 1.2% 3.9% High Fever 3.0% 2.7% 0.59 Traumatic Surgery 2.7% 0.80 Nutrition 2.3% Gastrointestinal Disorders 2.7% 0.49 3.3% Antibiotics 12.1% 14.6% 3.5% or prescription 0.16 5.9% Drug Use–Overthecounter Ear Infections 26.6% 0.005 Virus 10.0% 16.3% 13.5% Syndromes (e.g.FragileX) Allergies 0.74 33.0% Head Trauma 30.6% Brain Abnormalities Poisoning Mercury 24.1% 47.9% Emotional Trauma p-value Drug Use–Illegal 18.3% Environmental Exposure Percentage Events(Adverse) Birth 45.7% Percentage Immunizations (allresponses): Pregnancy Related Genetics “Don’t know”ornoresponse Parent Responses M .%65 0.005 0.10 6.5% 1.1% 0.02 1.1% 4.7% 26.5% 14.9% MMR DTaP orDTP Immunizations ingeneral Parent responses to question, “What do you think caused your caused think you do “What question, to responses Parent THE EPIDEMIOLOGY OFAUTISMIN CALIFORNIA Birth YearBirth 1983-85 (N=100) Birth YearBirth 1993-95 (N=161) ■ PAGE38 ○○○○○○○○○

THE EPIDEMIOLOGY OF AUTISM IN CALIFORNIA Study Aim6Results this question. we calculatedthatwouldneedasamplesizeof7,000 familiestoproperly answer proportion offamilieswhoare avoidingordelayingvaccinationinyoungersiblings, proportion offamilieswithanautisticchildthathavesubsequentchildren, and2)the cient toanswerthequestionposedinthisstudyaim. Basedonourfindingsof1)the vaccine-avoidant youngersiblingsinbothbirth cohorts wasonly19,which is insuffi- 10% oftheoldercohort and21%oftheyoungercohort. However, the totalnumberof to participate. Avoidance ofatleastonevaccineinyoungersiblingswasreported by the timetheywere enrolled had anyyoungersiblingsat of thechildren withautism unvaccinated siblings. vaccinated siblingswith autism whencomparing portion ofsiblingswith able difference inthepro- there shouldbeanobserv- the developmentofautism, vaccinations contributeto autism. We postulatedthatif would bediagnosedwith 1 in20youngersiblings recurrence rateof5%,about low (2%-10%).Assuminga tion, butstillisrelatively than inthegeneralpopula- families ismore common rence ofautismwithin younger siblings.Recur- or allvaccinationsin avoiding ordelayingsome anecdotally reported thatasignificantnumberoffamilieswithautisticchildren is designed part ofthisstudytomakeusepotential“naturalexperiment.”Ithasbeen T ○○○○○○○○○○○○○○○○○ o assesstheassociationbetweenimmunizationsanddevelopmentofautism,we In thisstudy, abouthalf THE EPIDEMIOLOGY OFAUTISMIN CALIFORNIA Avoidance of at least one vaccine in vaccine one least at of Avoidance younger siblings was reported by 10% by reported was siblings younger of the older cohort and 21% of the of 21% and cohort older the of younger cohort. younger ■ PAGE39 ○○○○○

THE EPIDEMIOLOGY OF AUTISM IN CALIFORNIA the olderMR cohortbutinonly3.9% of theyoungerMRcohort. Theyinterpreted Regional Centerrecord review study, theresearchers foundmisclassification in10%of between thetwoagegroups, butwedidnotfind adifference. Intheaforementioned percentage oftheriseinautismcases tomisclassificationifwehadfoundadifference misclassified inthepastcompared withthepresent. We mighthaveattributedsome birth cohorts. So,whilemisclassificationoccurs,children were notdisproportionately met DSM-IVcriteriaforautism.However, thispercentage wasconsistent inthetwo This explanationwasnotsupported byourdata. diagnosis inthepast,andinsteadreporting autisticchildren as“mentallyretarded?” weight toourresults. pation biases,hadresults similartoourown.Thisreplication offindingsgivesadded comparable inbothbirth cohorts. TheCroen study, whichwasnotsubjecttopartici- results. Ourfindingsonthepercentage ofautismcasesmeetingDSM-IVcriteriawere would havetoaffect onebirth cohortdifferently thantheothertoalteroverall respond toourletterandparticipate inthestudy. Thisinfluenceonparticipation the effects ofunmeasurablebiasesthatmayhaveinfluencedafamily’s willingnessto our response ratewaslow(18%and24%inthetwo agecohorts). Onemustconsider autism wasreliable for mostchildren intheRegionalCentersystem. this studywiththeADI-R),nonethelessbothstudiesconcludedthatdiagnosisof not conductindependentconfirmationoftheautismdiagnosis(aswasperformed in that 88%and89%metDSM-IVcriteriaforautism.AlthoughCroen