2014 Lancet Autism Seminar & Appendix

7232019 2014 Lancet Autism Seminar amp Appendix

httpslidepdfcomreaderfull2014-lancet-autism-seminar-appendix 143

Seminar

Autism

Meng-Chuan Lai Michael V Lombardo Simon Baron-Cohen

Autism is a set of heterogeneous neurodevelopmental conditions characterised by early-onset diffi culties in socialcommunication and unusually restricted repetitive behaviour and interests The worldwide population prevalence isabout 1 Autism aff ects more male than female individuals and comorbidity is common (gt70 have concurrent

conditions) Individuals with autism have atypical cognitive profiles such as impaired social cognition and socialperception executive dysfunction and atypical perceptual and information processing These profiles are underpinnedby atypical neural development at the systems level Genetics has a key role in the aetiology of autism in conjunctionwith developmentally early environmental factors Large-eff ect rare mutations and small-eff ect common variantscontribute to risk Assessment needs to be multidisciplinary and developmental and early detection is essential forearly intervention Early comprehensive and targeted behavioural interventions can improve social communication andreduce anxiety and aggression Drugs can reduce comorbid symptoms but do not directly improve social communicationCreation of a supportive environment that accepts and respects that the individual is diff erent is crucial

DefinitionIn 1943 child psychiatrist Leo Kanner described eight boysand three girls1 including 5-year-old Donald who wasldquohappiest when left alone almost never cried to go with hismother did not seem to notice his fatherrsquos home-comingsand was indiff erent to visiting relativeswandered aboutsmiling making stereotyped movements with his fingershellipspun with great pleasure anything he could seize upon tospinhellipWords to him had a specifically literal inflexiblemeaninghellipWhen taken into a room he completely

di d d th l d i t tl t f bj t rdquo I

evolved substantially in the past 70 years with anexponential growth in research since the mid-1990s(figure) Autism is now thought of as a set of neuro-developmental conditions some of which can beattributed to distinct aetiological factors such asMendelian single-gene mutations However most areprobably the result of complex interactions betweengenetic and non-genetic risk factors The many types arecollectively defined by specific behaviours centring onatypical development in social communication and un-

ll t i t d titi b h i d i t t

Lancet 2014 383 896ndash910

Published Online

September 26 2013

httpdxdoiorg101016S0140-6736(13)61539-1

Autism Research Centre

Department of Psychiatry

University of Cambridge

Cambridge UK (M-C Lai PhD

M V Lombardo PhD

Prof S Baron-Cohen PhD)

Department of Psychiatry

College of Medicine National

Taiwan University Taipei

Taiwan (M-C Lai) Department

of Psychology University ofCyprus Nicosia Cyprus

(M V Lombardo) and

Cambridgeshire and

Peterborough NHS Foundation

Trust Cambridge UK

(Prof S Baron-Cohen)

Correspondence to

Dr Meng-Chuan Lai Autism

Research Centre Department of

Psychiatry University of

Cambridge Douglas House

18B T i R d



disregarded the people and instantly went for objectsrdquo In usually restricted or repetitive behaviour and interests18B T i t R d

Seminar

How prevalence estimates will be aff ected by the newcriteria and how autism spectrum disorder will relate tothe newly created social (pragmatic) communicationdisorder (defined by substantial diffi culties with socialuses of both verbal and non-verbal communication butotherwise not meeting criteria for autism spectrumdisorder) remain to be assessed

Autism could potentially be subgrouped at clinical (egby developmental pattern or trajectory and comorbidity)cognitive and aetiological levels (eg by genetic andenvironmental correlates)6 Although the term autismspectrum disorder is frequently used the term autismspectrum condition also signals a biomedical diagnosisfor which individuals need support and recognises areasin which aff ected individuals are diff erent from thosewithout autism but without the negative overtones of the

disorder label

EpidemiologyPrevalenceThe prevalence of autism has been steadily increasingsince the first epidemiological study7 which showed that4middot1 of every 10 000 individuals in the UK had autism Theincrease is probably partly a result of changes in diag-nostic concepts and criteria8 However the prevalencehas continued to rise in the past two decades particularly

in individuals without intellectual disability despite

Figure The growth of autism research

Almost three times as many reports about autism were published between2000 and 2012 (n=16 741) as between 1940 and 1999 (n=6054) These

calculations are based on a keyword search of PubMed with the term ldquolsquoautismrsquo

OR lsquoautism spectrum disorderrsquo OR lsquopervasive developmental disorderrsquo OR

lsquoAsperger syndromersquordquo

1940 1950 1960 1970 1980 1990 2000 2010 20200

500

1000

1500

2000

2500

3000

N u m b e r o f r e p o r t s

p u b l i s h e d p e r y e a r

Year

Features

Core features in DSM-5 criteria

Persistent deficits in social

communication and social

interaction across multiple

Deficits in socialndashemotional reciprocity

Deficits in non-verbal communicative behaviours used for social

interaction



Seminar

Proportion of individuals

with autism aff ected

Comments

Developmental

Intellectual disability ~45 Prevalence estimate is aff ected by the diagnostic boundary and the definition of intelligence (eg whether verbal ability is used

as a criterion)

In individuals discrepant performance between subtests is common

Lan guage disord ers Variable In D SM-IV l angua ge de lay was a d efining fea tu re of autism ( autistic d isorder) b ut is no longe r incl ude d in D SM-5

An autism-specific language profile (separate from language disorders) exists but with substantial inter-individual variability

Attention-deficit hyperactivity

disorder

2 8ndash44 In DSM-IV no t diagnosed wh en occu rr ing in indiv iduals with au tism but no lo nger so in DSM- 5

Clinical guidance available

Tic disorders 14ndash38 ~6middot5 have Tourettersquos syndrome

Motor abnormality le79 See table 1

General medical

Epilepsy 8ndash30 Increased frequency in individuals with intellectual disability or genetic syndromes

Two peaks of onset early childhood and adolescence

Increases risk of poor outcome


Gastroint estinal pro blems 9 ndash70 Common sympto ms inclu de chronic co nstipation abdominal pain chronic diarrho ea and gast ro -o esophageal reflu x

Associated disorders include gastritis oesophagitis gastro-oesophageal reflux disease inflammatory bowel disease coeliacdisease Crohnrsquos disease and colitis


Immune dysregulation le38 Altered immune function which interacts with neurodevelopment could be a crucial biological pathway underpinning autism

Associated with allergic and autoimmune disorders

Genetic syndromes ~5 Collectively called syndromic autism

Examples include fragile X syndrome (21ndash50 of individuals aff ected have autism) Rett syndrome (most have autistic features

but with profiles diff erent from idiopathic autism) tuberous sclerosis complex (24ndash60) Downrsquos syndrome (5ndash39)

phenylketonuria (5ndash20) CHARGE syndrome (coloboma of the eye heart defects atresia of the choanae retardation of growth

and development or both genital and urinary abnormalities or both and ear abnormalities and deafness 15ndash50) Angelman

syndrome (50ndash81) Timothy syndrome (60ndash70) and Joubert syndrome (~40)

Sleep disorders 50ndash80 Insomnia is the most common

Cli i l id il bl



Seminar

Risk and protective factorsEpidemiological studies have identified various riskfactors32 but none has proven to be necessary or suffi cientalone for autism to develop Understanding of genendashenvironment interplay in autism is still at an early stage33 Advanced paternal or maternal reproductive age or bothis a consistent risk34ndash36 the underlying biology is unclearbut could be related to germline mutation particularly

hen paternal in origin 37ndash41 Alternati el indi iduals ho

the greater the individualrsquos disability58 The high frequencyof comorbidity could be a result of shared pathophysiologysecondary eff ects of growing up with autism sharedsymptom domains and associated mechanisms or over-lapping diagnostic criteria

Prognosis and outcomeA meta-analysis63 showed that individuals with autism

ha e a mortalit risk that is 2 8 times higher (95 CI



Comments

(Continued from previous page)

Behavioural

Aggressive behaviours le68 Often directed towards caregivers rather than non-caregivers

Could be a result of empathy diffi culties anxiety sensory overload disruption of routines and diffi culties with communication

Self-injurious behaviours le50 Associated with impulsivity and hyperactivity negative aff ect and lower levels of ability and speech

Could signal frustration in individuals with reduced communication as well as anxiety sensory overload or disruption of routines

Could also become a repetitive habit

Could cause tissue damage and need for restraint

Pica ~36 More likely in individuals with intellectual disability

Could be a result of a lack of social conformity to cultural categories of what is deemed edible or sensory exploration or both

Suicidal ideation o r att empt 11ndash14 Risks increase wit h concu rrent depress io n and behaviou ral pro blems and af ter being t eased o r bul lied

For version with full references see appendix DSM-IV=Diagnostic and Statistical Manual of Mental Disorders 4th edition DSM-5=Diagnostic and Statistical Manual of Mental Disorders 5th edition Particularly

in high-functioning adults

Table 983090 Common co-occurring conditions

See Online for appendix



Seminar

full-time education is 4676 Furthermore little is knownabout how ageing aff ects people with autism7677

Early signs and screeningEarly identification allows early intervention Previouslychildren with autism were often identified when olderthan 3ndash4 years but toddlers are now frequently diag-

nosed because atypical development is recognised earlyEarly indicators are deficits or delays in the emergence ofjoint attention (ie shared focus on an object) and pretendplay atypical implicit perspective taking deficits inreciprocal aff ective behaviour decreased response to ownname decreased imitation delayed verbal and non-verbal communication motor delay unusually repetitivebehaviours atypical visuomotor exploration inflexibilityin disengaging visual attention and extreme variation intemperament7879 These indicators contribute to screen-ing and diagnostic instruments for toddlers79 How-ever identification of high-functioning individuals is stilloften later than it should be80 particularly for females2324

Variability in age cognitive ability and sex leads todiff erential presentation and the need for appropriatescreening instruments (table 3) Care should be takenduring selection of screening instruments (and the cutoff for further action) because the target sample and purposeof screening vary81 Routine early screening at ages 18 and

24 th h b d d 82 Th d t d

Clinical assessmentDiagnostic assessment should be multidisciplinary anduse a developmental framework of an interview with theparent or caregiver interaction with the individualcollection of information about behaviour in communitysettings (eg school reports and job performance)cognitive assessments and a medical examination92 Co-

occurring conditions should be carefully screenedThe interview of the parent or caregiver should cover

the gestational birth developmental and health historyand family medical and psychiatric history It shouldhave specific foci the development of social emotionallanguage and communication cognitive motor and self-help skills the sensory profile and unusual behavioursand interests Behavioural presentation across diff erentcontexts should be investigated Ideally a standardisedstructured interview should be incorporated into theassessment process (table 3) Adaptive skills should bechecked with standardised instruments (eg Vinelandadaptive behaviour scales) In children parentndashchildinteraction and parent coping strategies should bespecifically investigated because they are relevant for theplanning of interventions

