What s Going On? The Question of Time Trends in Autism

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1 Viewpoint Wht s Going On? The Question of Time Trends in Autism Mrk F. Blxill, MBA SYNOPSIS Increses in the reported prevlence of utism nd utistic spectrum disorders in recent yers hve fueled concern over possible environmentl cuses. The uthor reviews the vilble survey literture nd finds evidence of lrge increses in prevlence in both the United Sttes nd the United Kingdom tht cnnot be explined by chnges in dignostic criteri or improvements in cse scertinment. Incomplete scertinment of utism cses in young child popultions is the lrgest source of predictble bis in prevlence surveys; however, this bis hs, if nything, worked ginst the detection of n upwrd trend in recent surveys. Comprison of utism rtes by yer of birth for specific geogrphies provides the strongest bsis for trend ssessment. Such comprisons show lrge recent increses in rtes of utism nd utistic spectrum disorders in both the U.S. nd the U.K. Reported rtes of utism in the United Sttes incresed from 3 per 10,000 children in the 1970s to 30 per 10,000 children in the 1990s, 10-fold increse. In the United Kingdom, utism rtes rose from 10 per 10,000 in the 1980s to roughly 30 per 10,000 in the 1990s. Reported rtes for the full spectrum of utistic disorders rose from the 5 to 10 per 10,000 rnge to the 50 to 80 per 10,000 rnge in the two countries. A precutionry pproch suggests tht the rising incidence of utism should be mtter of urgent public concern. SfeMinds, Crnford, NJ Address correspondence to: Mrk F. Blxill, MBA, 22 Fyerwether St., Cmbridge, MA 01238; tel ; fx ; e-mil <blxill.mrk@bcg.com> Assocition of Schools of Public Helth 536

2 Time Trends in Autism 537 Since the 1960s, utism reserchers hve published more thn 50 surveys tht provide estimtes of the frequency of utism in defined popultions. This survey bse provides significnt opportunity for nlysis, but lso poses mny difficulties with respect to interprettion. In recent yers, these difficulties hve come into shrp relief s reports of higher nd rising prevlence rtes hve fueled concern over possible environmentl cuses. 1,2 This survey literture hs been the subject of severl reviews nd commentries, 3 11 mny of them by single uthor. 3 8 This smll set of reviewers hve shred common interprettion regrding the trend evidence, emphsizing the notion tht utism is not n extremely rre disorder, 10 while rguing tht there is no evidence for n increse over time in the prevlence of utism. 5 In order to reconcile the full body of evidence with this interprettion, severl uthors hve suggested mechnisms tht might explin the reported increses in the pprent bsence of seculr trend, including dignostic substitution, chnging dignostic stndrds, 16 nd improved detection. 17 The controversy over the true rtes of utism might pper simple mtter, one tht is best resolved prospectively, with improvements in reporting procedures. In relity, the persistence of the trend controversy reflects vigorous debte over cuslity in the brodest sense. Is utism primrily genetic disorder, s mny would clim, 18 or do environmentl fctors ply stronger role thn previously cknowledged? In comprison to the methodologicl hypotheses, the serch for possible environmentl cuses hs generted fr greter controversy, prticulrly s itrogenic hypotheses hve been dvnced nd chllenged In the context of these controversies, creful review of the vilble literture is essentil. Assessment of trend evidence bers directly on the reltive explntory power of environmentl nd genetic theories. Cusl theories tht emphsize genetic inheritnce crry greter weight if disese frequency is unchnged over time, wheres rising incidence demnds environmentl explntions. Relible trend ssessment requires comprehensive synthesis of the best vilble evidence. 25,26 This rticle reviews the vilble survey evidence on the prevlence of utism in order to demonstrte tht the underlying rtes nd not merely the reported rtes of utism hve risen shrply in the U.S. nd the U.K. This discussion is divided into two sections. The first section provides n nlysis of the impct of survey design choices on frequency nd trend estimtes. The second section offers n in-depth quntittive nd qulittive comprison of 11 U.K. nd eight U.S. surveys published since the mid-1960s (see Tble 1). IMPACT OF DIFFERENCES IN SURVEY DESIGN Definitions The determintion of disese frequency requires, first, definition of the disese event. In the cse of utism, this determintion hs long been bsed on subjective psychologicl ssessments. Becuse utism hs no well-defined biologicl mrkers, the condition itself is n hypothesis, suggestion tht behind the behviorl description [lies] disese entity. 27 Not surprisingly, over the six decdes since Leo Knner first described the condition, 28 the stndrd definition hs been updted mny times (see Tble 2), incorporting chnges in nomenclture, dignostic criteri, ge of onset, nd disese ctegories. While the generl intent hs been to mke dignostic decisions more consistent, these revisions complicte the chllenge of compring findings cross nd within studies. Nomenclture. The word utism hs remined in constnt use since Knner dopted the term to describe erly infntile utism or infntile utism in 1943, 28 yet the ccompnying modifiers hve chnged with time. In Rutter s influentil moderniztion of the definition in 1978, 27 three relted terms utism, infntile utism, nd childhood utism were used somewht interchngebly. The third edition of the Dignostic nd Sttisticl Mnul of Mentl Disorders (DSM- III) 29 used infntile utism s the core descriptor, but lso plced utism in the context of the pervsive developmentl disorders (PDDs) for the first time. In 1987, revised edition, DSM-III-R, 30 bndoned the term infntile utism, in prt to recognize cses in which the onset of symptoms did not occur in erly infncy; DSM-III-R distinguished between utistic disorder nd pervsive developmentl disorder, not otherwise specified (PDD-NOS). In 1993, the World Helth Orgniztion published the Interntionl Clssifiction of Diseses, 10th revision (ICD-10) definitions, 31 which used the term childhood utism. One yer lter, the fourth DSM edition, 32 in most respects identicl to ICD-10, used the term utistic disorder. Dignostic criteri. Knner nd Eisenberg provided the first forml set of criteri for the dignosis of utism in 1956; the criteri focused on two dimensions of the condition: profound lck of ffective contct nd repetitive, ritulistic behvior, which must be of n elborte kind. 33 Prctitioners found these criteri somewht problemtic over the yers, in prticulr becuse they omitted the unusul lnguge nd communiction ptterns tht seemed to mny core element of the disese. Rutter s refinement introduced the concept of simultneous deficits in three behviorl domins: impired socil reltionships, impired lnguge nd communiction skills, nd insistence on smeness. 