andcolleaguesdid cohort metDSM-IVcriteriaforautism.Usingthesamebirth cohorts,ourstudyfound of children withCDERstatus1autismintheoldercohort and84%oftheyounger Croen andcolleagues,usingthebirth cohorts 1983-85and1993-95,foundthat85% Conclusion recently publishedstudythatevaluatedRegionalCenterrecords Our results, basedonADI-Rinterviewswithfamilies,are similartothefindingsofa importantly, thisclosecorrespondence didnotdiffer betweenthe two birthcohorts. Center SystemashavingCDERstatus1autismmetDSM-IVcriteriaforautism.More did notfindthistobethecase. children andincreasing for RegionalCenterservices thenumberofautismcases?We created thatincrease. epidemic, oriftheriseinautismcasescanbeexplainedbyfactorsthathaveartificially been anattempttodeterminewhetherornottheincreased numbersare duetoareal understand orforce ittofitaparadigmwithwhichweare comfortable. Thisstudyhas ing ofthecauseorcausesautism.Itisnaturaltodiscountthatwhichwedonot Increases ofthemagnitudethathavebeenreported challengeourlimitedunderstand- cern. Howtorespond totheseincreasing numbershasbeenapointofmajordebate. T ○○○○○○○○○ he riseinthenumberofautismcasesCaliforniahasbeenacauseformuchcon- In oursampleofchildren withmentalretardation (MR)wedidfindthat18%-19% Has theincrease incasesofautismbeencreated artificially byhaving“missed”the The AutismEpidemiologyStudyrequired thatfamiliesconsenttoparticipate, and These results showthatapproximately 90%ofchildren reported bytheRegional Has there been alooseninginthecriteriausedtodiagnoseautism,qualifyingmore THE EPIDEMIOLOGY OFAUTISMIN CALIFORNIA 35 . Thisstudyby ■ PAGE40 THE EPIDEMIOLOGY OF AUTISM IN CALIFORNIA and mostchildren bytheRegionalCenterSystemwere withautismserved born in increases intheStatepopulationaccount for lessthan10%oftheriseincasereports, tion duringthetimeperiod orbychildren withautismmovingintoCalifornia? No, andwouldlikelyfurtherservices increase thenumberofautismcasesreported. could bedoneaspart oftheannual reassessment ofchildren receiving RegionalCenter System woulddefinitivelyanswerthisimportant question.Such systematicscreening screening ofchildren withmentalretardation bytheCaliforniaRegionalCenter assume itisnohigherthan18%andsimilarinthe two birth cohorts. Universalautism ability tostatewhattheexactamountofmisclassification appearstobe.We can The lowenrollment rateintheMR groups and thebiasinenrollment dolimitour autism intheyoungercohort, sotheincrease inautismcaseswould belessdramatic. with fullsyndrome autism.There were fewerchildren reported withMRandnot birth cohort from 991to2,205,more thandoublingthenumberofchildren identified autism inthe1983-85birth cohort (0.10*12,139).Thatwouldraisethetotalforthat cohort asreported byCroen etal,thattranslatestoanadditional1,214children with children whomeetcriteriaforautism.Forexample,iftheratewere 10%intheolder group, evenamodestrateofmisclassificationsignificantlyincreases thenumberof number ofchildren intheMRgroup hashistoricallybeenmuchlarger thantheautism estimate thatwecalculated. group ofchildren withMRintheRegionalCentersystemislowerthan18% more willingtoparticipate,isassumethattherateofmisclassificationforwhole where familieswhosechildmayhaveanautismspectrumdisorder were somewhat ment biasdidnotdifferentially affect theMRgroup. Theoveralleffect ofthisbias, (odds ratio1.42intheoldercohort and1.44intheyoungercohort), sothisenroll- subject withanautismspectrumdisorder were consistentinthetwobirth cohorts trum disorder (CDER status2,4,or9).Howevertheoddsofenrollment foranMR MR were more likelytoenroll iftheirchildhadbeenreported withanautismspec- ing ourenrolled subjectswiththeCDERdata,wefoundthatparents ofchildren with participation rateandhowitmayhaveaffected ourresults andconclusions.Examin- cohort and15%fortheyoungercohort). AswithStudyAim1,wemustassessthislow lies whosechildren hadaprimarydiagnosisofMRandnotautism(10%fortheolder diagnosis withtheADI-R,are incontrasttotheirresults. on screening forautisticspectrumdisorders withtheSCQandverifyinganautism undercount ofmisclassificationcompared withactivescreening. Ourfindings, based have supported