Interviews with the individual should be interactiveand engaging to enable assessment of social-communi-cation characteristics in both structured and unstructured

t t A i i f ti h ld id ll b th d



Seminar

Age Description

Screening young children

Checklist for autism in toddlers (CHAT) 18 months 14-item questionnaire nine completed by parent or caregiver and five by

primary health-care provider takes 5ndash10 min

Ea rly scree ning of autistic traits (E SAT ) 14 mon ths 14-item questionnaire completed by health practitioners at well-baby visit

after interviewing parent or caregiver takes 5ndash10 min

Modified checklist for autism in toddlers (M-CHAT) 16ndash30 months 23-item questionnaire completed by parent or caregiver takes 5ndash10 min

Infant toddler checklist (ITC) 6ndash24 months 24-item questionnaire completed by parent or caregiver takes 5ndash10 min

Quantitative checklist for autism in toddlers

(Q-CHAT)

18ndash24 months 25-item questionnaire completed by parent or caregiver takes 5ndash10 min

ten-item short version available

Screening tool for autism in children aged 2 years

(STAT)

24ndash36 months 12 items and activities assessed by clinician or researcher after interacting

with the child takes 20 min intensive training nece ssary level-two

screening measure

Screening older children and adolescents

Social communication questionnaire (SCQ) gt4 years (and mental age

gt2 years)

40-item questionnaire completed by parent or caregiver takes 10ndash15 min

Social responsiveness scale first or second edition

(SRS SRS-2)

gt 2middot5 y ears 6 5-item quest io nnaire complet ed by parent caregiver t each er relat iv e or

friends (self-report form available for adult in SRS-2) takes 15ndash20 minChil dhood autism sc reening test (CA ST ) 4ndash11 years 37-ite m ques tionn aire completed by p arent or car egive r takes 10 ndash15 min

Autism spectrum screening questionnaire (ASSQ) 7ndash16 years 27-item questionnaire completed by parent caregiver or teacher takes

10 min

Autism spectrum quotient (AQ) child and

adolescent versions

Child 4ndash11 years

adolescent 10ndash16 years


ten-item short versions available

Screening adults

Autism spectrum quotient (AQ) adult version gt16 years (with average or

above-average intelligence)

50-item questionnaire self-report takes 10ndash15 min ten-item short

version available

The Ritvo autism Asperger diagnostic scale-revised

(RAADS R)

gt18 years (with average or

above average intelligence)

80-item questionnaire self-report done with a clinicia n takes 60 min



Seminar

Although many (high-functioning) individuals withautism achieve some degree of explicit or controlledmentalising101 the implicit automatic and intuitivecomponents are still impaired even in adulthood102 Early-onset mentalising diffi culties seem to be specific toautism but late-onset deficits are reported in disorderssuch as schizophrenia103 Mentalising is closely entwined

with executive control and language104 so that thedichotomous view of social versus non-social cognition ispotentially misleading in autism

Historically the domain of mentalising has beenlargely centred on others but self-referential cognitionand its neural substrates are also atypical in autism105106 Therefore deficits in the social domain are not onlyabout diffi culties in the processing of information aboutother people but also about processing of self-referentialinformation the relationship that self has in a socialcontext and the potential for using self as a proxy tounderstand the social world

A consistent network of brain regionsmdashincluding themedial prefrontal cortex superior temporal sulcustemporoparietal junction amygdala and fusiform gyrusmdashare hypoactive in autism across tasks in which socialperception and cognition are used100107108 Dysfunction inthe so-called mirror system (ie brain regions that are activeboth when an individual performs an action and observes

th f i th ti ) h b

that frontal parietal and striatal circuitry are themain systems implicated in executive dysfunction inautism107108 Executive dysfunction is not specific toautism it is commonly reported in other neuropsychiatricconditions (although with diff erent patterns) One viewis that strong executive function early in life could protectat-risk individuals from autism or other neurodevelop-

mental conditions by compensating for deficits in otherbrain systems112

Individuals with autism often have a preference for andsuperiority in processing of local rather than globalsensory-perceptual features (table 4) Individuals withoutautism often show the opposite profile This diff erencecould explain the excellent attention to detail enhancedsensory-perceptual processing and discrimination andidiosyncratic sensory responsivity (ie hyper-reactivity orhyporeactivity to sensory input or unusual interest insensory features of the environment) in autism It couldalso contribute to the exceptional abilities disproportion-ately recorded in individuals with autism113114 Addition-ally top-down information processing in individuals withautism is often characterised by reduced recognition ofthe global context115 and a strong preference to deriverule-based systems113 The neural bases are spatiallydistributed and task dependent but converge onenhanced recruitment of primary sensory cortices

d d it t f i ti d f t l ti



Seminar

volume and microstructural properties)121ndash123 moleculargenetics (cell adhesion molecules and synaptic proteinsand excitatoryndashinhibitory imbalance)124 and informationprocessing have given rise to the idea that autism ischaracterised by atypical neural connectivity rather thanby a discrete set of atypical brain regions Ideas about theprecise way in which connectivity is atypical vary from

decreased fronto-posterior and enhanced parietal-occipitalconnectivity117125 reduced long-range and increased short-range connectivity126 to temporal binding deficits127 Al-though none fully explains all the data (findings dependon the definition of connectivity the developmental stageof the individual the spatial and temporal scales task vs no-task conditions how motion artifacts are handled andspecific neural systems of concern) they support theheuristic value of the tenet that neural networks in autismare atypical in various ways

One frequently reported neuroanatomical feature ofautism is a trajectory of generalised early brain over-growth when aged 6ndash24 months128 Other than increasesin total brain volume the amygdala is enlarged in youngchildren with autism129 although this enlargement is nolonger present by adolescence130 Early brain overgrowthtends to be reported more in boys who have develop-mental regression than in other subgroups131 and mightbe a result of generalised physical overgrowth132 or biased

f h d i f i t t di 133 Add

dogma of the so-called immune privilege of the CNS 141 Frequency of immunological anomalies is increased inindividuals with autism and their families142 In autismaltered immune processes aff ect a wide array of neuro-developmental processes (eg neurogenesis proliferationapoptosis synaptogenesis and synaptic pruning) withpersistent active neuroinflammation increased concen-

trations of pro-inflammatory cytokines in serum and cere-brospinal fluid and altered cellular immune functions143 Maternal IgG antibodies that target the fetal brain or othergestational immune dysregulation could be pathogenic insome cases144 Neuroimmune mechanisms could have keyroles in some aspects of the pathophysiology of autismbut the exact biology awaits clarification

In autism alterations in both serotonin andγ-aminobutyric-acid (GABA) systems have been reportedquite consistently145 such as hyperserotonaemia and analtered developmental trajectory of brain serotoninsynthesis capacity and reduction in the expression ofGABA synthetic enzymes and receptors Because of theirrelation with affi liative and social behaviours theoxytocin and vasopressin systemsrsquo roles in social impair-ments in autism are an active focus of investigationincluding treatment trials146 The role of androgens (andoestrogens) in modulation of risks and protectionsparticularly prenatally in the emergence of autism is also

b i t t d22 147 i i f th l ti id f



Seminar

mutations with large eff ect sizes and common variationswith smaller eff ect sizes have a role124151

Rare mutations (ie minor allele frequency lt5 in thegeneral population) are frequently identified in autism andcan occur in the form of Mendelian genetic syndromes (so-called syndromic autism occurring in about 5 of allindividuals with autism) chromosomal abnormalities

(about 5) rare copy number variations (5ndash10)151ndash153 andde novo and transmitted point mutations (single nucleotidevariants) identified by exome sequencing150153 De novomutations (copy number variations in the form of micro-deletion or microduplication and single nucleotide vari-ants in the form of nonsense splice-site and frameshiftmutations) that occurred in the germline (especiallypaternal) have a large eff ect size and could be causal37ndash41 particularly in simplex cases (ie when only one individualin the family has autism) Equally copy number variationswith moderate eff ect sizes and variable expressivity andpenetrance could have some role124 However each identi-fied copy number variation only occurs in at most about1 of individuals with autism again suggesting sub-stantial genetic heterogeneity152 Some of these raremutations are clinically identifiable therefore screening isrecommended as part of routine clinical examination9495

In terms of common variants (eg single nucleotidepolymorphisms with allele frequency gt5 in the general

l ti ) id i ti t di h

communication reductions in disability and comorbiditypromotion of independence and provision of support tofamilies Additionally individuals should be helped tofulfil their potential in areas of strength Although autismis rooted in biology most eff ective interventions so farare behavioural and educational drugs have had only aminor role so far

Behavioural approachesVarious behavioural approaches exist156ndash158 and are classi-fied here into five complementary categories (table 5)Comprehensive approaches target a broad range of skills(cognitive language sensorimotor and adaptive behav-iours) via long-term intensive programmes and aregrouped into applied behaviour analysis and structuredteaching (table 5)159 The models based on applied behav-iour analysis originate from the Lovaas method160 and arecollectively referred to as early intensive behaviouralintervention The Early Start Denver Model is a furtherdevelopment in which a developmental framework andrelationship aspects are emphasised (table 5) Earlyintensive behavioural intervention seems to enable thedevelopment of intelligence communication and adap-tive function and to a lesser extent language daily livingskills and socialisation161 A shift from atypical to typi-cal neurophysiology has been reported after 2 years of

i t ti ith th E l St t D M d l 162 H



Seminar

to enable transfer of skills to real-life settings andincreasing parentsrsquo and caregiversrsquo self-confidence(table 5)156 Programmes can be comprehensive(eg parent delivery of the Early Start Denver Model) ortargeted (eg at joint attention or communicationtable 5) The benefit of parent-mediated interventionalone is unclear and results are inconsistent (table 5)

Nevertheless parental and family involvement isimportant in therapist-mediated programmes79158

Sensory integration therapymdashfrequently used inoccupational therapymdashis sometimes off ered as one

component of a comprehensive programme to addresssensory-based problems However its eff ectiveness isinconclusive167 and it should not be considered as aroutine intervention for autism168

The US Health Resources and Services Administration158 and the UK National Institute for Health and CareExcellence74 have provided clinical guidelines for behav-

ioural interventions They stress that comprehensiveintervention should immediately follow diagnosis andshould be individualised (on the basis of developmen-tal level needs and assets) and engage the family

Target group Evidence for

eff ectiveness

Intervention framework and goals

Behavioural approaches

Comprehensive ABA-based

Early intensive behavioural intervention Young children (usually

aged lt5 years)

Low or moderate Based on ABA principles usually home-based or school-based application of discrete

trial training (ie teaching in simplified and structured steps) 11 adult-to-child ratiointensive teaching for 20ndash40 hweek for 1ndash4 years

Early intensive behavioural intervention

integrated with developmental and

relationship-based approaches (eg ESDM

and floortime [developmental individual-

diff erence relationship-based model])

Young children (usually

aged lt5 years)

Moderate or insuffi cient for

ESDM not established for

floortime

ESDM aims to accelerate childrenrsquos development in all domains intervention targets

derived from assessment of developmental skills stresses social-communicative

development interpersonal engagement imitation-based interpersonal

development and social attention and motivation integration of ABA principles and

pivotal response training (ie a naturalistic approach targeting so-called pivotal areas

of a childrsquos development including motivation response to multiple cues

self-management and initiation of social interactions)