27 In one form or nother, these three domins hve determined the opertionl definition of utism ever since. Some evidence suggests tht the shift wy from the Knner criteri my hve effectively brodened the scope of the dignosis. One group of investigtors in Finlnd pplied both the Knner criteri nd the ICD-10 criteri in popultion survey. 34 These reserchers interpreted the Knner criteri s more restrictive nd reported lower rte for wht they clled clssic utism of 5.6 per 10,000, compred with 12.2 per 10,000 for childhood utism. The men prevlence rte for 11 studies using the Knner criteri ws two per 10, This compres to men of seven per 10,000 for 13 surveys of infntile utism tht pplied either the Rutter or DSM-III criteri or similr post-knner clinicl criteri Age of onset is the one criterion tht hs chnged most mesurbly over time. Knner nd Eisenberg implied n ge ssumption by using the term erly infntile utism. Rutter 27 (followed by DSM-III) set specific ge of onset limit of erlier thn 30 months. The DSM III-R criteri relxed this limit, requiring only tht the ge of onset occur during

3 538 Viewpoint Tble 1. Overview of 54 published reports of studies tht provide disese frequency sttistics on utism, utistic spectrum disorders (ASDs), nd relted disorders. Number of cses Author(s) Loction Yer of publiction per 10,000 children Lotter 35 Englnd Treffert 36 U.S Ymzki et l. 37 Jpn Tnino 38 Jpn Hg nd Miymoto 39 Jpn Nki 40 Jpn Brsk 41 Denmrk Wing nd Gould 42 Englnd Bohmn et l. 46 Sweden Hoshino et l. 43 Jpn Ishii nd Tkhshi 47 Jpn McCrthy et l. 44 Irelnd Gillberg 48 Sweden Steinhusen et l. 49 Germny Steffenburg nd Gillberg 50 Sweden Burd et l. 45, U.S Mtsuishi et l. 51 Jpn Tnoue et l. 52 Jpn Bryson et l. 86 Cnd Ritvo et l. 53 U.S Aussilloux et l. 54 Frnce Sugiym nd Abe 55 Jpn Cildell nd Mmelle 56 Frnce Gillberg et l. 60 Sweden Fombonne nd du Mzubrun 57 Frnce Herder 88 Norwy Rumeu-Rusquette et l. 58,79 Frnce Deb nd Prsd 82 U.K Hond et l. 66 Jpn Fombonne et l. 79 Frnce Wignyosumrto et l. 87 Indonesi Webb et l. 89 U.K Arvidsson et l. 93 Sweden Sponheim nd Skejdl 94 Norwy Cliforni Deprtment of Developmentl Services 2,b U.S. 1999/ (pek) Tylor et l. 20 U.K Kdesjo et l. 85 Sweden Irie 90 Jpn Kielinen et l. 34 Finlnd Bird et l. 78,c U.K Hillmn et l. 84 US 2000 Chkrbrti nd Fombonne 61 U.K Fombonne et l. 62 U.K (ASDs) Powell et l. 67 U.K Kye et l. 68 U.K Bertrnd et l. 80 U.S Sturmey nd Jmes 83 U.S Dvidovitch et l. 91 Isrel Mgnusson nd Semundsen 92 Icelnd Croen et l. 12 U.S Scott et l. 95 U.K (ASDs) Lingm et l. 63 U.K Gurney et l. 73 U.S (ASDs) Yergin-Allsopp et l. 75 U.S (ASDs) A lter survey 77 exmined the sme popultion. The uthors consider tht the findings of the second survey confirm the originl findings. b An erlier survey 1 exmined the sme popultion. The uthors consider the lter report to contin the more ccurte estimtes. c An erlier survey 74 exmined the sme popultion. The uthors consider the lter report to contin the more ccurte estimtes

4 Time Trends in Autism 539 Tble 2. Chnges in nomenclture nd mjor shifts in dignostic criteri in widely ccepted definitions of utism Knner nd Eisenberg 33 Rutter 27 DSM-III 29 DSM-III-R 30 ICD /DSM-IV 32 Dte published Lrger ctegory PDD PDD PDD Autism Nomenclture Erly infntile Infntile utism; Infntile Autistic disorder Autistic disorder utism; infntile utism; utism utism childhood utism Age t onset None By 30 months By 30 months During infncy or By 36 months of symptoms specified childhood Relted disorders Other infntile Infntile utism/ PDD-NOS PDD-NOS; psychoses residul stte; Asperger s syndrome; typicl PDD Rett s syndrome; childhood onset disintegrtive disorder A number of studies bsed on the dignostic criteri outlined in DSM-III nd DSM-III-R used the term utistic-like condition to refer to certin relted disorders, lthough this term ws not included in the officil definition of pervsive developmentl disorders. PDD = pervsive developmentl disorder NOS = not otherwise specified infncy or childhood. ICD-10 nd DSM-IV set n ge limit t 36 months, in prt rection to the problem posed by the expnded definition introduced in DSM-III-R. 59 Other utistic spectrum dignoses. DSM-III introduced, in brod sense, the concept of spectrum of utistic disorders through PDDs, nd specificlly introduced the term typicl PDD, which some found useful, 45,77 while others pplied the term utistic-like condition. 50,60 DSM-III-R introduced the term PDD-NOS, which ws retined in DSM-IV. By contrst, ICD- 10 opted to use the term typicl utism. In recent yers, reserchers hve begun dopting the phrse utistic spectrum disorders (ASDs), used interchngebly with PDDs. The ASDs include utism nd PDD-NOS, s well s lrger list of relted disorders, including Asperger s syndrome, childhood disintegrtive disorder, nd Rett s syndrome. Asperger s cses represent pproximtely 14% to 19% of the ASD popultion, 20,61 63 while reported rtes re very low for childhood disintegrtive disorder 64 nd Rett s syndrome ( well-chrcterized genetic disorder). 