thisdiagnosis.Thus,arecord review alonemayresult inan group whometDSM-IVcriteriaforautismwhoseRegionalCenter record wouldnot not record aCDERstatus1autismdiagnosis.There were otherchildren inthisstudy MR group whometDSM-IVcriteriaforautismeventhoughtheirCDERrecords did autism diagnosisisconsidered. Inourstudy, there were somecases ofchildren inthe ever, theRegionalCenterrecord wouldhavedocumentationofautismonlywhenan qualifying forRegionalCenterserviceshadchangedduringthestudyperiod.How- these results tomeanthatthereliability oftheCDERdiagnosisMRforchildren Can the observed increaseCan theobserved beaccounted foranincrease intheoverallStatepopula- It isworth consideringwhatthesemisclassificationnumbersmean.Becausethe In theAutismEpidemiologyStudy, theresponse ratewasespeciallylowforfami- THE EPIDEMIOLOGY OFAUTISMIN CALIFORNIA ■ PAGE41 THE EPIDEMIOLOGY OF AUTISM IN CALIFORNIA of children with autisminCalifornia. cases presenting totheRegionalCentersystemisnotanoverestimation ofthenumber increase represents atrueincrease incases ofautisminCalifornia, andthenumberof artificial increase inautismcases,weconcludethatsome,ifnotall,oftheobserved increase inin-migration ofchildren withautismtoCalifornia.Without evidenceforan autism; more misclassification ofautismcasesasmentallyretarded inthepast;oran can beattributedtoartificial factors,suchaslooseningofthediagnosticcriteriafor number ofunvaccinatedyoungersiblings(StudyAim 6). association ofimmunizationswithautismrecurrence infamiliesduetoourlow their associationwithautism.Unfortunately, thisreport wasunabletoevaluatethe among thetopresponses. There isahighlevelofconcern aboutimmunizationsand related eventswere frequently reported byparents. Immunization concerns ranked that they“don’t know” ortheydidnotrespond. Geneticsandpregnancy- orbirth- pants inthestudyhavearangeofbeliefsastowhatcausesautism.Mostparents said the youngerchildren withautism. provements intheirchild’s autism.Improvements were notedespeciallybyparents of creased intheyoungergroup. Onamore hopefulnote,mostparents reported im- developmental milestones,asreported during theADI-R,hadnotsignificantlyin- the youngergroup; and lessmentalretardation intheyoungergroup. Regression of the twogroups includereports of more gastrointestinal symptomsduring infancyin investigated couldexplainthetriplingincases.Differences thatwere notedbetween what changingfactorsmighthavecausedthisincrease inautism.Nosinglefactor between thetwobirth cohorts, searching fordifferences inthehopeofexplaining in casesthanhasbeenreported. would decrease thenumberofcasesinoldercohort andcreate asteeperincrease increase thelikelihoodofachangeinresidence. Adjustingforout-migrationthen decrease prevalent casesintheolderagecohort,asgreater periodoftimewould not significantlyso,basedonourobservations.Out-migrationwouldbemore likelyto nia probably represents anoverestimation ofknownRegionalCenterclients, although database wasnolongerresiding intheState.ThecumulativetotalofcasesCalifor- instances where achildreported withautisminCaliforniaandcountedtheCDER into California. out-of-state isnotunexpected,giventhattheoldergroup hashadmore timetomove children with autism.Thefindingthatagreater proportion ofolderchildren are born pected toseeagreater proportion ofout-of-California births amongtheyounger in autismcasestochildren withautismmovingintoCalifornia,wewouldhaveex- of children intheoldercohort were bornintheState.To attributesomeoftheincrease California. Basedonparental report, 93%ofchildren intheyoungercohort and87% The AutismEpidemiologyStudydidnotfindevidence thattheriseinautismcases What doparents thinkcausedtheirchild’s autism?Thedatashowedthatpartici- In thisstudyweaskedmanyquestionsofparents. We compared theresponses One additionalissueregarding mobilityshouldbementioned.We found57 THE EPIDEMIOLOGY OFAUTISMIN CALIFORNIA ■ PAGE42 THE EPIDEMIOLOGY OF AUTISM IN CALIFORNIA II Thedisturbanceisnotbetteraccounted for byRett’s Disorder or (III) functioning inatleastoneofthefollowingareas, with Delaysorabnormal (II) Appendix 1 Source: TheAmericanPsychiatricAssociation:Diagnostic