Floortime emphasises functional emotional development individual diff erences in

sensory modulation processing and motor planning relationships and interactions

Comprehensive structured teaching



Seminar

Additionally they emphasise that social-communicationtraining (with a focus on social skills) should be off ered

d b l i di id l h ld h t iti t

disorder requires more study170 but is promising and hasbeen recommended (table 5)171 Initial evidence suggests

th t t ti l d i t f


eff ectiveness



Drugs

Antipsychotic drugs

Risperidone aripiprazole Children adolescents

and adults

Children moderate

(risperidone) or high

(aripiprazole) for eff ect andhigh for adverse eff ect

adolescents and adults

insuffi cient but might have

eff ects as in children

To reduce challenging behaviours and repetitive behaviours potential adverse eff ects

include weight gain sedation extrapyramidal symptoms and hyperprolactinaemia

(risperidone)

Selective serotonin reuptake inhibitors

Citalopram escitalopram fluoxetine and

others

Children adolescents

and adults

Insuffi cient for eff ect and

adverse eff ect

To reduce repetitive behaviours potential adverse eff ects include activation symptoms

(agitation) and gastrointestinal discomfort

Stimulant

Methylphenidate Children adolescents

and adults


adverse eff ect might be

helpful clinical guidelineestablished

To reduce attention-deficit hyperactivity disorder symptoms potential adverse eff ects

include insomnia decreased appetite weight loss headache and irritability

For version with full references see appendix ABA=applied behaviour analysis ESDM=Early Start Denver Model Suggested by available systematic reviews and meta-analyses with criteria directly following or

similar to the Grading of Recommendations Assessment Development and Evaluation Working Group recommendation diff erent ratings for the same model or agent are from diff erent reports

Table983093 Interventions by major model or agent



Seminar

recognition and interventions rely Third eff ective indiv-idualised educational and biomedical interventions for thewhole lifespan need to be established Fourth key environ-mental factors that interact with the complex geneticarchitecture of autism need to be identified Fifth howautism aff ects individuals in diff erent cultural contextsneeds to be understood Finally environments should be

made more autism friendlyContributors

M-CL did the initial literature search summarised findings andprepared the first draft of the report MVL prepared figures All authorscontributed to the writing of the report

Conflicts of interest

We declare that we have no conflicts of interest

Acknowledgments

All authors are supported by the European Autism InterventionsmdashA Multicentre Study for Developing New Medications (which receivessupport from the Innovative Medicines Initiative Joint Undertaking[grant agreement 115300] resources of which are composed of financialcontribution from the European Unionrsquos Seventh FrameworkProgramme [FP72007-2013] European Federation of PharmaceuticalIndustries and Associations companies and Autism Speaks) M-CL issupported by Wolfson College (University of Cambridge UK) MVL issupported by the British Academy and Jesus College (University ofCambridge UK) SB-C is supported by the Wellcome Trust the UKMedical Research Council the National Institute for Health ResearchCollaboration for Leadership in Applied Health Research and Care forCambridgeshire and Peterborough NHS Foundation Trust the AutismResearch Trust the European Union ASC-Inclusion Project and Target

A ti G W th k W i T S d Di b T t f

14 Baron-Cohen S Scott FJ Allison C et al Prevalence ofautism-spectrum conditions UK school-based population studyBr J Psychiatry 2009 194 500ndash09

15 Hsu S-W Chiang P-H Lin L-P Lin J-D Disparity in autismspectrum disorder prevalence among Taiwan National HealthInsurance enrollees age gender and urbanization eff ectsRes Autism Spectr Disord 2012 6 836ndash41

16 Idring S Rai D Dal H et al Autism spectrum disorders in thestockholm youth cohort design prevalence and validity PLoS One

2012 7 e41280 17 Blumberg SJ Bramlett MD Kogan MD Schieve LA Jones JR

Lu MC Changes in prevalence of parent-reported autism spectrumdisorder in school-aged US children 2007 to 2011ndash2012 HyattsvilleMD National Center for Health Statistics 2013

18 Russell G Rodgers LR Ukoumunne OC Ford T Prevalence ofparent-reported ASD and ADHD in the UK findings from theMillennium Cohort Study J Autism Dev Disord 2013 publishedonline May 30 DOI101007s10803-013-1849-0

19 Saemundsen E Magnusson P Georgsdottir I Egilsson ERafnsson V Prevalence of autism spectrum disorders in anIcelandic birth cohort BMJ Open 2013 3 e002748

20 Brugha TS McManus S Bankart J et al Epidemiology of autismspectrum disorders in adults in the community in EnglandArch Gen Psychiatry 2011 68 459ndash65

21 Barger BD Campbell JM McDonough JD Prevalence and onset ofregression within autism spectrum disorders a meta-analyticreview J Autism Dev Disord 2013 43 817ndash28

22 Baron-Cohen S Lombardo MV Auyeung B Ashwin EChakrabarti B Knickmeyer R Why are autism spectrum conditionsmore prevalent in males PLoS Biol 2011 9 e1001081

23 Begeer S Mandell D Wijnker-Holmes B et al Sex diff erences in thetiming of identification among children and adults with autismspectrum disorders J Autism Dev Disord 2013 43 1151ndash56

24 Giarelli E Wiggins LD Rice CE et al Sex diff erences in the

l ti d di i f ti t di d



Seminar

36 Lampi KM Hinkka-Yli-Salomaki S Lehti V et al Parental age andrisk of autism spectrum disorders in a Finnish national birthcohort J Autism Dev Disord 2013 published online March 12DOI101007s10803-013-1801-3

37 Michaelson JJ Shi Y Gujral M et al Whole-genome sequencing inautism identifies hot spots for de novo germline mutation Cell 2012 151 1431ndash42

38 Kong A Frigge ML Masson G et al Rate of de novo mutations andthe importance of fatherrsquos age to disease risk Nature 2012 488 471ndash75

39 Neale BM Kou Y Liu L et al Patterns and rates of exonic de novomutations in autism spectrum disorders Nature 2012 485 242ndash45

40 OrsquoRoak BJ Vives L Girirajan S et al Sporadic autism exomesreveal a highly interconnected protein network of de novomutations Nature 2012 485 246ndash50

41 Sanders SJ Murtha MT Gupta AR et al De novo mutationsrevealed by whole-exome sequencing are strongly associated withautism Nature 2012 485 237ndash41

42 Sucksmith E Roth I Hoekstra RA Autistic traits below the clinicalthreshold re-examining the broader autism phenotype in the 21stcentury Neuropsychol Rev 2011 21 360ndash89

43 Roelfsema MT Hoekstra RA Allison C et al Are autism spectrum

conditions more prevalent in an information-technology regionA school-based study of three regions in the Netherlands J Autism Dev Disord 2012 42 734ndash39

44 Brown AS Sourander A Hinkka-Yli-Salomaki S McKeague IWSundvall J Surcel HM Elevated maternal C-reactive protein andautism in a national birth cohort Mol Psychiatry 2013 publishedonline Jan 22 DOI101038mp2012197

45 Gardener H Spiegelman D Buka SL Prenatal risk factors forautism comprehensive meta-analysis Br J Psychiatry 2009 195 7ndash14

46 Volk HE Lurmann F Penfold B Hertz-Picciotto I McConnell RTraffi c-related air pollution particulate matter and autism JAMA Psychiatry 2013 70 71ndash77

47 Roberts EM English PB Grether JK Windham GC Somberg L

W lff C M t l id i lt l ti id li ti

59 Lugnegard T Hallerback MU Gillberg C Personality disorders andautism spectrum disorders what are the connectionsCompr Psychiatry 2012 53 333ndash40

60 Joshi G Wozniak J Petty C et al Psychiatric comorbidity andfunctioning in a clinically referred population of adults with autismspectrum disorders a comparative study J Autism Dev Disord 201343 1314ndash25

61 Kohane IS McMurry A Weber G et al The co-morbidity burden ofchildren and young adults with autism spectrum disorders

PLoS One 2012 7 e33224 62 Simonoff E Jones CR Baird G Pickles A Happe F Charman T

The persistence and stability of psychiatric problems in adolescentswith autism spectrum disorders J Child Psychol Psychiatry 201354 186ndash94

63 Woolfenden S Sarkozy V Ridley G Coory M Williams K Asystematic review of two outcomes in autism spectrum disordermdashepilepsy and mortality Dev Med Child Neurol 2012 54 306ndash12

64 Bilder D Botts EL Smith KR et al Excess mortality and causes ofdeath in autism spectrum disorders a follow up of the 1980s UtahUCLA autism epidemiologic study J Autism Dev Disord 201343 1196ndash204

65 Howlin P Goode S Hutton J Rutter M Adult outcome for childrenwith autism J Child Psychol Psychiatry 2004 45 212ndash29

66 Billstedt E Gillberg C Gillberg C Autism after adolescencepopulation-based 13- to 22-year follow-up study of 120 individualswith autism diagnosed in childhood J Autism Dev Disord 200535 351ndash60

67 Howlin P Moss P Savage S Rutter M Social outcomes in mid- tolater adulthood among individuals diagnosed with autism andaverage nonverbal IQ as children J Am Acad Child Adolesc Psychiatry 2013 52 572ndash81

68 Farley MA McMahon WM Fombonne E et al Twenty-yearoutcome for individuals with autism and average or near-averagecognitive abilities Autism Res 2009 2 109ndash18

69 F t i C Wi t AS B PS Si d l t l



Seminar

83 Al-Qabandi M Gorter JW Rosenbaum P Early autism detectionare we ready for routine screening Pediatrics 2011 128 e211ndash17

84 Ozonoff S Iosif AM Baguio F et al A prospective study of theemergence of early behavioral signs of autism J Am Acad Child Adolesc Psychiatry 2010 49 256ndash66

85 Chawarska K Macari S Shic F Decreased spontaneous attention tosocial scenes in 6-month-old infants later diagnosed with autismspectrum disorders Biol Psychiatry 2013 74 195ndash203

86 Wan MW Green J Elsabbagh M Johnson M Charman T

Plummer F Quality of interaction between at-risk infants andcaregiver at 12ndash15 months is associated with 3-year autism outcome J Child Psychol Psychiatry 2013 54 763ndash71

87 Elison JT Paterson SJ Wolff JJ et al White matter microstructureand atypical visual orienting in 7-month-olds at risk for autismAm J Psychiatry 2013 published online March 20 DOI101176appiajp201212091150

88 Elsabbagh M Fernandes J Jane Webb S Dawson G Charman TJohnson MH Disengagement of visual attention in infancy isassociated with emerging autism in toddlerhood Biol Psychiatry 2013 74 189ndash94

89 Elsabbagh M Mercure E Hudry K et al Infant neural sensitivity todynamic eye gaze is associated with later emerging autismCurr Biol 2012 22 338ndash42

90 Wolff JJ Gu H Gerig G et al Diff erences in white matter fibertract development present from 6 to 24 months in infants withautism Am J Psychiatry 2012 169 589ndash600

91 Messinger D Young GS Ozonoff S et al Beyond autism a babysiblings research consortium study of high-risk children at threeyears of age J Am Acad Child Adolesc Psychiatry 2013 52 300ndash08

92 Ozonoff S Goodlin-Jones BL Solomon M Evidence-basedassessment of autism spectrum disorders in children andadolescents J Clin Child Adolesc Psychol 2005 34 523ndash40