65 Methodologicl issues: nomenclture nd dignostic criteri. The core definition of utism hs remined reltively stble since Rutter s introduction of the three min behviorl domins in 1978, 27 fcilitting comprison of rte estimtes over time. Erly surveys tht pplied the Knner criteri my hve reported lower utism rtes thn lter studies becuse the Knner criteri were more restrictive. This modest effect my contribute to perception of n incresing trend over time. The three sets of DSM criteri for utism hve vried modestly in bredth. Some hve rgued tht the move from DSM-III to DSM-III-R brodened the concept of utism, contributing to n pprent increse in prevlence over time; however, in the shift from the DSM- III-R criteri to the DSM-IV/ICD-10 criteri, corrective nrrowing occurred. 59 Thus, differences over time in the bredth of the dignostic criteri re unlikely to hve hd meningful effect on reported disese frequency. Any comprison of surveys must tke into ccount differences in disese definitions, in prticulr whether PDD-NOS nd Asperger s syndrome re included in the definition of utism. Mesurements of disese frequency The overwhelming mjority of utism surveys hve used prevlence rtes s the primry mesure of disese frequency. A smll minority of studies hve reported incidence rtes of vrious kinds, 20,66 68 but the ctul differences in ssumptions, dt sources, nd methods mke these incidence clcultions little different from reported prevlence rtes. The emphsis on prevlence reporting fits well with the historicl consensus mong utism reserchers tht utism is lrgely (if not exclusively) genetic in origin, unlikely to vry in disese frequency over time, nd unlikely to demonstrte seculr chnges in incidence. 3 In principle, incidence clcultions re essentil for trend ssessment. But developing incidence mesures for utism presents specil difficulties. Mesuring incidence rtes requires clerly identifible incidence times. With respect to utism, mny reserchers hve conflted time of onset with time of detection, due to both theoreticl nd prcticl complexities. In prctice, most reserchers opt for simplicity nd report prevlence rtes. Those few studies tht report incidence rtes hve used wide rnge of incidence times,

5 540 Viewpoint including ge t dignosis, 20,67,68 yer of birth, 66,68 ge t onset of symptoms (sometimes clled ge t prentl concern ), 20 nd (lthough this mesure is lso used in clculting prevlence rtes) ge t entry into services system. 1,2 Prevlence clcultions cn vry from cumultive incidence rtes in numerous wys. First, they my underestimte cumultive incidence by filing to count cses in which the disese condition hs lpsed. In utism, since the presence of the disese condition is defined by its onset t certin stge of development, this concern is irrelevnt in principle. In prctice, since the few follow-up studies hve shown the condition to be persistent, 69,70 it my be unimportnt. Second, prevlence clcultions my underestimte older popultions if excess cse mortlity increses with ge. Studies in Cliforni hve found excess mortlity mong utistic children (lrgely due to ccidentl drowning deths), 71,72 but not in utistic dults. In ddition, this excess mortlity ws extremely smll reltive to the popultion size. Third, most prevlence surveys fil to djust for net migrtion effects, i.e., the effect of children with utism moving in nd out of the study re. These three issues hve concerned some reviewers, 10,21 but there is little evidence in the literture for systemtic lrge effect on either disese frequency or trend. Finlly, prevlence rtes cn vry from true disese rtes when cse scertinment is incomplete. This is n importnt issue ddressed further in the following section on cse finding. The studies reviewed for the purposes of this rticle hve used four min pproches to reporting disese frequency: 1. Point prevlence with no strtifiction by ge or birth yer. This common pproch ws used in 23 of the 54 studies listed in Tble Point prevlence with strtifiction by birth yer nd/ or ge. This pproch hs been used most frequently, with 28 of 54 studies employing some form of strtifiction. Studies reporting strtified prevlence rtes provide potentilly useful trend informtion. 3. Cumultive incidence, defined by mny utism reserchers s the number of cses dignosed within specified ge-t-dignosis window divided by the totl popultion t risk. 20,53,68,73 These studies re most relibly informtive with respect to trend, but they re few in number. 4. Incidence. Only one study climed to mesure incidence. 67 The uthors gthered dt on ge t dignosis but did not provide ny dt on birth yers, mking comprison to other studies impossible. Methodologicl issues: mesurement of disese frequency. The common prctice of using point prevlence mesures fcilittes the collection nd comprison of survey dt. Point prevlence mesures tht hve been strtified by ge nd/or birth yer provide dditionl informtion for trend ssessment by llowing for the comprison of frequencies nd trends within s well s cross studies. Comprisons of prevlence estimtes cross studies must tke into ccount differences in study design tht ffect frequency ssessment, especilly differences in the scope of the utism definition. Comprisons of birth cohort disese prevlence estimtes within studies must tke into ccount specific design choices tht ffect trend ssessment. Cse-finding: scertinment issues There re mny prcticl obstcles to recognizing utism in young child. These problems strt in the home, where delys in recognition will produce scertinment filures under ny survey method. The three behviorl domins of utism re not medicl problems nd cn be overlooked for substntil periods of time: socil interction problems cn be interpreted s due to hering impirments, nd delys in lnguge development cn be explined by the phenomenon of lte-tlking children. Prdoxiclly, the insistence on smeness of utistic children cn lso mke them pper to be esy children, since they my mke few demnds. Further delys cn occur once concerned prents hve recognized tht their child hs serious developmentl issues; the process of scheduling forml clinicl ssessment cn tke mny months. While definitions of utism hve generlly specified the time for the onset of symptoms s 30 to 36 months, the ge of dignosis crries no similr requirement. Dignoses cn come s erly s 18 months with specilized methods, 74,78 or s lte s 10 yers of ge. A number of utism surveys report men or medin ges t dignosis (see Tble 3), with wide vrition cross the popultions mesured. A few surveys reporting lower ges t dignosis hve bsed their clcultions on truncted smples, removing lter ges t dignosis from their clcultions. 