andStatisticalManualofMentalDisorders, Edition, Washington Fourth Atotalofsix(ormore) itemsfrom (A),(B),and(C),withatleasttwo (I) DSM-IV DiagnosticCriteriafor299.0AutisticDisorder ○○○○○○○○○○○○○○○ Association, 1994. C Restrictedrepetitive andstereotyped patternsofbehavior,(C) interests and B Qualitativeimpairmentsincommunicationas manifested byatleastone (B) A Qualitativeimpairment insocialinteraction,asmanifestedbyatleasttwoof (A) from (A),andoneeachfrom (B)and(C) Childhood Disintegrative Disorder. Symbolicorimaginativeplay (C) Languageasusedinsocialcommunication (B) Socialinteraction (A) onset priortoage3years: .Persistent preoccupation with parts ofobjects. 4. Stereotyped andrepetitive motormannerisms(e.g.hand orfingerflapping 3. Apparently inflexibleadherence tospecific,nonfunctionalroutines 2. Encompassingpreoccupation with oneormore stereotyped andrestricted 1. activities, asmanifestedbyatleastoneofthefollowing: .Lackofvaried,spontaneousmake-believeplayorsocial imitativeplay 4. Stereotyped andrepetitive useoflanguageoridiosyncraticlanguage. 3. Inindividualswithadequatespeech,markedimpairment intheability 2. Delayin,ortotallackof,thedevelopmentofspoken language(not 1. of thefollowing: .Lackofsocialoremotionalreciprocity (Examples:Notactively 4. Alackofspontaneousseekingtoshare enjoyment,interests, or 3. Failure todeveloppeerrelationships appropriate todevelopmentallevel. 2. Markedimpairmentsintheuseofmultiplenonverbalbehaviorssuchas 1. the following: or twisting,complexwhole-bodymovements). or rituals. patterns ofinterest thatisabnormaleitherinintensityorfocus. appropriate todevelopmentallevel. to initiateorsustainaconversationwithothers. of communicationsuchasgesture ormime). accompanied byanattempttocompensatethrough alternativemodes or involvingothersinactivitiesonlyastools“mechanical”aids). participating insimplesocialplayorgames,preferring solitaryactivities, or pointingoutobjectsofinterest tootherpeople). achievements withotherpeople,(e.g.,byalackofshowing,bringing, social interaction. eye-to-eye gaze,facialexpression, bodyposture, andgestures toregulate THE EPIDEMIOLOGY OFAUTISMIN CALIFORNIA D.C.,AmericanPsychiatric ■ PAGE43 THE EPIDEMIOLOGY OF AUTISM IN CALIFORNIA NORTH BAY Appendix 2 Regional CenterLocations EAST BAY RC OFTHE ○○○○○○○○○○○○○○○ GATE GOLDEN SAN ANDREAS REDWOOD COAST THE EPIDEMIOLOGY OFAUTISMIN CALIFORNIA FAR NORTHERN TRI-COUNTIES COUNTY RC OFORANGE SAN DIEGO WESTSIDE LANTERMAN Within LosAngelesCounty Regional CenterLocations SEE MAP ABOVE ALTA CALIFORNIA VALLEY MOUNTAIN CENTRAL VALLEY HARBOR KERN LOS ANGELES SOUTH CENTRAL LOS ANGELES EASTERN ■ POMONA SAN GABRIEL/ COUNTY LOS ANGELES NORTH PAGE44 INLAND THE EPIDEMIOLOGY OF AUTISM IN CALIFORNIA Appendix 3 ○○○○○○○○○○○○○○○ THE EPIDEMIOLOGY OFAUTISMIN CALIFORNIA ■ PAGE45 THE EPIDEMIOLOGY OF AUTISM IN CALIFORNIA THE EPIDEMIOLOGY OFAUTISMIN CALIFORNIA ■ PAGE46 THE EPIDEMIOLOGY OF AUTISM IN CALIFORNIA THE EPIDEMIOLOGY OFAUTISMIN CALIFORNIA ■ PAGE47 THE EPIDEMIOLOGY OF AUTISM IN CALIFORNIA THE EPIDEMIOLOGY OFAUTISMIN CALIFORNIA ■ PAGE48 THE EPIDEMIOLOGY OF AUTISM IN CALIFORNIA THE EPIDEMIOLOGY OFAUTISMIN CALIFORNIA ■ PAGE49 THE EPIDEMIOLOGY OF AUTISM IN CALIFORNIA THE EPIDEMIOLOGY OFAUTISMIN CALIFORNIA ■ PAGE50 THE EPIDEMIOLOGY OF AUTISM IN CALIFORNIA THE EPIDEMIOLOGY OFAUTISMIN CALIFORNIA ■ PAGE51 THE EPIDEMIOLOGY OF AUTISM IN CALIFORNIA THE EPIDEMIOLOGY OFAUTISMIN CALIFORNIA ■ PAGE52 THE EPIDEMIOLOGY OF AUTISM IN CALIFORNIA THE EPIDEMIOLOGY OFAUTISMIN CALIFORNIA ■ PAGE53 THE EPIDEMIOLOGY OF AUTISM IN CALIFORNIA THE EPIDEMIOLOGY OFAUTISMIN CALIFORNIA ■ PAGE54 THE EPIDEMIOLOGY OF AUTISM IN CALIFORNIA THE EPIDEMIOLOGY OFAUTISMIN CALIFORNIA ■ PAGE55 THE EPIDEMIOLOGY OF AUTISM IN CALIFORNIA THE EPIDEMIOLOGY OFAUTISMIN CALIFORNIA ■ PAGE56 THE EPIDEMIOLOGY OF AUTISM IN CALIFORNIA THE EPIDEMIOLOGY OFAUTISMIN CALIFORNIA ■ PAGE57 THE EPIDEMIOLOGY OF AUTISM IN CALIFORNIA THE EPIDEMIOLOGY OFAUTISMIN CALIFORNIA ■ PAGE58 THE EPIDEMIOLOGY OF AUTISM IN CALIFORNIA Appendix 4 Epidemiology Study. thank themfortheirvaluablecontributionstotheresearch designoftheAutism W Panel Scientific Advisory ○○○○○○○○○○○○○○○ rfso fEieilg Eeiu)Montreal, Quebec School ofPublicHealth Professor ofEpidemiology(Emeritus) Walter O.Spitzer, M.D.,M.P.H. Professor ofEpidemiology PreventiveMedicine Samuel Shapiro, M.B.,B.Ch.,F.R.C.P.