93 Coleman M Gillberg C The autisms 4th edn New York NYOxford University Press 2012

94 H il KM S h f CP Th ti f ti t

108 Philip RC Dauvermann MR Whalley HC Baynham K Lawrie SMStanfield AC A systematic review and meta-analysis of the fMRIinvestigation of autism spectrum disorders Neurosci Biobehav Rev 2012 36 901ndash42

109 Hamilton AF Reflecting on the mirror neuron system in autisma systematic review of current theories Dev Cogn Neurosci 20133 91ndash105

110 Geurts HM Corbett B Solomon M The paradox of cognitiveflexibility in autism Trends Cogn Sci 2009 13 74ndash82

111 White SJ The triple I hypothesis taking another(lsquos) perspectiveon executive dysfunction in autism J Autism Dev Disord 201343 114ndash21

112 Johnson MH Executive function and developmental disordersthe flip side of the coin Trends Cogn Sci 2012 16 454ndash57

113 Baron-Cohen S Ashwin E Ashwin C Tavassoli T Chakrabarti BTalent in autism hyper-systemizing hyper-attention to detail andsensory hypersensitivity Philos Trans R Soc Lond B Biol Sci 2009364 1377ndash83

114 Mottron L Bouvet L Bonnel A et al Veridical mapping in thedevelopment of exceptional autistic abilities Neurosci Biobehav Rev 2013 37 209ndash28

115 Happe F Frith U The weak coherence account detail-focusedcognitive style in autism spectrum disorders J Autism Dev Disord 2006 36 5ndash25

116 Samson F Mottron L Soulieres I Zeffi ro TA Enhanced visualfunctioning in autism an ALE meta-analysis Hum Brain Mapp 2012 33 1553ndash81

117 Minshew NJ Keller TA The nature of brain dysfunction in autismfunctional brain imaging studies Curr Opin Neurol 201023 124ndash30

118 Ohnishi T Matsuda H Hashimoto T et al Abnormal regionalcerebral blood flow in childhood autism Brain 2000 123 1838ndash44

119 Baruth JM Wall CA Patterson MC Port JD Proton magneticresonance spectroscopy as a probe into the pathophysiology of

ti t di d (ASD) i A ti R 2013



Seminar

133 Raznahan A Wallace GL Antezana L et al Compared to whatEarly brain overgrowth in autism and the perils of populationnorms Biol Psychiatry 2013 published online May 23DOI101016jbiopsych201303022

134 Via E Radua J Cardoner N Happe F Mataix-Cols D Meta-analysisof gray matter abnormalities in autism spectrum disorder shouldAsperger disorder be subsumed under a broader umbrella ofautistic spectrum disorder Arch Gen Psychiatry 2011 68 409ndash18

135 Duerden EG Mak-Fan KM Taylor MJ Roberts SW Regional

diff erences in grey and white matter in children and adults withautism spectrum disorders an activation likelihood estimate (ALE)meta-analysis Autism Res 2012 5 49ndash66

136 Schumann CM Noctor SC Amaral DG Neuropathology of autismspectrum disorders postmortem studies In Amaral DGDawson G Geschwind DH eds Autism spectrum disordersNew York NY Oxford University Press 2011 539ndash65

137 Courchesne E Mouton PR Calhoun ME et al Neuron number andsize in prefrontal cortex of children with autism JAMA 2011306 2001ndash10

138 Voineagu I Wang X Johnston P et al Transcriptomic analysis ofautistic brain reveals convergent molecular pathology Nature 2011474 380ndash84

139 Casanova MF Neuropathological and genetic findings in autismthe significance of a putative minicolumnopathy Neuroscientist 2006 12 435ndash41

140 Rubenstein JL Three hypotheses for developmental defects thatmay underlie some forms of autism spectrum disorderCurr Opin Neurol 2010 23 118ndash23

141 McAllister AK van de Water J Breaking boundaries inneural-immune interactions Neuron 2009 64 9ndash12

142 Goines P Zimmerman A Ashwood P Van de Water J Theimmune system autoimmunity allergy and autism spectrumdisorders In Amaral DG Dawson G Geschwind DH eds Autismspectrum disorders New York NY Oxford University Press

2011 395 419

156 Dawson G Burner K Behavioral interventions in children andadolescents with autism spectrum disorder a review of recentfindings Curr Opin Pediatr 2011 23 616ndash20

157 Vismara LA Rogers SJ Behavioral treatments in autismspectrum disorder what do we know Annu Rev Clin Psychol 2010 6 447ndash68

158 Maglione MA Gans D Das L Timbie J Kasari C Nonmedicalinterventions for children with ASD recommended guidelines andfurther research needs Pediatrics 2012 130 (suppl 2) S169ndash78

159 Callahan K Shukla-Mehta S Magee S Wie M ABA versusTEACCH the case for defining and validating comprehensivetreatment models in autism J Autism Dev Disord 2010 40 74ndash88

160 Smith T Eikeseth S O Ivar Lovaas pioneer of applied behavioranalysis and intervention for children with autism J Autism Dev Disord 2011 41 375ndash8

161 Reichow B Barton EE Boyd BA Hume K Early intensive behavioralintervention (EIBI) for young children with autism spectrumdisorders (ASD) Cochrane Database Syst Rev 2012 10 CD009260

162 Dawson G Jones EJ Merkle K et al Early behavioral interventionis associated with normalized brain activity in young children withautism J Am Acad Child Adolesc Psychiatry 2012 51 1150ndash59

163 Kasari C Patterson S Interventions addressing social impairmentin autism Curr Psychiatry Rep 2012 14 713ndash25

164 Kaale A Smith L Sponheim E A randomized controlled trial ofpreschool-based joint attention intervention for children withautism J Child Psychol Psychiatry 2012 53 97ndash105

165 Kasari C Paparella T Freeman S Jahromi LB Language outcomein autism randomized comparison of joint attention and playinterventions J Consult Clin Psychol 2008 76 125ndash37

166 Landa RJ Holman KC OrsquoNeill AH Stuart EA Interventiontargeting development of socially synchronous engagement intoddlers with autism spectrum disorder a randomized controlledtrial J Child Psychol Psychiatry 2011 52 13ndash21

167 Zimmer M Desch L Sensory integration therapies for children

ith d l t l d b h i l di d P di t i 2012



Supplementary appendix

This appendix formed part of the original submission and has been peer reviewedWe post it as supplied by the authors

Supplement to Lai M-C Lombardo MV Baron-Cohen S Autism Lancet2013 published

online Sept 26 httpdxdoiorg101016S0140-6736(13)61539-1



$amp() +)- ) 01 +234)562- 732 8)52amp21 9lt=gt1 73)5 (AB31 amp() 1 AACDD6E162125$Dlt1ltltFD7ltGFH=F9lt=gtFltI=Jlt

lt

$amp )+- amp01 23 424$5-6

Appendix Table 1 Behavioural characteristics of autism


Persistent deficits in social communication

and social interaction across multiple

contexts

Deficits in social-emotional reciprocity

Deficits in non-verbal communicative behaviours used for social interaction

Deficits in developing maintaining and understanding relationships

Restricted repetitive patterns of behaviour

interests or activities

Stereotyped or repetitive motor movements use of objects or speech

Insistence on sameness inflexible adherence to routines or ritualised patterns of verbal or

non-verbal behaviour

Highly restricted fixated interests that are abnormal in intensity or focus

Hyper- or hypo-reactivity to sensory input or unusual interest in sensory aspects of the environment

Associated features not in DSM-5 criteria

Atypical language development and

abilities2

Preschool age (lt 6 years) frequently deviant and delayed in comprehension two-thirds have

difficulty with expressive phonology and grammar

School age (≧6 years) deviant pragmatics semantics and morphology with relatively intact

articulation and syntax (ie early difficulties are resolved)

Motor abnormalities Motor delay hypotonia catatonia deficits in coordination movement preparation and planning

praxis gait and balance

Excellent attention to detail




Appendix Table 2 Common co-occurring conditions

Condition Proportion of

individualswith autism

affected

Comments

Developmental

Intellectual disability ~45 Prevalence estimate is affected by the diagnostic boundary and the definition of intelligence

(eg whether verbal ability is used as a criterion)


Language disorders Variable In DSM-IV language delay was a defining feature of autism (autistic disorder) but is nolonger included in DSM-5

An autism-specific language profile (separate from language disorders) exists but with

substantial inter-individual variability2

Attention-deficit hyperactivitydisorder

28-44 - In DSM-IV not diagnosed when occurring in individuals with autism but no longer so inDSM-5

Clinical guidance available11

Tic disorders 14-38 ~6middot5 have Tourettersquos syndrome

Motor abnormality ≦7913 14 See Appendix Table 1

General medical

Epilepsy 8-30 Increased frequency in individuals with intellectual disability or genetic syndromes

Two peaks of onset early childhood and adolescence Increases risk of poor outcome

Clinical guidance available4 16

Gastrointestinal problems 9-70 Common symptoms include chronic constipation abdominal pain chronic diarrhoea and

gastro-oesophageal reflux18

Associated disorders include gastritis oesophagitis gastro-oesophageal reflux disease

inflammatory bowel disease coeliac disease Crohnrsquos disease and colitis19





=

Immune dysregulation ≦3820 Altered immune function which interacts with neurodevelopment could be a crucial

biological pathway underpinning autism21 Associated with allergic and autoimmune disorders20 22

Genetic syndromes ~5 Collectively called lsquosyndromic autismrsquo

Examples include fragile X syndrome (21-50 of individuals affected have autism) Rett

syndrome (most have autistic features but with profiles different from idiopathic autism)

tuberous sclerosis complex (24-60) Downrsquos syndrome (5-39) phenylketonuria (5-20)

CHARGE syndrome (coloboma of the eye heart defects atresia of the choanae retardation

of growth and development or both genital and urinary abnormalities or both and ear

abnormalities and deafness 15-50) Angelman syndrome (50-81) Timothy syndrome

(60-70) and Joubert syndrome (~40)

Sleep disorders 50-80 Insomnia is the most common

Clinical guidance available4 26 27

Psychiatric

Anxiety 42-56-

Common across all age groupsMost common are social anxiety disorder (13-29 of individuals with autism clinical

guidance available28) and generalised anxiety disorder (13-22)7-9

High-functioning individuals are more susceptible (or symptoms are more detectable)29

Depression 12-70 - Common in adults less common in children

High-functioning adults who are socially less impaired are more susceptible (or symptoms

are more detectable)30

Obsessive-compulsive disorder 7-24 - Shares the repetitive behaviour domain with autism that may cut across nosological

categories

Important to distinguish between repetitive behaviours that do not involve intrusive

anxiety-causing thoughts or obsessions (part of autism) and those that do (and are part of

obsessive-compulsive disorder)Psychotic disorders 12-17 Mainly in adults

Most commonly recurrent hallucinosis9




G

High frequency of autism-like features (even a diagnosis of autism spectrum disorder or

pervasive developmental disorder) preceding adult-onset (52)31 and childhood-onsetschizophrenia (30-50)32

Substance use disorders ≦16 Potentially because individual is using substances as self-medication to relieve anxiety