20,61,67 Other studies report medin ges t dignosis rnging from 3 to 6 yers of ge, 1,2,63,68 or mens rnging from 3.9 to 6.9 yers of ge. 8,36,75,76 This wide vrition nd reltively lte verge ge t dignosis rgues for cution in interpreting surveys bsed on young children nd especilly those bsed on survey popultions tht include children younger thn 5 yers of ge. Severl recent surveys using dministrtive dt hve demonstrted the disproportionte effect of scertinment bis on younger birth cohorts. Reports from sttes tht hve updted their cse files over period of severl yers demonstrte clerly the wy in which young children cn enter survey popultion grdully over time. This effect hs been described in Minnesot nd Cliforni. 2,73 Recent experience with Cliforni survey dt hs reveled how misinterprettion of trends bsed on mixed ge groups in survey popultion cn led to erroneous conclusions Argubly, however, scertinment bis cn be reduced with ggressive cse-finding methods, which ccelerte the ge of dignosis. One useful test of the impct of scertinment is to compre findings from repeted cse-finding efforts, i.e., pirs of surveys tht cover identicl geogrphic res nd birth popultions but in different time frmes. Three such pirs of surveys hve been published (Tble 4). One such pir ws initited in North Dkot, 45,77 where two PDD prevlence surveys (neither strtified by ge) were conducted more thn decde prt by the sme reserch group. The first survey identified 98% of the cses found 12 yers lter; this high cse scertinment rte ws likely due to high medin ge in the erlier survey, wide ge rnge,

6 Time Trends in Autism 541 Tble 3. Age of utism dignosis in selected U.K. nd U.S. studies Author(s) Age t dignosis Time period United Kingdom Tylor et l yers (medin) (birth yer) Powell et l yers (medin) (birth yer) Chkrbrti nd Fombonne yers b (men) (yer dignosed) Kye et l yers (medin); rnge (birth yer) Lingm et l yers (medin) (birth yer) United Sttes Treffert yers (men) (yer dignosed) Cliforni Deprtment of Developmentl Services yers (medin) Up to 1987 (yer entered services system) Croen et l yers (men) (birth yer) Mndell et l yers (men) (clim yer) Cliforni Deprtment of Developmentl Services yers (medin) Up to 2002 (yer entered services system) Yergin-Allsopp et l yers (men) (birth yer) Cse collection in this study ws truncted to exclude children who were dignosed fter 60 months of ge. This exclusion mkes the medin ge t dignosis low estimte of eventul ge of dignosis in this cse popultion. b Cse collection in this study ws truncted to exclude children who were dignosed fter 78 months of ge. This exclusion mkes the men ge t dignosis low estimte of eventul ge of dignosis in this cse popultion. nd low overll prevlence in the survey popultion. A second pir of surveys (with strtified ge cohorts) ws conducted four yers prt in region in Sweden tht includes the city of Goteburg nd the rurl Bohusln re. 50,60 The first survey found wide vrition in prevlence rtes cross ge cohorts, rnging from two per 10,000 to 11 per 10,000. These reserchers reported complete scertinment fter n intervl of four yers for the cohort ged 8 to 10 yers in the originl survey. For the cohort ged 4 to 6 yers, the scertinment rte declined to 73%, nd for children younger thn ge 4, the scertinment rte ws only 23%. In this survey pir, wht ppered to be declining time trend in the first survey popultion ws not replicted in the second survey. Finlly, third pir of surveys ws initited in the Tble 4. Description of three survey pirs: identicl geogrphic res nd popultions Cse scertinment Loction, description, nd findings Erlier study Lter study rte in erlier study North Dkot Burd et l Burd et l Age rnge t time of study 2 18 yers yers Number of cses % Prevlence of PDDs 3.26 per 10, per 10,000 Goteburg/Bohusln, Sweden Steffenburg nd Gillberg, Gillberg et l Age rnge t time of study 7 10 yers yers Number of cses % Age rnge t time of study 4 6 yers 8 10 yers Number of cses % Age rnge t time of study 3 yers 4 7 yers Number of cses % Prevlence of PDDs 6.6 per 10, per 10,000 South Est Thmes Helth Region, U.K. Bron-Cohen et l Bird et l Age t time of study 18 months 7 yers Number of cses % Prevlence of utism 6.3 per 10, per 10,000 Lower number of cses in lter study due to one child hving moved out of study region. PDD = pervsive developmentl disorder

7 542 Viewpoint South Est Thmes Helth Region in Englnd to test the efficcy of newly designed Checklist for Autism in Toddlers (CHAT). 74,78 The reserchers first crried out creful survey of 18-month-old children to see if the CHAT could predict utism t n erly ge. Although the CHAT checklist showed high specificity rte (98%) for childhood utism, the first survey filed to scertin the mjority of cses found in the sme popultion six yers lter. The utism scertinment rte for the combined medium nd high risk groups from the first survey ws only 20%. This pttern of scertinment bis cn lso be detected in the seven single surveys tht provide nnul birth cohort prevlence estimtes cross wide ge rnges. 2,43,56,63,75,79,80 (Personl communiction, Ron Huff, PhD, Cliforni Deprtment of Developmentl Services, Februry 2003). Birth cohort prevlence rtes for children ges 6 or older show wide rnge of trends, from declining to flt to shrply incresing, cross the seven surveys. Yet ech study shows pronounced nd rpid decline in prevlence rtes with decresing ge in ge cohorts younger thn 6 yers. Interestingly, these declines re comprble in dministrtive surveys nd ctive cse-finding surveys. If scertinment lgs in utism surveys hve predictble effect on trend ssessments, then this effect cn only be more pronounced for other utism spectrum dignoses with lter medin ges t dignosis. One recent U.K. survey reporting ge t dignosis for the full utism spectrum reported medin ge t dignosis for Asperger s syndrome of 8.1 yers, compred with medin ge of 4.3 yers for typicl utism (PDD-NOS), nd 3.3 yers for childhood utism. 