(E) SchoolofMedicine Professor ofBiostatisticsandEpidemiology James Schlesselman,Ph.D. DisordersandStroke Professor andChair Marc B.Schenker, M.D.,M.P.H. CenteronHumanDevelopment MontrealChildren'sHospital Program Director ofClinicalTrials M.D. Deborah Hirtz, ofPediatrics Department Director ofChildPsychiatry Eric Fombonne,M.D. Affiliation Professor Geraldine Dawson,Ph.D. Assistant Professor Davis,M.D.,M.P.H.Robert DevelopmentalDisabilities Centers Associate DirectorforScienceandPolicy Coleen Boyle,Ph.D. Name/Title e gratefullyacknowledgethemembersofScientificAdvisoryPanel,and THE EPIDEMIOLOGY OFAUTISMIN CALIFORNIA Canada McGill University New York, New York Columbia University Miami, Florida and PublicHealth ofEpidemiology Department University ofMiami Davis, California Davis University ofCalifornia, ofEpidemiologyand Department Bethesda, Maryland National InstitutesofHealth National InstituteofNeurological Canada Montreal, Quebec McGill University McGill UniversityHealthCentre Seattle, Washington and Disability University ofWashington Seattle, Washington University ofWashington Atlanta, Georgia for DiseaseControlandPrevention Defectsand National CenterforBirth ■ PAGE59 THE EPIDEMIOLOGY OF AUTISM IN CALIFORNIA Appendix 5 content ofthequestionnaire included: naire (eitherbyself-completingawrittenquestionnaire The orbyphoneinterview). F Questionnaire List ofquestionsaskedontheAutismEpidemiologyStudy ○○○○○○○○○○○○○○○ amilies ofallchildren participating inthestudywere askedtocompleteaquestion- ■ ■ ■ ■ ■ ■ ■ ■ ■ ■ Interest inparticipating in future follow-upstudies. problem? What doesthefamilythinkcausedtheirchild’s autism orotherdevelopmental History ofregression ofdevelopmentalmilestones History ofsignificantgastrointestinal symptoms Immunization/vaccination historyofthechildand younger siblings Perinatal complications second degree relatives): (groupedFamily history underfirstdegree, seconddegree, orgreater than Diagnostic information the ageoffive Mobility, includingplaceofbirth, movementintoorwithinCalifornia upto Demographic information Exposure toalcohol,cigarettes, orstreet drugsduringthepregnancy Augmentation orinductionoflabor Vaccinations whilepregnant Viral infectionswhilepregnant Infertility treatments Mental retardation Tic disorder, obsessive-compulsivedisorder, depressive Autism orrelated disorders Presence orabsenceofotherpotentialco-morbidconditions Presence orabsenceofcerebral palsy Presence orabsenceofseizure history Presence orabsenceofmentalretardation, includinga Determination ofdiagnosisautism Birth order Parental education Handedness (right/left/both) Place ofbirth Race/ethnicity disorder, bipolardisorder question aboutIQscores THE EPIDEMIOLOGY OFAUTISMIN CALIFORNIA ■ PAGE60 THE EPIDEMIOLOGY OF AUTISM IN CALIFORNIA Sample for Study Aim 1, Autism Epidemiology Study. Epidemiology Autism 1, Aim Study for Sample Appendix 6 Table A1: Subjects Study of Identification – Data CDER Study Aim1 Sample SizeCalculationsforeachStudyAim criteria. (or more) increase oftheobserved incasesofautismwasduetochanges indiagnostic 1985 vs.1993-1995).With thissamplesize,we coulddetermine whetherornot20% CDER status1autismdeterminedtheRegionalCenterandcountyforthatcase. individual children withautism.TheCDERrecord thatfirstreported thediagnosisof 1 autismborn in1983-1985and1993-1995.We created an unduplicatedlistof Centers fortheyears1986to1999. Department provided ofDevelopmental Services CDERdatagrouped byRegional groups ofchildren withCDERstatus1autismbasedonagecriteria.TheCalifornia ○○○○○○○○○○○○○○○ Regional Center CDER status1autismby etieRgoa etr7 0 . 