Oppositional defiant disorder 16-28 Oppositional behaviours could be a manifestation of anxiety resistance to change stubborn

belief in the correctness of own point of view difficulty seeing anotherrsquos point of view lack

of awareness of the effect of own behaviour on others or lack of interest in social

compliance10

Eating disorders 4-5 Could be a misdiagnosis of autism particularly in female individuals because both involverigid behaviour inflexible cognition self-focus and focus on details33

Personality disorders Particularly in high-functioning adults

Paranoid personality disorder 0-19 Could be secondary to difficulty understanding othersrsquo intentions and negative interpersonal

experiences34

Schizoid personality disorder 21-26 Partially overlapping diagnostic criteria with autism

Similar to Wingrsquos lsquolonersrsquo subgroup35

Schizotypal personality

disorder

2-13 Some overlapping criteria with autism especially those shared with schizoid personality

disorder

Borderline personality disorder 0-9 Could have similarity in behaviours (eg difficulties in interpersonal relationships

misattributing hostile intentions problems with affect regulation) which requires careful

differential diagnosis

Could be a misdiagnosis of autism particularly in female individuals

Obsessive-compulsive

personality disorder

19-32 Partially overlapping diagnostic criteria with autism

Avoidant personality disorder 13-25 Could be secondary to repeated failure in social experiences

Behavioural

Aggressive behaviours ≦6836 Often directed towards caregivers rather than non-caregivers

Could be a result of empathy difficulties anxiety sensory overload disruption of routines

and difficulties with communication




I

Self-injurious behaviours ≦5037 Associated with impulsivity and hyperactivity negative affect and lower levels of ability and

speech37 Could signal frustration in individuals with reduced communication as well as anxiety

sensory overload or disruption of routines

Could also become a repetitive habitCould cause tissue damage and need for restraint


Could be a result of a lack of social conformity to cultural categories of what is deemed

edible or sensory exploration or both

Suicidal ideation or attempt 11-14 Risks increase with concurrent depression and behavioural problems and after being teased

or bullied39




F

Appendix Table 3 Screening and diagnostic instruments

Instrument Age Description Source


Checklist for Autism in Toddlers

(CHAT)41

at 18 months 14-item questionnaire nine completed by

parentcaregiver and five by primary

health-care provider takes 5-10 min

Public domain

httpwwwautismorgukworking-withh

ealthscreening-and-diagnosischecklist-fo

r-autism-in-toddlers-chataspx

Early Screening of Autistic Traits(ESAT)42

at 14 months 14-item questionnaire completed by health practitioners at well-baby visit after

interviewing parentcaregiver takes 5-10

min

Provided in the initial paper

Modified Checklist for Autism in

Toddlers (M-CHAT)44

16-30 months 23-item questionnaire completed by

parentcaregiver takes 5-10 min

Public domain

httpwwwmchatscreencom

Infant Toddler Checklist (ITC) 6-24 months 24-item questionnaire completed by parentcaregiver takes 5-10 min

Public domainhttpfirstwordsfsuedupdfchecklistpdf

Quantitative Checklist for Autism

in Toddlers (Q-CHAT)46


parentcaregiver takes 5-10 min 10-item

short version available47

Public domain

httpwwwautismresearchcentrecomarc

_tests

Screening Tool for Autism in

Children aged Two Years

(STAT)48

24-36 months 12 items and activities assessed by clinician

or researcher after interacting with the child

takes 20 min intensive training necessary

level-two screening measure

httpstatvueinnovationscom

Screening older children and

adolescents

Social CommunicationQuestionnaire (SCQ)49

gt4 years (andmental age gt2

years)

40-item questionnaire completed by parentcaregiver takes 10-15 min

Western Psychological Services(httpwwwwpspublishcom)




H

Social Responsiveness Scale First

or Second Edition (SRS SRS-2)50

gt2middot5 years 65-item questionnaire completed by

parentcaregiver teacher relative or friends(self-report form available for adult in

SRS-2) takes 15-20 min

Western Psychological Services

(httpwwwwpspublishcom)

Childhood Autism Screening Test(CAST)51

4-11 years 37-item questionnaire completed by parentcaregiver takes 10-15 min

Public domainhttpwwwautismresearchcentrecomarc

_tests

Autism Spectrum Screening

Questionnaire (ASSQ)52

7-16 years 27-item questionnaire completed by

parentcaregiver or teacher takes 10 min

particularly sensitive for high-functioning

individuals


Autism Spectrum Quotient (AQ)

child53 and adolescent54 versions

Child 4-11

years

Adolescent

10-16 years

50-item questionnaire completed by


short versions available47 particularly

sensitive for high-functioning individuals

Public domain


_tests

Screening adults


adult version55

gt16 years (with

average or

above-average

intelligence)

50-item questionnaire self-report takes

10-15 min 10-item short version available47


individuals

Public domain


_tests

The Ritvo Autism Asperger

Diagnostic Scale-Revised

(RAADS-R )56

gt18 years (with

average or

above-average

intelligence)

80-item questionnaire self-report done with

a clinician takes 60 min


Diagnosis structured interview

The Autism DiagnosticInterview-Revised (ADI-R )57

Mental age gt2years

93-item interview of parentcaregiver takes1middot5-3 h intensive training necessary


The Diagnostic Interview for All 362-item interview of parentcaregiver takes httpwwwautismorgukour-servicesdi




K

Social and Communication

Disorders (DISCO)58

chronological

and mental ages

2-4 h intensive training necessary agnosing-complex-needsthe-diagnostic-i

nterview-for-social-and-communication-disorders-discoaspx

The Developmental Dimensional

and Diagnostic Interview (3Di)59

gt2 years 266-item computer-assisted interview of

parentcaregiver takes 2 h 53-itemshort-form available which takes 45 min60

intensive training necessary

httpwwwixdxorg3di-indexhtml

Diagnosis observational

measure

The Autism Diagnostic

Observation Schedule First or

Second Edition (ADOS

ADOS-2)61

gt12 months Clinical observation via interaction select

one from five available modules according to

expressive language level and chronological

age takes 40-60 min intensive training

necessary



Childhood Autism Rating ScaleFirst or Second Edition (CARS

CARS-2)62

gt2 years 15-item rating scale completed by clinicianor researcher takes 20-30 min accompanied

by a questionnaire done by parentcaregiver

moderate training necessary





J

Appendix Table 4 Cognitive domains in autism research

Domain Main behavioural features Main cognitive (psychological) constructs

Social cognition and

social perception

Atypical social interaction and social

communication

Gaze and eye contact emotion perception face processing biological

motion perception66 social attention and orienting67 social motivation68 social reward processing69 non-verbal communication70 imitation71

affective empathy and sympathy72 joint attention73 pretend play74 theory ofmind or mental perspective taking75-77 self-referential cognition78

alexithymia (difficulty understanding and describing own emotions)79 80

metacognitive awareness81

Executive function Repetitive and stereotyped behaviour

atypical social interaction and social

communication

Cognitive flexibility planning inhibitory control attention shifting

monitoring generativity working memory82

lsquoBottom-uprsquo and

lsquotop-downrsquo (local vs global) information

processing

Idiosyncratic sensory-perceptual

processing excellent attention todetail restricted interests and repetitive

behaviour atypical social interaction

and social communication

Global vs local perceptual functioning (superior low-level sensory-perceptual

processing)

83-85

lsquocentral coherencersquo (global vs local preference)

84

lsquosystemisingrsquo (drive to construct rule-based systems ability to understand

rule-based systems knowledge of factual systems)86

Local processing involves sensory and perceptual inputs global processing involves higher-level cortical control




lt

Appendix Table 5 Interventions for autism

Category Major modelagent Target

group

Evidence foreffectiveness


Behaviouralapproaches

1

Comprehensive

ABA-based

EIBI Young

children

(usually aged

lt5 years)

Low or

moderate89

Based on ABA principles usually home-based or

school-based application of lsquodiscrete trial trainingrsquo (ie

a method of teaching in simplified and structured steps

instead of teaching an entire skill in one go the skill is

broken down and built-up using discrete trials that

teach each step one at a time) 11 adult-to-child ratio

intensive teaching for 20-40 hweek for 1-4 years87 90

EIBI integrated with

developmental and

relationship-basedapproaches (eg ESDM and

Floor-time)

Young

children

(usually agedlt5 years)

Moderate or

insufficient88 for

ESDM notestablished for

Floor-time

ESDM aims to accelerate childrenrsquos development in all

domains intervention targets derived from assessment

of developmental skills stresses social-communicativedevelopment interpersonal engagement

imitation-based interpersonal development and social

attention and motivation integration of ABA principles

and lsquopivotal response trainingrsquo (ie a naturalistic

approach targeting pivotal areas of a childs

development including motivation response to

multiple cues self-management and initiation of social

interactions)91

Floor-time (Developmental Individual-Difference

Relationship-Based model) emphasises functional




ltlt

emotional development individual differences in

sensory modulation processing and motor planning

relationships and interactions92

2 Comprehensive

structuredteaching

TEACCH Children

adolescentsand adults

Low Provides structures of the environment and activities

that can be understood by the individual usesindividualsrsquo relative strengths in visual skills and

interests to supplement weaker skills uses individualsrsquo

special interests to engage for learning supports

self-initiated use of meaningful communication93

3

Targeted

skill-based

intervention

PECS Non-verbal

individuals

Moderate Teaches spontaneous social-communication skills

through use of symbols or pictures94

Training in joint attention

pretend play socially

synchronous behaviourimitation emotion

recognition theory of

mind and functional

communication

Children Not established

but potentially

effective95

Fairly short-term (weeks to months) training sessions

targeting establishment of particular social cognitive

abilities fundamental to typical social-communicationdevelopment95-98

Teaching social skills (eg

emotion recognition

turn-taking) with areas of

interests (eg in machines

and systems)

Children

adolescents

and adults

Not established

but potentially

effective99-101

Short-term (weeks to months) interventions with DVDs

(eg Mindreading100 or The Transporters

99) or Lego

therapy101

Social skill training School-age

(≧6 years)

Low or

moderate89

Fairly short-term (weeks to months) training sessions to

build social skills usually through a group format95 102




lt

children

adolescents

and adults

Training in living skills and

autonomy

Children


Not established Targets establishment of living skills and

self-management to build autonomy positive behaviour support103 104

Vocational intervention Adolescentsand adults

Insufficient Eg interview training and on-the-job support

4 Targeted

behavioural

intervention for

anxiety and

aggression

CBT ABA Children

adolescents

and adults

Not established CBT to reducing anxiety modifies dysfunctional

thoughts compared with ordinary CBT CBT modified

for autism relies less on introspection and more on

teaching of practical adaptive skills with concrete

instructions often combined with social skill training

systematic desensitisation is useful particularly for

individuals with intellectual disability106

ABA to reduce aggression applies functional

behaviour assessment and teaches alternative

behaviours skills include antecedent manipulations

changes in instructional context reinforcement-basedstrategies and behaviour reduction strategies107