63 This pttern suggests tht ny survey reporting trend evidence for popultions of children younger thn 10 yers of ge my understte both the ASD trend nd the reltive proportion of core utism cses vs. cses of less severe ASDs. Methodologicl issues: scertinment. Obstcles to recognizing utism in children younger thn 5 yers of ge cn led to scertinment bis, distorting trend evidence in surveys tht do not control for ge effects, either reducing positive trend or suggesting negtive trend where reported rtes re stble. Survey popultions tht hve high proportions of young children my yield reported prevlence significntly below ctul disese frequency. Aggressive cse-finding my reduce scertinment bis by ccelerting dignoses in smll popultions, but ppers not to eliminte it. The scertinment effect holds with comprble strength in dministrtive surveys nd in surveys using ggressive cse-finding methods. The lter ge t dignosis for Asperger s syndrome nd PDD-NOS increses the risk of misinterprettion of trend evidence in surveys tht ttempt to mesure disese frequency of ll ASDs. Cse finding: popultion restrictions, cse identifiction, nd cse vlidtion methods Popultion restrictions. Some utism reserchers hve mde specific choices tht restrict their surveys popultion coverge. These include the following: limiting cse finding to mentlly retrded children or children in specil schools, 81,82 choice likely to downwrdly bis reported rtes; focusing on mles only, 68 choice likely to yield higher rtes bsed on the high mle/femle rtio in utism; or truncting the cse-finding period t n erly ge, 61,68 choice likely to downwrdly bis reported rtes. Cse identifiction. Incresingly, utism surveys hve been conducted using cses identified entirely from centrlized dtbses. These dtbses re generlly designed to fcilitte the dministrtion of service delivery nd my be more or less relible s epidemiologicl resources. Often clled dministrtive surveys, efforts relying on centrl dtbses re less costly to conduct thn surveys tht rely on independent identifiction nd vlidtion of cses, often from multiple sources, especilly when the former do not require individul interviews for cse vlidtion. In the United Sttes, specil eduction benefits re dministered t the stte level, so severl recent dministrtive surveys hve been undertken t the stte level. 2,73,83,84 In the United Kingdom, helth cre services dtbses hve provided the cse identifiction for similr dministrtive surveys. 20,63,68 When reserchers rely on service providers rther thn centrl dtbse to identify potentil cses, cses my be missed through non-coopertion t mny stges. Concerns regrding the effectiveness of cse-finding in such surveys hve been extensively reviewed elsewhere; 3,4 issues include institutionl coverge nd response rtes, prent refusl rtes, dignostic interview completion rtes, nd the qulity of dignostic instruments. One recent review hs hypothesized tht rising rtes of utism hve resulted in prt from improved cse identifiction in recent surveys bsed on smll survey popultions ( 50,000). 11 These uthors rgue tht smll surveys hve generted disproportiontely high number of reports of prevlence in excess of 10 per 10,000. Arguing ginst this hypothesis is the observtion tht surveys of lrge popultions in the U.S. nd the U.K. hve yielded ASD nd utism rtes consistently greter thn 10 per 10,000 nd hve lso reported upwrd trends during their survey periods. 2,63,73,83 The sme review lso suggests tht close coordintion with routine developmentl check in preschool children cn explin high levels of cse identifiction, pointing for support to severl Jpnese surveys tht hve found prevlence rtes greter thn 10 per 10, ,52,55,66 Arguing ginst this suggestion re numerous erlier Jpnese surveys tht reported lower utism rtes, 37 40,43,47 given no evidence of chnging prctices in Jpn. Additionlly, none of the published Jpnese surveys hs ever reported rte of utism greter thn 25 per 10,000, the rnge of concern for recent surveys in the U.S. nd U.K. Cse vlidtion. Methodologicl fetures of both dministrtive nd intensive cse-recruitment surveys cn ffect the qulity of dignoses nd the ccurcy of disese rtes. These include choice of screening instruments nd instruments for intensive ssessment nd/or record review, numbers of informnts, nd methods to ensure inter-rter relibility. These methods re reviewed in depth elsewhere. 3,4 Recent experience hs shown tht surveys with ggressive cse vlidtion methods cn uncover more cses of utism

8 Time Trends in Autism 543 nd PDD thn surveys tht work entirely from dministrtive records. But even these experiences cn provide support for the usefulness of dministrtive dtbses. One recent study in Atlnt estimted tht only 41% of children with PDDs hd been given n utism dignosis by school dministrtors, 75 but the survey s definition of PDDs included Asperger s syndrome, wheres the school system my hve pplied more restrictive definition of utism. School sources were the min source for cse identifiction: only 3% of the children in the smple who were clssified by the reserchers s hving PDDs were identified through dtbses other thn school records. This low percentge of missed cses underscores the vlue of centrl dtbses in identifying cses nd lso the importnce of specifying PDD ctegories for vlidtion purposes. Methodologicl issues: popultion restrictions, cse identifiction, nd cse vlidtion method. Use of restricted popultions bsed on ge or receipt of services my led to underestimting true disese frequency by reducing the potentil for cse identifiction; lterntively, restricting the study popultion to mles my led to overestimting the true frequency. Administrtive surveys bsed on centrl dtbses my provide lower estimtes of disese frequency thn surveys tht rely on independent cse-finding nd vlidtion. The impct of this effect is hrd to ssess bsed on current dt nd is influenced by the qulity nd coverge of specific dtbses. Smller survey popultions my llow for better cse identifiction rtes. Differences in cse vlidtion methods my explin disese frequency differences cross surveys. REVIEW OF U.S. AND U.K. STUDIES Previous utism reviews hve consistently concluded tht utism incidence rtes show no cler time trend These reviews, however, hve shred three mjor flws: use of flwed met-nlytic methods, limited survey evidence, nd indequte correction for scertinment bis. Criticl exmintion of methods for cross-survey comprisons A single uthor, Fombonne, hs been the most ctive reviewer nd interpreter of utism surveys. 