917 5 13 19 2.8 4 8 20 8 208 4.8 5.8 14 12 21 15 75 163 7 63 2 3.2 19 6 25 21 3 17 28 3.9 13 256 2.3 17 1.5 3 16 19 3.0 7 101 4 169 81 142 24 23 12 1.5 Westside 3.6 RegionalCenter 191 2.7 11 26 2.3 Valley MountainRegional Center 74 7 96 4.6 3 13 Tri-Counties RegionalCenter 267 25 18 64 5.0 70 South CentralLosAngelesRegional Center 37 206 5.8 San Gabriel/PomonaRegionalCenter 2.9 75 11 5 12 199 4 26 San DiegoRegionalCenter 16 7 21 45 San AndreasRegionalCenter 298 2.1 283 40 Regional CenteroftheEastBay 2.5 4 Regional CenterofOrangeCounty 51 99 12 86 13 Redwood CoastRegionalCenter 37 3.8 LosAngeles CountyRegionalCenter North 5.7 1.8 41 BayRegional Center North 15 61 Regional Center Lanterman 263 90 RegionalCenter Kern Inland RegionalCenter 16 46 Harbor RegionalCenter 51 Golden GateRegionalCenter RegionalCenter Far Northern LosAngelesRegionalCenter Eastern Central Valley RegionalCenter RegionalCenter Alta California The target studysamplewas250children ineachagecohort (yearofbirth 1983- We constructedasamplingframeusingallrecords forchildren withCDERstatus CDER datafrom all21RegionalCentersinCalifornia were usedtoidentifytwo Cases of CDER status 1 autism by Regional Center and the Corresponding the and Center Regional by autism 1 status CDER of Cases OAS9132928259 258 3,209 991 TOTALS THE EPIDEMIOLOGY OFAUTISMIN CALIFORNIA 1983-85 by yearofbirth CDER Cases, 939 ai 938 1993-95 1983-85 Ratio 1993-95 by yearofbirth Sample size, ■ PAGE61 THE EPIDEMIOLOGY OF AUTISM IN CALIFORNIA Estimation of cohort size necessary to detect a change in the diagnostic criteria used for used criteria diagnostic the in change a detect to necessary size cohort of Estimation Assumptions considerations: size Sample respond tothesecondmailing. non-participating family. Similarly, non-responders were replaced iftheyfailedto were replaced bythenextchildonrandomizedlistfrom thesamecenteras packets were mailedbasedontheserandomlyorder lists.Badaddresses andrefusals cohort. Arandomlyordered listwascreated foreachRegionalCenter. Recruitment number ofchildren withCDERstatus1autismineachRegionalCenterforage number ofchildren sampledfrom eachRegionalCenterwasproportional tothe the entire State.Table A1showsthesestratificationsbyRegional Center. Thetarget amount, thenitwouldaccount for20%oftheobservedincrease incases. in correspondence ratesof85%and75%.Ifdiagnosticcriteriachanged bythis sample of500(250from eachcohort)wouldbelarge enoughtodetectthedifference was more likelythatitwouldonlyberesponsible foraportion oftheincrease. A total criteria were tocontributeanartificial increase inthereported casesofautism,it status 1autismcaseswouldmeetDSM-IVcriteria.If looseningofthediagnostic and p show achangeinthediagnosticthreshold ofthismagnitude(assumingpower=80% At thisextreme, only18studysubjects(9from eachcohort) to wouldbenecessary 842 ofthe3,209CDERstatus1autismcaseswould meetDSM-IVcriteriaforautism. diagnostic threshold toaccountforalloftheobservedincrease inautismcases,only more casesofCDERstatus1autisminCohort 2thanCohort 1.Forachangein increaseaccount forsomeoftheobserved betweenthetwocohorts. There are 2,218 cases). cases” and481casesthatare notfullsyndrome autism(out of3,209CDERstatus1 cohorts then85%ofCohort 2wouldmeetDSM-IVcriteria,representing 2728“true something otherthanfullsyndrome autism.Ifthere isnodifference betweenthetwo the 991CDERstatus1caseswouldrepresent 842“truecases”and149casesof Status 1wouldmeetDSM-IVcriteriaforautismCohort 1.With thisassumption, CDER status1autismmatchedthiscriteria.We assumedthat85%ofcasesCDER drome autismacross bothagecohorts, andtoassesshowcloselythediagnosisof CDER status1autism.We chosetouse DSM-IVcriteriaasthestandard forfullsyn- We didnothavedataapriorionchangesinthethreshold formeetingadiagnosisof CDER status 1 autism 1 status CDER Two-stage samplingwasdonetoobtainastudysamplethatrepresentative of While hypotheticallypossible,itwashighlyunlikely thatonly1outof4CDER A changeinthediagnosticthreshold forthecasesofCDERstatus1autismcould We madeseveralassumptionstoestimatethesamplesizeneededfor thisstudy. ■ ■ ■ ≤ 0.05). Observed increaseObserved innumberofcasesbetweenthecohorts=2218 Number ofcasesCDERstatus1autisminthe1993-95cohort =3209 Number ofcasesCDERstatus1autisminthe1983-85cohort =991 THE EPIDEMIOLOGY OFAUTISMIN CALIFORNIA ■ PAGE62 THE EPIDEMIOLOGY OF AUTISM IN CALIFORNIA regional center and the corresponding sample for Study Aim 2. Aim Study for sample corresponding the and center regional CDER Data – Identification of Study Subjects Study of Identification – Data CDER Study Aim2 Assumptions Table A2. size calculation,therateof misclassificationwasassumedtodecrease from 1983to DSM-IV criteria)wasunknown attheoutsetofthisstudy. For thepurposesofsample having mentalretardation. due toachangeintherateofmisclassificationautismamongchildren listedas tion ofwhetherornot50%(ormore) increase oftheobserved incasesofautismis mental retardation withoutCDERstatus1autism. 