5 Parent-mediated

early

intervention

Training for joint

attention108 parent-child

interaction and

communication109 or

models like pivotal

response training

Young

children

Insufficient or

low112

Teaches parent or caregiver intervention strategies that

can be applied in home and community settings

potentially increasing parental efficacy and enabling

childrsquos generalisation of skills to real-life settings88 112




lt=

P-ESDM and More

Than Words111

Drugs

1 Antipsychotic

drugs

Risperidone aripiprazole Children


Children

moderate(risperidone) or

high(aripiprazole) for

effect and high

for adverse

effect113

adolescents and

adults

insufficient but

might have effects

as in children114

To reduce challenging behaviours and repetitive

behaviours potential adverse effects include weightgain sedation extrapyramidal symptoms and

hyperprolactinaemia (risperidone)

2

SSRI Citalopram escitalopram

fluoxetine and others

Children

adolescents

and adults

Insufficient for

effect and adverse

effect113-115

To reduce repetitive behaviours potential adverse

effects include lsquoactivation symptomsrsquo (agitation) and

gastro-intestinal discomfort

3 Stimulant Methylphenidate Children

adolescents

and adults

Insufficient for

effect and adverse

effect113 might be

helpful clinical

guideline

established11

To reduce attention-deficit hyperactivity disorder

symptoms potential adverse effects include insomnia

decreased appetite weight loss headache and

irritability




ltG

Evidence level Suggested by available systematic reviews and meta-analyses with criteria directly following or similar to the Grading of

Recommendations Assessment Development and Evaluation (GRADE) Working Group recommendation116 different ratings for the same model

or agent are from different reports lsquo Not establishedrsquo indicates no available systematic review or meta-analysis to date

Abbreviations ABA applied behaviour analysis CBT cognitive behavioural therapy EIBI early intensive behavioural intervention ESDM

Early Start Denver Model PECS Picture Exchange Communication System P-ESDM parent delivery of the ESDM SSRI selective serotonin

reuptake inhibitor TEACCH Treatment and Education of Autistic and related Communication-handicapped Children




ltI

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85) NU1 ltR 9Jgt HltJ=1

ltH1 8( ^- amp)3C4 N8- W(B aS- =56- W(5(A) a^- +UM S- 0)6V)A5 S- A )1 ]U)()A2- 6)$2BB- )6 A5)A3A 2O $)BA52ABA)

6B2565B 6U6()B VA 7NB ) 2BB(B 5C25A1 L6)A5B1 ltR ) +-- ) 7ltltK1




ltH

ltK1 8( ^- W(B aS- =56- W(5(A) a^- X2252B X- +UM S- +VB SN- A )1 T2336)A2B O25 U)()A2 )6 A5)A3A 2O 2332

$)BA52ABA) C5243B 65 VA 7NB1 L6)A5B1 ltR ) +-- ) 7ltJJ1

ltJ1 8)(3) +1 6) 232546AB )(AB3 )$B A2 6)$2BB )6 A5)A3A1 Z(52A5)C(AB1 ltR 9=gt =H1

1 amp Y- 7( ^L- amp b7- YB( SP- Y()$ X+- amp)$ PY- A )1 amp232546AM 2O )5$ )6 )(A233( 6B)BB C)AAB VA )(AB3

BCA5(3 6B2565 )A2V6 C2C()A24)B6 BA(6M1 TB)5 (AB3 7CA5(3 NB2565B1 lt=R 9gt Ilt1

lt1 25 amp- amp)5)$) - BV226 L1 ^ 52 2O 33( 6MBO(A2 A C)A2CMB22$M 2O )(AB31 85) 8)U Q33(1 ltR amp9=gt

=K=J1

1 a2B L- f3353) - BV226 L- 0) 6 P)A5 S1 ^ 33( BMBA3- )(A233(AM- )5$M- )6 )(AB3 BCA5(3 6B2565B1 Q

3)5) Na- N)VB2 a- aBV6 NY- 6A25B1 (AB3 7CA5(3 NB2565B1 ZV b25[- Zb EO256 cU5BAM L5BBR ltlt1 C1 =JIGltJ1

=1 7A S+- L)5[B)[ ZZ- aBV6 NY1 T)5 5A6 U)5)A2 )(AB3 4$$ A2 B A O25BA )6 ) OV A5B1 Z(521 lt=R 9gt

Jltlt1

G1 2BB S- Y2V L1 (AB3 BCA5(3 6B2565B $A BM6523B 3C)A2B O25 6)$2BB- A5UA2 )6 (65BA)6$ A V65

)(AB3 BCA5(3 6B2565 C2C()A21 S QAA NB)4 TB1 JR 9ltgt KIH=1

I1 8U(A2 - 2)U52 T- BB)65 T- )_ 8- amp(5)A22 L1 7M6523 )(AB3 )(BB )6 C)A2$A C)AV)MB1 P256 S L6)A51

JR 9=gt ltFJHF1

F1 X2A)$) 7- 85223) ]1 7C 65 VA )(AB3 BCA5(3 6B25651 L6)A5 Z(521 ltR 9Ggt GIlt1




ltK

H1 )2V 8- 8M)5B X- S2B2 X- PBB 7- 85) L- a263) 7]- A )1 C5)A C)AV)M O25 A 6AO)A2- U)()A2- )6

3))$3A 2O B23) 65 )6 )62BAB VA )(AB3 BCA5(3 6B2565B1 L6)A5B1 ltR )$ +-- 7ltFG1

K1 ^MB2 X]- amp5(BB Na1 NOO5A)A$ $O(A2$ )(AB3 )6 B2) C24)1 S (AB3 NU NB2561 ltR 9Hgt ltGHHJ1

J1 PB452A N- a)62V XN- N0A ampS- L2352M S1 ^ C5BA)A2 2O )EAM 65 VA C5U)BU 6U2C3A) 6B2565B1 S

amp6 62B LBM2C)53)21 IR )9=gt GHHJF1

=1 7A5$ +- N)VB2 a- ]BAB - a5B2 S1 amp)5)A5BAB )BB2)A6 VA C5B 2O 6C5BBU BM3CA23B )6(AB VA )(AB3

BCA5(3 6B25651 S (AB3 NU NB2561 KR 9Fgt ltltltK1

=lt1 c$ Y)54)[ - +($$)56 ^- a45$ amp1 QB )(AB3 BCA5(3 6B2565 2332 B_2C5)g LBM)A5M TB1 ltR )(9ltgt ltH1

=1 T)C2C25A S- amp)U_ - a5BA N- 66$A2 - a2$A)M Z1 (AB3 BCA5(3 6B2565B )6 62262BA B_2C5) ) )6

422$) 2A54(A2B A2 ) 5)A2 5UBA61 S 3 )6 amp6 62B LBM)A5M1 JR 9ltgt ltK1

==1 65B)V - ^5)B(5 S- Y)34522[ N- ^)A(5) X- 736A c1 QB )25E) 5U2B) ) U5B2 2O )(AB3 BCA5(3 6B2565Bg ](5 ])A

NB256 TU1 ltltR )(9Fgt GFHG1

=G1 +($$)56 ^- Y)54)[ c- a45$ amp1 L5B2)AM 6B2565B )6 )(AB3 BCA5(3 6B2565B V)A )5 A 2A2Bg amp23C5

LBM)A5M1 ltR 9Ggt ===G1

=I1 P$ +1 )(ABA BCA5(31 +)A1 ltJJHR $9JJ=gt ltHFltF1

=F1 X) 7- )_(5[ 1 $$5BB2 65 )6 )62BAB VA 7N C5U) )6 5B[ O)A25B1 S (AB3 NU NB2561 ltltR )9Hgt

JF=H1




ltJ

=H1 T)56B amp- U5 amp- ZB2 +- 2BB S1 7Od(52(B 4)U2(5 6U6()B VA )(AB3 BCA5(3 6B2565 )6 AA() 6B)4AM1 S

QAA NB)4 TB1 ltR amp9Igt GHFKJ1

=K1 +20(2 70- )AB2 S+1 amp232546 CBM2C)A22$M )6(AB VA (AB3 7CA5(3 NB2565B )6 AA() 6B)4AB1 TB NU NB)41

JR $9Fgt ltKKJF1

=J1 )MB 7N- a253) - YV$a)5) S- 7M6 ]1 7(6 6)A2 )6 )AA3CAB 65 VA )(AB31 TB)5 (AB3 7CA5(3

NB2565B1 lt=R 9ltgt ltJltJ1

G1 7A25 ]- 7([2VB[ +- Z)6)( S- +V 8- 526 ]8- (A LS- A )1 ^ C2322$M )6 ) 255)AB 2O B(6) A2($AB

)6 4)U25B M2(A VA )(AB3 BCA5(3 6B2565B1 S (AB3 NU NB2561 lt=1

Glt1 8)52amp2 7- amp2E - 8)56 a- 7VAA)3 S- Z$A$) Z- 25$) X- A )1 LBM22$) 3)5[5B A 6AA2 2O )(AB3 O)M

) )5$ C2C()A21 85 S LBM)A5M1 ltJJFR )amp9gt ltIKF=1

G1 NA_ amp- 7V[B 7- U) N)) ]- U) ]$)6 Y- 8(A))5 SX1 75$ O25 )(ABA BCA5(3 6B2565 65 )$6 ltGltI 32AB1 QQC2C()A2 B5$ VA A ])5M 75$ 2O (ABA ^5)AB `(BA2)5 9]7^gt1 NB$ )6 $5) O6$B1 S (AB3 NU NB2561 FR

amp9Fgt Hlt=1

G=1 7V[B 7Y- NA_ amp- U) N)) ]- X5[2O QY- U) ]$)6 Y- 8(A))5 SX1 75$ O25 )(ABA BCA5(3 65 )$6 ltG A2 ltI

32AB1 Q A 6U2C3A 2O A ])5M 75$ 2O (ABA ^5)AB `(BA2)5 9]7^gt1 S (AB3 NU NB2561 FR amp9Fgt H==1

GG1 X3) S- T24B N+- 0A2) L]- L)6M S- 8225BA Yamp- ]BB5 ]+- A )1 ^ 326O6 [BA O25 )(AB3 A2665B ) O22V(C

BA(6M UBA$)A$ A )5M 6AA2 2O )(AB3 BCA5(3 6B2565B1 S (AB3 NU NB2561 KR 9Igt KH=J1




GI1 PA54M - 852B))662E 7- L) 0- ZVA2 +1 0)6)A2 2O A QO)A^2665 amp[BA )B ) 452)64)6 B55 O25 )(AB3

BCA5(3 6B2565B O523 J A2 G 32AB 2O )$1 (AB31 KR )9Igt GKHIltlt1

GF1 B2 amp- 8)52amp2 7- PV5$A 7- amp)53) ^- T5 S- L)B2 a- A )1 ^ `ampY^ 9 ()AA)AU ampY[BA O25 (AB3 ^2665Bgt

) 253)M 6BA54(A6 h()AA)AU 3)B(5 2O )(ABA A5)AB )A ltKG 32AB 2O )$ C53)5M 5C25A1 S (AB3 NU NB2561 KR 9KgtltGltGI1

GH1 B2 amp- (M($ 8- 8)52amp2 71 ^2V)56 45O iT6 W)$Bi O25 )(AB3 B5$ ^ 725A (AB3 7CA5(3 (2AA )6 A 725A