3 8 This reviewer hs conducted three met-nlyses of utism time trends. 3,4,6 In these cross-survey comprisons, he hs correlted reported prevlence estimtes with the yers in which the selected surveys were published. The first met-nlysis showed n increse in utism rtes over time, but the correltion ws not sttisticlly significnt. 3 The lter nlyses showed rising trend tht reched sttisticl significnce. 4,6 In ech cse, however, the uthor ttributed ny positive trend in reported prevlence rtes to methodologicl chnges. Other reviewers hve supported him in this opinion. 10,11 Until recently, this ws resonble inference to drw from the literture. Reviewers hve emphsized the difficulty of ssessing trends ginst bckground of regulr chnges in dignostic criteri. When dtes of publiction re used in met-nlysis, n nlysis of time trends will revel little beyond n pprent effect of chnges in dignostic stndrds. An ssessment (not shown) of ll published prevlence studies by dignostic criteri set (Knner, Rutter/DSM-III, DSM-III-R, 60,82,85 92 nd DSM-IV through ,12,20,34,61 63,66 68,73,75,78 80,92 96 ) revels tht prevlence ws reltively stble until the most recent set of dignostic criteri ws introduced. Relying on the dte of publiction cn obscure lrge differences in the study popultions observed. For exmple, three Scndinvin studies published in three-yer period used mrkedly different popultions: Swedish study published in 1997 mesured the prevlence of utism in 3- to 6-yer-old popultion born from 1988 through ; nother Swedish study published two yers lter, in 1999, focused on 7-yer-olds who were born in 1985, severl yers before the children in the first group 85 ; while Norwegin study published between the two covered wide rnge of ge cohorts nd mesured prevlence rtes going bck s fr s In ddition, combining surveys from loctions s widely seprted s Yokohm, Cliforni, nd Goteburg gretly increses the potentil for non-comprbility. None of the three met-nlyses chose surveys bsed on country groupings, therefore risking the introduction of confounding environmentl fctors tht re geogrphiclly specific. With the publiction since 1999 of six U.S. studies nd seven U.K. studies, the opportunity for useful geogrphic comprison hs improved gretly. An lterntive pproch is to synthesize evidence from utism surveys using the following methods: Anlyze surveys from single country seprtely insted of grouping seprte regions together. Use the most common mesure of disese frequency: point prevlence. Compre prevlence reports bsed on birth dtes of children in the survey popultion, not the publiction dte. Highlight differences in dignoses, distinguishing (using DSM-IV nomenclture) utistic disorder from PDD- NOS nd Asperger s syndrome. Identify ll possible sources of bis resulting from specific survey design choices. Cross-survey comprisons: U.K. nd U.S. studies Tbles 5 nd 6 show how fctors likely to ffect comprisons cross surveys (fctors ffecting frequency estimtes) nd within surveys (fctors ffecting trend estimtes) impct 11 U.K. studies nd eight U.S. studies tht provide usble utism rte dt. Frequency fctors include the following: use of the Knner criteri, relince on dministrtive dtbses, erly ge trunction of the survey popultion, restrictions of the survey popultion bsed on school or mentl sttus, nd gender restrictions. Surveys pplying one of these fctors my report lower utism rtes thn other surveys; however, in the cse of gender restrictions, reltive rtes will be higher when only mles re included. Although scnt evidence supports popultion effect, the sizes of the survey popultions re

9 544 Viewpoint Tble 5. Description of 11 U.K. surveys of utism prevlence, with fctors ffecting the ssessment of disese frequency nd time trends Lotter Wing nd Gould Deb nd Prsd Webb et l. Tylor et l. Fombonne et l Geogrphic re Middlesex Cmberwell Northestern Scotlnd Wles North Thmes re Multiple Birth yer rnge Survey popultion 78,000 35, ,814 73, ,000 10,438 Number of cses per 10,000 children Autism 4.1 (95% CI 2.7, 5.5) 4.9 (95% CI 2.9, 7.8) 9 (95% CI 7.2, 11) 7.2 (95% CI 5.3, 9.3) 5.3 PDD, not including Asperger s ASD, including Asperger s (95% CI 16.2, 36.0) Fctors ffecting prevlence Dignostic criteri Knner 33 Knner 33 DSM-III-R 30 DSM-III-R 30 ICD ICD Centrl dtbse No No No No Yes No Age trunction No No No No No No Popultion restriction No No Yes No No No Gender restriction No No No No No No Fctors ffecting trend Yer of birth brekdowns No b No b Yes b Yes c Yes, but NA b Yes b Age vrition (rnge) No (8 10) No ( 15) Yes (5 19) Yes (3 15) Yes (5 16) Yes (5 15) Ages 5 yers No Yes No Yes No No Asperger s included No No No No Yes Yes continued on p. 545