1983-85 and1993-95.Samplingwasbasedonanunduplicatedlistofchildren with study, welimitedthestudypopulationtotwobirth cohorts ofchildren, yearofbirth gional Centersfortheyears1986to1999.To becomparablewithotheraspectsofthis fornia Department ofDevelopmentalServicesprovided CDERdatagrouped byRe- groups ofchildren withmentalretardation withoutCDERstatus1autism.TheCali- status 1autism)byRegionalCenter Mental Retardation(without etieRgoa etr353309 9 8 10 15 0.94 10 12 323 28 13 0.75 14 0.99 14 345 11 340 23 554 12 3 12 13 19 8 7 452 0.96 14 558 0.88 9 0.85 0.83 1,036 5 0.58 17 478 26 7 489 8 1,078 510 13 Westside 14 RegionalCenter 11 387 0.48 0.90 542 Valley 0.90 MountainRegionalCenter 572 0.65 24 616 7 Tri-Counties 0.58 RegionalCenter 13 705 668 97 7 14 286 South CentralLosAngelesRegionalCenter 232 0.84 306 San Gabriel/PomonaRegionalCenter 0.78 780 0.79 201 9 318 San DiegoRegionalCenter 358 961 14 7 526 San AndreasRegionalCenter 478 9 517 8 0.58 Regional CenteroftheEastBay 1,146 0.73 Regional CenterofOrangeCounty 612 17 653 235 10 Redwood CoastRegionalCenter 16 229 LosAngelesCountyRegionalCenter North 0.64 0.73 407 BayRegionalCenter North 0.36 315 RegionalCenter Lanterman 512 335 RegionalCenter Kern 265 Inland RegionalCenter 795 461 Harbor RegionalCenter 736 Golden GateRegionalCenter RegionalCenter Far Northern LosAngelesRegionalCenter Eastern Central Valley RegionalCenter RegionalCenter Alta California The rateofmisclassification (casesofMRwithoutCDERstatus1autismthat meet The target studysamplewas250ineachagegroup. Thiswouldpermitdetermina- CDER datafrom all21RegionalCentersinCalifornia were usedtoidentifytwo Cases of Mental Retardation without status 1 autism by autism 1 status without Retardation Mental of Cases oa 21992507 6 258 262 0.76 9,275 12,139 Total THE EPIDEMIOLOGY OFAUTISMIN CALIFORNIA 1983-85 by yearofbirth CDER Cases, 939 ai 938 1993-95 1983-85 Ratio 1993-95 by yearofbirth Sample size, ■ PAGE63 THE EPIDEMIOLOGY OF AUTISM IN CALIFORNIA more thanthe991children identified. 1,457 suchchildren wouldhavebeenmissedintheoldercohort, representing 147% as havingmentalretardation were foundtomeetDSM-IVcriteriaforautism,then CDER status1autisminthissameagecohort. Ifasmany12%ofchildren classified account for607missingcasesofautismcompared tothe991children identifiedwith misclassification rateamongthe12,139children inthe1983-1985cohort could potential toaccountforalarge numberof“missing”casesautism.A5% children determined tohavementalretardation withoutCDERstatus1autismhasthe a difference between5%and12%withap-valueof0.05.Misclassificationamong increaseobserved inautismcases. Misclassification, ifitwere afactor, wouldmore likelycontributetoaportion ofthe (62 ineachgroup). Suchanextreme changein misclassification wasunlikely. 991). Thesamplesizenecessarytodetectadifference between5%and22%is124 among children withMRin1983-1985is22%(22%*12139–5%9275=3209- increaseobserved inautismcasescouldbeexplainedifthemisclassificationrate 1995. Assuminga5%misclassificationrateamong1993-1995cohort, thenallofthe Study Aim5 Study Aim4 CDER status1autismineachagegroup, orapproximately 500study participants. cohort. Acomparisonoftwo proportions, 15%and25%,requires 249children with autism wouldneedtohavebeenborn out-of-state,ascompared to15%oftheolder among children withautism,then25%oftheyoungeragecohort withCDERstatus1 p-value of0.05. California birth certificate. Samplesizeestimateswere basedonapowerof80%and considerations size Sample Study Aim3 age cohorts, allowingdetectionofdifferences of12%ormore. dren withCDERstatus1autism