`()AA)AU amp[BA O25 (AB3 A2665B lt- )BB )6 =- 2A52B j255A6k1 S 3 )6 amp6 62B LBM)A5M1 ltR )9gt

lt H1

GK1 7A2 P+- amp22526 ]]- ^(55 +- L2_62 7+1 LBM23A5 C52C5AB 2O A 7^^ O25 )5M )(AB3 B5$1 S (AB3 NU NB2561 GR

9Fgt FJltHlt1

GJ1 amp25B2 amp- Y(B 0- L[B - TB 7- amp22[ ]Y- S51- +UA) 8+- A )1 8AV ) Tamp )6 ) )56 C) 6B2 3)[$ )6 3)[$ 6B2B

)42(A (B$ A 7amp`1 S amp6 LBM2 LBM)A5M1 HR 9Jgt J=G1

I1 amp2BA)A2 SZ- +)UBB5 LN- f)$ b- 44) - a5)M ^- ^266 TN1 T)C6 h()AA)AU )BBBB3A 2O )(ABA B2) 3C)53A 4M

)BB5223 A)5B1 S 3 )6 amp6 62B LBM)A5M1 HR amp9ltgt ltFFKHF1

Ilt1 P)3B S- 72AA W- 7A2AA amp- B2 amp- 82A2 L- 8)52amp2 7- A )1 ^ amp7 9amp6226 BC5$5 7M6523 BAgt ABA )(5)M1 (AB31

IR (9ltgt GIFK1

I1 ]5B 7- a45$ amp- P$ +1 B5$ h(BA2)5 O25 BC5$5 BM6523 )6 2A5 $O(A2$ )(AB3 BCA5(3 6B2565B

B22 )$ 651 S (AB3 NU NB2561 ltJJJR (9gt ltJGlt1




lt

I=1 (M($ 8- 8)52amp2 7- PV5$A 7- B2 amp1 ^ (AB3 7CA5(3 `(2AA amp65lB 05B2 9`amp6gt1 S (AB3 NU NB2561

KR 9Hgt lt=G1

IG1 8)52amp2 7- Y2[BA5) T- X[3M5 T- PV5$A 71 ^ (AB37CA5(3 `(2AA 9`gt)62BA U5B21 S (AB3 NU NB2561

FR amp9=gt =G=I1

II1 8)52amp2 7- PV5$A 7- 7[5 T- )5A S- amp(4M ]1 ^ )(AB3BCA5(3 h(2AA 9`gt U6 O523 BC5$5

BM6523D$O(A2$ )(AB3- 3)B )6 O3)B- BABAB )6 3)A3)A)B1 S (AB3 NU NB2561 ltR )9ltgt IltH1

IF1 TAU2 T- TAU2 ]T- a(A5 N- TAU2 S- Y(O)$ NY- )2 P- A )1 ^ TAU2 (AB3 BC5$5 N)$2BA 7)TUB6 9TN7Tgt )

B) A2 )BBBA A 6)$2BB 2O (AB3 7CA5(3 NB2565 )6(AB ) A5)A2) U)6)A2 BA(6M1 S (AB3 NU NB2561 ltltR )9Kgt ltHFKJ1

IH1 +256 amp- T(AA5 - + amp2(A(5 1 (AB3 N)$2BA QA5UVTUB6 ) 5UB6 U5B2 2O ) 6)$2BA A5UV O25 )5$U5B 2O

6U6()B VA C2BB4 C5U)BU 6U2C3A) 6B2565B1 S (AB3 NU NB2561 ltJJGR 9Igt FIJKI1

IK1 P$ +- +[)3 7T- +44M 7S- a2(6 S- +)5234 1 ^ N)$2BA QA5UV O25 72) )6 amp233()A2 NB2565B 4)[$52(6-A55)A5 5)4AM )6 ) (B1 S amp6 LBM2 LBM)A5M1 R 9=gt =HI1

IJ1 7[(B N- P)55$A2 T- 8B2C N- amp2V6(5M c- +)( S- )6M P- A )1 6U2C3A)- 63B2) )6 6)$2BA A5UV 9=6gt )

2U 23C(A5_6 )BBBB3A O25 )(AB3 BCA5(3 6B2565B1 S 3 )6 amp6 62B LBM)A5M1 GR 9Igt IGKIK1

F1 7)A2B LS- )6M PL- L((5) X- X))5A - P)55$A2 T- 7[(B NY1 ^ 2BA5(A2 )6 U)6)A2 2O ) B25A O253 2O A

6U2C3A)- 6)$2BA )6 63B2) A5UV1 ](5 amp6 62B LBM)A5M1 JR )9Kgt IltG1

Flt1 +256 amp- TB 7- +)345A +- amp22[ ]Y- S51- +UA) 8+- N+)U25 Lamp- A )1 ^ )(AB3 6)$2BA 24B5U)A2 B6($5 ) BA)6)56

3)B(5 2O B2) )6 233()A2 6OAB )BB2)A6 VA A BCA5(3 2O )(AB31 S (AB3 NU NB2561 R $9=gt I=1




F1 )$M)5 ampQ- L)62O 01 W)A25 BA5(A(5 U)()A2 2O A 6226 )(AB3 5)A$ B)1 S (AB3 NU NB2561 HR 9Jgt ltHKHJG1

F=1 7d( - S2B2 Y1 AMC) M 2A)A )(AB3 326B- 3)B3B )6 6U2C3A1 Z(52B 824)U TU1 JR 9Kgt

ltGltG1

FG1 Y)53B 8- )5A - P)) a+1 W)) 32A2 52$A2 )(AB3 BCA5(3 6B2565B ) 5UV 2O 4)U25) )6 (523)$$

BA(6B1 Z(52CBM2 TU1 ltR $9=gt J=1

FI1 P$A 7- X26VM X- X)VB5 Z1 W) 6AAM 52$A2 )(AB3 BCA5(3 6B2565B 5UV 2O 4)U25) BA(6B1 Z(52B

824)U TU1 ltR amp9=gt ltFKG1

FF1 X)B5 N- LC5M X1 NB5(CA6 )A2 C5CA2 )(AB3 4)U25) U6- (5262C2AMCB- )6 6)$2BA (AAM1 NU

amp2$ Z(52B1 ltR 9ltgt I=I1

FH1 N)VB2 a- ^2A X- 442AA T- BA5$ S- (B2 S- ]BAB - A )1 ])5M B2) )AAA2 3C)53AB )(AB3 B2) 25A$- d2A

)AAA2- )6 )AAA2 A2 6BA5BB1 NU LBM21 GR $9gt HltK=1

FK1 ampU)5 amp- X2B a- ^52) 0- 8526[ ]7- 7(A_ T^1 ^ B2) 32AU)A2 A25M 2O )(AB31 ^56B amp2$ 71 ltR)amp9Ggt =ltJ1

FJ1 NA5 a71 W(A2) 3)$A 5B2) 3)$$ 2O )(AB3 BCA5(3 6B2565B1 N)2$(B amp Z(52B1 ltR )9=gt =ltJIlt1

H1 ^)A)3 N1 amp) A V256 )OO256 )(ABA BCA5(3 6B2565g +262- cX SBB) X$BM L(4B5BR J1

Hlt1 7UU5 - aB S1 E)3)A2 2O A BA)A 2O 3A)A2 5B)5 65 VA )(AB3 QBB(B 2O 6OA2 )6 3A2622$M1 TB

NU NB)41 ltR )9Igt JHFKG1




=

H1 8)52amp2 7- PV5$A 71 ^ 3C)AM h(2AA ) UBA$)A2 2O )6(AB VA BC5$5 BM6523 25 $ O(A2$ )(AB3- )6

253) BE 6OO5B1 S (AB3 NU NB2561 GR 9gt ltF=HI1

H=1 (6M L- 7(U) +- )BA5$25$ 1 C)5) )6 6BA54(A6C52BB$ 326 2O d2A )AAA2- B2) 2$A2 )6 )(AB31 (AB3

TB1 JR 9ltgt lt1

HG1 S)5526 amp1 5UV 2O 5B)5 A2 C5A6 C)M )(AB31 (AB31 =R 9Ggt =HJJ1

HI1 82(5 S1 L(AA$ A25M 2O 36 AB C) CBM22$) EC))A2B 2O A B2232A2)233()AU 3C)53AB )(ABA

BCA5(3 6B25651 (AB31 ltR )amp9=gt FGF1

HF1 7d( 1 7C2A)2(B A25M 2O 36 )6 AB )4B )(AB3 BCA5(3 6B2565B1 Z(52BABA1 ltltR )9gt ltKlt=1

HH1 8)52amp2 71 646BB BB)M 2 )(AB3 )6 A25M 2O 361 82BA2 Q^ L5BBD85)6O256 822[BR ltJJI1

HK1 +234)562 0- 8)52amp2 71 ^ 52 2O A BO 3646BB )(AB31 amp2B2(B amp2$1 ltltR $9ltgt lt=G1

HJ1 W5A c1 PM V 6 2$AU EC))A2B 2O )(AB31 ` S ]EC LBM2 9Y2Ugt1 ltR amp9ltltgt H=J1

K1 856 a- amp22[ T1 E6 32A2B A 2A54(A2 2O )EAM3) A2 A 32A2) BM3CA23B 2O )(AB31 ^5)B)A2) CBM)A5M1 lt=R

KI1

Klt1 amp)55(A5B L1 Y2V V [2V 2(5 2V 36B A 5)A2BC 4AV 365)6$ )6 3A)2$A21 8)U 85) 71 JR 9gt

ltlt=KR 6B(BB2 =KK1

K1 Y ]+1 ]U)()A$ A A25M 2O E(AU 6MBO(A2 )(AB31 NU2C3A) TUV1 GR 9gt ltKJ==1




G

K=1 2AA52 +- N)VB2 - 72(5B Q- Y(45A 8- 8(5)[ S1 ])6 C5CA() O(A2$ )(AB3 ) (C6)A- )6 $A C5CB 2O

)(ABA C5CA21 S (AB3 NU NB2561 FR amp9ltgt HG=1

KG1 Y)CC W- W5A c1 V)[ 25 )2(A 6A)O2(B6 2$AU BAM )(AB3 BCA5(3 6B2565B1 S (AB3 NU NB2561 FR

amp9ltgt II1

KI1 L)BA6 a5)A X- N)UB a1 L5CA2 )6 )CC5CA2 )(AB3 5dA$ A U5B )BB(3CA21 L2B ^5)B T 72 +26 8 82 71

JR amp9ltIgt lt=J=K1

KF1 8)52amp2 71 (AB3- MC5BMBA3_$- )6 A5(A1 S ]EC LBM2 9amp2BA5gt1 KR amp)9ltgt FGHI1