10 Tble 5 (continued). Description of 11 U.K. surveys of utism prevlence, with fctors ffecting the ssessment of disese frequency nd time trends Chkrbrti nd Lingm et l. Kye et l Scott et l Fombonne Bird et l Geogrphic re North London U.K. Cmbridgeshire Stffordshire South Est Thmes Helth Region Birth yer rnge Survey popultion 186,206 70,000 43,472 15,500 16,235 Number of cses per 10,000 children Autism (95% CI 11.0, 24.6) 30.8 (95% CI 22.9, 40.6) PDD, not including Asperger s (95% CI 46.8, 70.9) ASD, including Asperger s (95% 49.5, 65.8) 62.6 (95% CI 50.8, 76.3) Fctors ffecting prevlence Dignostic criteri ICD ICD ICD ICD ICD Centrl dtbse Yes Yes No No No Age trunction No Yes (2 5) No Yes ( ) No Popultion restriction No No No No No Gender restriction No Yes (mle) No No No Fctors ffecting trend Yer of birth brekdowns Yes d Yes d No b No b No b Age vrition (rnge) Yes (1 16) No No (5 11) No (2 6) No (7) Ages <5 yers Yes NA No Yes No Asperger s included Yes No Yes Yes No NOTE: Arrows indicte study design fetures with potentil impct on reported outcomes, with downwrd-pointing rrows indicting possible downwrd effect on frequency or trend estimtes nd upwrd-pointing rrows indicting possible upwrd impct. Combined prevlence of 6.9 per 10,000 for utistic children nd children with similr but less mrked fetures. b Autism rtes by ge cohort nd times of dt collection provided by uthors, llowing lignment of ge cohort with birth yers. c Autism rtes by yer of birth provided by uthors. d Autism rtes by yer of birth provided by uthors grphiclly. CI = confidence intervl PDD = pervsive developmentl disorder ASD = utistic spectrum disorder NA = not pplicble Time Trends in Autism 545

11 Tble 6. Description of eight U.S. surveys of utism prevlence, with fctors ffecting the ssessment of disese frequency nd time trends Cliforni Sturmey Yergin- Ritvo Burd Deprtment of nd Allsopp Bertrnd Gurney Treffert et l. et l. Developmentl Jmes et l. et l. et l Services Geogrphic re Wisconsin Uth North Cliforni Texs Atlnt, Brick Minnesot Dkot GA Township, NJ Birth yer rnge Survey popultion 899, , ,986 14,200,000 3,565, ,456 8,896 1,600,000 Number of cses per 10,000 children Autism (95% CI 0.6, 0.9) (95% CI 2.1, 2.8) (95% CI 28, 56) PDD, not including Asperger s (95% CI 2.5, 4.2) ASD, including Asperger s (95% CI 32, 36) (95% CI 51, 88) Fctors ffecting prevlence Dignostic criteri Knner 33 DSM-III 29 Knner 33 DSM-IV 32 DSM-IV 32 DSM-IV 32 DSM-IV 32 Centrl dtbse Yes No No Yes Yes No No Yes Age trunction No No No No No No No No Popultion restriction No No No No No No No No Gender restriction No No No No No No No No Fctors ffecting trend Yer of birth brekdowns No Yes c Yes b Yes c Yes, but NA Yes d Yes Yes c Age vrition (rnge) No (3 12) Yes (5 32) Yes (6 17) Yes (3 10) Yes (3 10) No Ages 5 yers Yes Yes Yes No No Yes Yes No Asperger s included No No No No No Yes Yes/No Yes NOTE: Arrows indicte study design fetures with potentil impct on reported outcomes, with downwrd-pointing rrows indicting possible downwrd effect on frequency or trend estimtes nd upwrd-pointing rrows indicting possible upwrd impct. Autism rtes by ge cohort nd times of dt collection provided by uthors, llowing lignment of ge cohort with birth yers. b Number of utism cses by yer of birth provided by uthors grphiclly, llowing clcultion of rtes using stte census of live births. 96 c Autism rtes by yer of birth provided by uthors. d Autism rtes by yer of birth provided by uthors grphiclly. CI = confidence intervl PDD = pervsive developmentl disorder ASD = utistic spectrum disorder NA = not pplicble 546 Viewpoint

12 Time Trends in Autism 547 shown in the Tbles nd my lso be fctor ffecting frequency. Fctors ffecting trend ssessment relte to scertinment bis nd include the following: the vilbility of trend informtion for the survey period, the inclusion of rnge of ge groups in the survey popultion, the inclusion of children younger thn 5 yers of ge in the survey popultion, nd the inclusion of Asperger s syndrome in the survey scope. Ech of the lst three fctors my depress evidence of n underlying trend. A lrge trend effect my lso ffect comprisons cross surveys. Figure 1 shows comprison of reported prevlence rtes cross surveys from the U.K. nd U.S., using the mid-point yer of birth s the bsis for compring survey popultions. This comprison demonstrtes tht reported utism rtes in the U.K. rose from 10 per 10,000 19,35,42,83,89 to the 17 to 31 per 10,000 rnge 61,78 over 40 yers nd tht reported PDD rtes rose to pproximtely 60 per 10,000 in the sme period. 61,78,95 According to the reported confidence intervls (CIs), these chnges re sttisticlly significnt. The mgnitude of the increse ppers lrger in the U.S. thn in the U.K. The U.K. dt show strong inflection point round 1990, wheres utism rtes in the U.S. pper to hve begun their rise in the 1980s. The mount of useful comprtive informtion expnds when one exmines detils of the published reports (Figure 2). In the U.K., strting with the erliest surveys bsed on children born before 1990 in Middlesex, 35 Cmberwell, 42 Scotlnd, 82 nd Wles, 89 the prevlence rtes for utism were generlly well below 10 per 10,000. In surveys including children born fter 1990, reported utism rtes were both higher 20 nd rising. 20,68,78 Ech of these surveys hd unique fetures. A survey in the North Thmes helth region showed remrkble rising trend in numbers of utism cses by birth yer. 20 An dministrtive survey with one of the most credible trend reports (this design controlled for ge-tscertinment bis) found cler increse using mesure of cumultive incidence by birth yer. 68 This result is difficult to compre to those of other surveys since this study used dt on boys only (introducing n upwrd bis) nd dministrtive dt truncted to 2- to 5-yer-olds (introducing downwrd bis). The South Est Thmes survey provided well-supported nd high estimte of utism prevlence 30.8 per 10,000 in single ge cohort with smll popultion nd effective cse-finding. 78 One survey in Stffordshire stnds out s n exception; 61 the reported utism rte is modestly lower thn in other recent surveys, while the reported PDD rte (including Asperger s syndrome) is the highest ever reported in the U.K. Evidence from U.K. surveys of the full rnge of ASDs lso supports n incresing trend. A survey tht smpled multiple res showed rising trend from pproximtely Four recent surveys found similrly high rtes, 61,63,78,95 three with rtes of pproximtely 60 per 10,000 61,78,95 nd fourth Figure 1. Reported prevlence of utism nd utistic spectrum disorders (ASDs), by midpoint yer of birth, United Kingdom nd United Sttes, United Kingdom k United Sttes l s Cses per 10, o ASD Autism Midpoint yer of birth Midpoint yer of birth NOTE: These grphs show prevlence estimtes from 11 U.K. nd 8 U.S. studies. For studies with survey popultions spnning rnge of birth yers, the midpoint of the birth yer rnge is used. Lotter b Wing nd Gould c Deb nd Prsd d Webb et l e Tylor et l f Fombonne et l g Lingm et l h Kye et l i Scott et l k Bird et l l Treffert m Ritvo et l n Burd et l o Cliforni Deprtment of Developmentl Services p Sturmey nd Jmes q Yergin-Allsopp et l r Bertrnd et l s Gurney et l j Chkrbrti nd Fombonne