willbequeried.Comparisonsmadebetween would allowfordetectionofa12%difference betweengroups. was attempted.Ifthefullsamplewere enrolled thencomparisonsbetween agecohorts of 500children withCDERstatus1autismand500children withmentalretardation recently publishedstudy tions forthisstudyaimwere basedonverbalreports byDr. Croen inadvanceofher tion accountsfor20%oftheincreased numberofchildren withautism.Theassump- The samplesizewouldbesufficient todetectwhetherornotanincrease inin-migra- Aim 1.Thetarget studysamplewas250foreachbirth cohort. A samplesizeof500(250ineachagegroup) wouldprovide 80%powertodetect If 20%oftheincreased number ofcaseswere duetoincreases inin-migration Study Aim1determinesthe samplesizeforthisstudyaim.Familiesof500chil- Study Aims1and2determinedthesamplesizefor thisstudyaim.Atarget sample To estimatesamplesizethefollowingassumptionsandconsiderationswere made: The samplesizeconsiderationsforthisstudyaimwere similartothatforStudy THE EPIDEMIOLOGY OFAUTISMIN CALIFORNIA 35 thatshowed85%ofCDERstatus1autismcasesmatchtoa ■ PAGE64 THE EPIDEMIOLOGY OF AUTISM IN CALIFORNIA Study Aim6 aim. Iffeasible,itwouldbeattempted. number ofadditionalfamiliesthatwouldneedtoberecruited toaccomplishthisstudy tions foryoungersiblings,samplesizecalculationswouldbedonetodeterminethe younger siblingsandtheproportion offamilieschoosingtorefuse oravoidvaccina- include additionaleligiblefamilies.Basedontheproportion ofstudychildren with study armbutrealized thatwemightneedtoexpandthenumberoffamilies siblings whoare atleast18monthsofage.We aimedtohave159familiesineach unknown howmanychildren withautismselectedforthestudywould haveyounger have 90%powertofindathree-fold increased risksecondarytovaccination.Itwas autism/PDD secondarytovaccination.With 159familiesineachstudyarm,wewould (exposed/unexposed) wewouldhave90%powertofindatwo-foldincreased riskfor one affected child,usinganalphaof0.05,with474familiesineachstudyarm tion ofanapproximate 5%autismorPDDrecurrence riskwithinfamilieswithatleast The samplesizerequirements forthisstudyaimare asfollows:withtheassump- THE EPIDEMIOLOGY OFAUTISMIN CALIFORNIA ■ PAGE65 THE EPIDEMIOLOGY OF AUTISM IN CALIFORNIA Acknowledgments have beendone. they shared withustheirstoriesandhistories,withoutwhichthisworkcouldnot short supply. Through —eitherface-to-face,orbyquestionnaire ourinterviews — appreciative ofthetimeandenergy theygavetous,especiallywhenbothare oftenin letter inquiringiftheywouldliketoparticipate inaresearch study. We are deeply W ○○○○○○○○○○○○○○○○○○○○○○○ e wouldliketoacknowledgeandthankallofthefamilieswhoresponded toour ■ ■ ■ ■ ■ ■ We alsogratefullyacknowledgethefollowing: their support andexpertiseintheproduction ofthisreport. Martha AlcottandSteveDanafrom UCDavisHealthSystemPublicAffairs for Ronsin Photocopy, Inc. for thecertification process. go toStephenGuter, M.A.,forconductingadditionalADI-Rvideotapereviews 2001, andforproviding criticalreview ofthetraineevideotapes.Thanksalso Dr. SusanRisiforconductingtheADI-RtrainingatUCDavisApril11-13, Center staff whoassistedusinthis study. The AssociationofRegionalCenterAgencies(ARCA)andallthe intheGreaterinterviews LosAngelesandSanDiegoregions. Neuropsychiatric InstituteandHospital,fortheirworkconducting ADI-R Dr. MarianSigmanandstaff attheUniversityofCalifornia, LosAngeles, guiding thestudycontractandbudgetingprocess. throughout thestudy. SpecialthankstoChristineHarlanforoverseeingand crucial earlystages,andforproviding on-goingadministrativesupport Care at theUniversityofCalifornia,Davisforsupporting thestudyin The facultyandstaff oftheCenterforHealthServicesResearch inPrimary THE EPIDEMIOLOGY OFAUTISMIN CALIFORNIA ■ PAGE66 THE EPIDEMIOLOGY OF AUTISM IN CALIFORNIA 1Wakefield AJ,MurchSH,AnthonyA,LinnellJ,CassonDM,MalikM,Berelowitz M,DhillonAP, etal.Ileal-lymphoid-nodular 21 ComiAM,ZimmermanAW, VH,LawPA, Frye PeedenJN.Familialclusteringofautoimmunedisorders andevaluationof 19 Taylor B,Miller E,FarringtonCP, Petropoulos MC,Favot-MayaudI,LiJ,Waight PA. Autismandmeasles,mumps,rubella 13 SE,Welch RodierPM,Bryson JP. 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