13 548 Viewpoint Figure 2. Reported prevlence of utism nd utistic spectrum disorders (ASDs), by yer of birth, United Kingdom nd United Sttes, United Kingdom: utism 60 United Sttes: utism Cses per 10,000 Cses per 10, r k h 20 j 20 p b c d e l m o Yer of birth Yer of birth 80 United Kingdom: ASDs 80 United Sttes: ASDs 60 i j r k 60 s f g q e 0 0 n Yer of birth Yer of birth NOTE: These grphs show prevlence estimtes from 11 U.K. nd 8 U.S. studies. Horizontl lines represent estimtes for multi-yer birth cohorts. Squres represent estimtes for single-yer birth cohorts. Broken lines re used to link multiple estimtes from the sme study. Lotter k Bird et l b Wing nd Gould c Deb nd Prsd d Webb et l e Tylor et l f Fombonne et l g Lingm et l h Kye et l i Scott et l l Treffert m Ritvo et l n Burd et l o Cliforni Deprtment of Developmentl Services p Sturmey nd Jmes q Yergin-Allsopp et l r Bertrnd et l s Gurney et l j Chkrbrti nd Fombonne with rtes peking t 50 per 10, These recent survey reports cn be compred with two erlier reports. 20,35 A survey of children born in the 1950s found low prevlence rte of only 2.8 per 10,000 for children who hd similr but less mrked fetures thn children dignosed with utism. 35 A survey of children born from 1979 through 1992 found rte of 3.4 per 10,000 for typicl utism. 20 The results of seven U.S. surveys re lso shown in Figure 2. These surveys support conclusions similr to those for the U.K. The erly utism surveys show cler convergence in disese frequency from the 1950s through 1980, with four different studies reporting rtes consistently lower thn three per 10,000. 2,36,45,53 Such low rtes held in dministrtive surveys nd ctive cse-finding surveys nd cross four sttes. More recent dt show mrked (if grdul) increse for utism in Cliforni 2 nd lso in New Jersey, 80 to levels 30 per 10,000. This 10-fold increse holds both within 2 nd cross surveys. An incresing trend ws lso reported in survey of Missouri children. 84 Three U.S. surveys report rtes for ASDs of 43 per 10,000, per 10,000, 73 nd 80 per 10, These rtes re both considerbly higher thn the erliest PDD rtes reported in North Dkot, 45 which peked t 7 per 10,000 round 1980, nd ll three survey popultions showed higher frequency in lter birth cohorts during survey periods. The Minnesot survey ws well controlled with respect to scertinment, nd reported rising prevlence rtes mong 8-yerolds over five-yer period; the uthors ttributed the threefold rte increse to chnging dministrtive prctices. 73 Surveys of 3- to 10-yer-old popultions in Georgi 75 nd New Jersey 80 shred nerly identicl scertinment bis problems, with likely higher rtes of Asperger s syndrome in the

14 Time Trends in Autism 549 older ge cohorts nd likely incomplete scertinment of ll PDDs in the 3 to 5 yer ge group. 75,80 These bises my hve the effect of dmpening evidence of rising rtes while lso skewing the shpe of the trend. (This skew my be especilly relevnt in the Georgi study, in which lrge number of children who hd not received prior utism dignosis were reclssified into the PDD ctegory. 75 ) Like the utism evidence, the dt for PDDs point to roughly 10-fold increse for ll ASDs from the 1970s to the erly-to-mid 1990s. 45,73,75,79 CONCLUSIONS The evidence supporting n incresing rte of utism in the U.K. nd the U.S. hs gthered strength. Although both the nomenclture nd the criteri set used to define utism hve chnged over the yers, these chnges re not so gret s to prevent comprtive nlysis nd do not explin mjor differences in reported prevlence over time. The lrgest stble source of vribility in reported utism rtes comes from incomplete scertinment in young ge cohorts, which limits the bility to detect n underlying nd rising seculr trend. Reviews tht hve downplyed the rising trend hve overemphsized unimportnt methodologicl problems, employed flwed met-nlytic methods, nd filed to tke into ccount the most relevnt bises in survey methodologies. Point prevlence comprisons mde within nd cross surveys conducted in specific geogrphic res, using yer of birth s reference for trend ssessment, provide the best bsis for inferring disese frequency trends from multiple surveys. A comprison of U.K. nd U.S. surveys, tking into considertion chnging definitions, scertinment bis, nd cse-finding methods, provides strong support for conclusion of rising disese frequency. The rte of utism in the U.S., once reported s 3 per 10,000, hs now risen to 30 per 10,000, 10-fold increse. The rte of utism in the U.K., once reported s 10 per 10,000, hs risen to roughly 30 per 10,000. Reported rtes for ASDs in both countries hve risen from the 5 to 10 per 10,000 rnge to the 50 to 80 per 10,000 rnge. This review hs found little evidence tht systemtic chnges in survey methods cn explin these increses, lthough better scertinment my still ccount for prt of the observed chnges. A precutionry pproch therefore suggests tht incresed rtes of utism nd relted disorders be ccepted s n urgent public helth concern. REFERENCES 1. Cliforni Deprtment of Developmentl Services. Chnges in the popultion of persons with utism nd pervsive developmentl disorders in Cliforni s developmentl services system: 1987 through 1998: report to the Legislture. Scrmento: Cliforni Helth nd Humn Services Agency, Deprtment of Developmentl Services; Cliforni Deprtment of Developmentl Services. 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