KH1 T2V 8- 8)5A2 ]]- 82M6 8- Y(3 X1 ])5M ABU 4)U25) A5UA2 9]Q8Qgt O25 M2($ 65 VA )(AB3 BCA5(3 6B2565B

97Ngt1 amp25) N)A)4)B 7MBA TU1 ltR )$ ampNJF1

KK1 P)55 f- LA5B +- 7)A Z- W2BBW$ SY- a)BB5 - 0BA5)0)65V S1 BMBA3)A 5UV 2O )5M ABU A5UA2

O25 )(AB3 BCA5(3 6B2565B1 L6)A5B1 ltltR )9Igt lt==ltlt1

KJ1 )$2 - a)B N- N)B +- ^34 S- X)B)5 amp1 Z236) A5UA2B O25 65 VA 7N 523366 $(6B )6 O(5A5

5B)5 6B1 L6)A5B1 ltR )$ +-- 7ltFJHK1

J1 T2V 81 U5UV 2O 3A)))MBB 2 )5M ABU 4)U25) A5UA2 O25 M2($ 65 VA )(AB3 BCA5(3 6B2565B1 S

(AB3 NU NB2561 ltR 9Ggt Ilt1

Jlt1 T2$5B 7S- N)VB2 a1 ])5M 7A)5A NU5 26 O25 b2($ amp65 VA (AB3 L5232A$ +)$()$- +)5$- )6 ]$)$3A1 ZV

b25[- Zb ^ a(O256 L5BBR lt1




I

J1 a5BC) 7Q- P65 7- 732B T1 ^ amp6 VA 7C) Z6B ]2(5)$$ QAA() )6 ]32A2) a52VA1 T)6$- L5B(B

822[BR ltJJK1

J=1 B42U a8- 7) 01 ^ ^]ampampY C52$5)3 A 5) 2O U64)B6 C5)A1 S (AB3 NU NB2561 ltR $9Igt IHJ1

JG1 826M - W52BA +1 ^ LA(5 ]E)$ amp233()A2 7MBA31 8)U 26O1 ltR 9Igt HIGG1

JI1 X)B)5 amp- L)AA5B2 71 QA5UA2B )665BB$ B2) 3C)53A )(AB31 amp(55 LBM)A5M TC1 ltR )9Fgt Hlt=I1

JF1 8$5 7- aU5B amp- ampOO256 L- 052U - X)A X- Y2664) ]- A )1 ^25M 2O 6 A5)$ 65 VA )(AB3 ) 5)623_6

2A526 A5)1 S (AB3 NU NB2561 ltltR )9Kgt JJHltF1

JH1 Q$5B2 81 85O 5C25A OOA 2O ) O2(B6 3A)A2 A5UA2 2 B2) O(A2$ 65 VA )(AB31 S (AB3 NU NB2561 ltR

9Kgt ltHFKH=1

JK1 ) Ta1 W(A2) 233()A2 A5)$ 5UV 2O A A5)A(5 5)A6 A2 65 VA )(AB31 ]6()A2 )6 ^5)$ NU2C3A) NB)4AB1 FR )9=gt lt=1

JJ1 a2) - BV ]- a5))65 b- ampA2[ 7- N)M X- +$$AA 0- A )1 ])$ 32A2 52$A2 65 VA )(AB3 BCA5(3

26A2B ) A5UA2 (B$ )3)A6 UB VA 5) 32A2) O)B1 S (AB3 NU NB2561 ltR $9=gt FJHJ1

lt1 a2) - 8)52amp2 71 7MBA3_$ 3C)AM A)$ )6(AB VA BC5$5 BM6523 25 $O(A2$ )(AB3 A2 52$_ 23CE

32A2B (B$ A5)AU 3(A36)1 NU LBM2C)A21 FR )9gt IJltFltH1

ltlt1 VB a- a5))65 b- Y(3C5M - 8)52amp2 71 +]a A5)CM )6 A B2) (B 2O )$()$ C52$5)33 ) U)()A2 2O AV2 B2)

B[B A5UA2B O25 65 VA $ O(A2$ )(AB3 )6 BC5$5 7M65231 S (AB3 NU NB2561 KR 9ltgt ltJGGIH1




F

lt1 T2V 8- 7A5 - 02[3)5 W1 72) B[B $52(CB O25 C2C )$6 F A2 lt VA )(AB3 BCA5(3 6B2565B 97Ngt1 amp25) N)A)4)B

7MBA TU1 ltR ampNKIltlt1

lt=1 7543) +- X2$ T+1 W2BA5$ BO3))$3A L)5A6U56 CU2A) 5BC2B A5)$ O25 65 VA )(ABA 6B25651 Q N1

Y]- SB L7- 6A25B1 LBM2B2) A5)A3A O25 6 )6 )62BA 6B2565B ]3C5)M 4)B6 BA5)A$B O25 ) C5)A1 P)B$A2-Namp 35) LBM22$) BB2)A2R ltJJF1 C1 III1

ltG1 +(MBM S- Y255 TY- N()C a- 4 TP- 8 XT1 L2BAU 4)U25 B(CC25A VA O)3B1 Q +(MBM S- N()C a- 4 TP-

6A25B1 W)3B )6 C2BAU 4)U25 B(CC25A 665BB$ C5243 4)U25B O)3M 2AEAB1 8)A325- N L)( 8522[BR 1 C1 =G=1

ltI1 ^)M25 S+- LA5B +- 7)A Z- N2U N- 0BA5)0)65V S- P)55 f1 BMBA3)A 5UV 2O U2)A2) A5UA2B O25

M2($ )6(AB VA )(AB3 BCA5(3 6B2565B1 L6)A5B1 ltR )$9=gt I=ltK1

ltF1 +)$ T- T$BA5 - +)(656) 7- B4)($ X- Y)5$ 1 ^5)A3A 2O )EAM )(AB3 BCA5(3 6B2565B (B$ 2$AU 4)U2(5

A5)CM BMBA3)A 5UV1 NU Z(525)41 ltR )9ltgt I=F=1

ltH1 852B) S- Y)M 1 5UV 2O 4)U25) A5UA2B O25 A A5)A3A 2O )$$5BB2 6U6()B VA 6U2C3A) 6B)4AB1 TB

NU NB)41 ltltR 9gt G=HGF1

ltK1 X)B)5 amp- a(B5(6 amp- P2$ amp- XV2 7- +2[ S1 T)623_6 2A526 )5$U5 36)A6 d2A $)$3A A5UA2 O25 A2665B

VA )(AB31 S (AB3 NU NB2561 ltR $9Jgt ltGIIF1

ltJ1 a5 S- amp)53) ^- amp2) Y- 656 amp- 723B 0- Y2V L- A )1 L)5A36)A6 233()A2O2(B6 A5)A3A 65

VA )(AB3 9Lamp^gt ) 5)623B6 2A526 A5)1 +)A1 ltR 9JH=gt ltIF1




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disregarded the people and instantly went for objectsrdquo In usually restricted or repetitive behaviour and interests18B T i t R d

Seminar

How prevalence estimates will be aff ected by the newcriteria and how autism spectrum disorder will relate tothe newly created social (pragmatic) communicationdisorder (defined by substantial diffi culties with socialuses of both verbal and non-verbal communication butotherwise not meeting criteria for autism spectrumdisorder) remain to be assessed

Autism could potentially be subgrouped at clinical (egby developmental pattern or trajectory and comorbidity)cognitive and aetiological levels (eg by genetic andenvironmental correlates)6 Although the term autismspectrum disorder is frequently used the term autismspectrum condition also signals a biomedical diagnosisfor which individuals need support and recognises areasin which aff ected individuals are diff erent from thosewithout autism but without the negative overtones of the

disorder label

EpidemiologyPrevalenceThe prevalence of autism has been steadily increasingsince the first epidemiological study7 which showed that4middot1 of every 10 000 individuals in the UK had autism Theincrease is probably partly a result of changes in diag-nostic concepts and criteria8 However the prevalencehas continued to rise in the past two decades particularly

in individuals without intellectual disability despite

Figure The growth of autism research

Almost three times as many reports about autism were published between2000 and 2012 (n=16 741) as between 1940 and 1999 (n=6054) These

calculations are based on a keyword search of PubMed with the term ldquolsquoautismrsquo

OR lsquoautism spectrum disorderrsquo OR lsquopervasive developmental disorderrsquo OR

lsquoAsperger syndromersquordquo

1940 1950 1960 1970 1980 1990 2000 2010 20200

500

1000

1500

2000

2500

3000

N u m b e r o f r e p o r t s

p u b l i s h e d p e r y e a r

Year

Features


Persistent deficits in social

communication and social

interaction across multiple

Deficits in socialndashemotional reciprocity

Deficits in non-verbal communicative behaviours used for social

interaction



Seminar



Comments

Developmental


as a criterion)





disorder





General medical

















Cli i l id il bl



Seminar








Comments


Behavioural
















Seminar













Seminar

Age Description









(Q-CHAT)




(STAT)



screening measure



gt2 years)



(SRS SRS-2)




10 min


adolescent versions





Screening adults




version available


(RAADS R)






Seminar





th f i th ti ) h b







Seminar











Seminar











Seminar








eff ectiveness





aged lt5 years)









aged lt5 years)



floortime













Seminar




th t t ti l d i t f


eff ectiveness



Drugs

Antipsychotic drugs


and adults

Children moderate








(risperidone)



others


and adults


adverse eff ect



Stimulant


and adults











Seminar






Acknowledgments


















Seminar





























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2011 395 419























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$amp )+- amp01 23 424$5-6





contexts













abilities2














affected

Comments

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General medical












=













Psychiatric

Anxiety 42-56-








categories








G







compliance10




experiences34




disorder


disorder









Behavioural







I









or bullied39




F





(CHAT)41




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min



Toddlers (M-CHAT)44



Public domain









Public domain


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(STAT)48







adolescents



years)






H











_tests






individuals




Child 4-11

years

Adolescent

10-16 years





Public domain


_tests

Screening adults


adult version55

gt16 years (with

average or

above-average

intelligence)




individuals

Public domain


_tests



(RAADS-R )56

gt18 years (with

average or

above-average

intelligence)






Mental age gt2years







K


Disorders (DISCO)58

chronological

and mental ages










measure




ADOS-2)61





necessary




CARS-2)62








J




social perception


communication








communication





processing






processing)

83-85


84







lt



group




1

Comprehensive

ABA-based

EIBI Young

children

(usually aged

lt5 years)

Low or

moderate89









developmental and


Floor-time)

Young

children


Moderate or

insufficient88 for


Floor-time










interactions)91






ltlt




2 Comprehensive

structuredteaching

TEACCH Children







3

Targeted

skill-based

intervention

PECS Non-verbal

individuals







mind and functional

communication


but potentially

effective95





emotion recognition



and systems)

Children

adolescents

and adults

Not established

but potentially

effective99-101



99) or Lego

therapy101


(≧6 years)

Low or

moderate89






lt

children

adolescents

and adults


autonomy

Children






4 Targeted

behavioural

intervention for

anxiety and

aggression

CBT ABA Children

adolescents

and adults












5 Parent-mediated

early

intervention

Training for joint


interaction and

communication109 or

models like pivotal

response training

Young

children

Insufficient or

low112








lt=

P-ESDM and More

Than Words111

Drugs

1 Antipsychotic

drugs



Children



effect and high

for adverse

effect113

adolescents and

adults

insufficient but

might have effects

as in children114




2



Children

adolescents

and adults

Insufficient for

effect and adverse

effect113-115





adolescents

and adults

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effect and adverse

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helpful clinical

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th f i th ti ) h b







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2011 395 419























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contexts













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(STAT)48







adolescents



years)






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individuals

Public domain


_tests



(RAADS-R )56

gt18 years (with

average or

above-average

intelligence)






Mental age gt2years







K


Disorders (DISCO)58

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measure




ADOS-2)61





necessary




CARS-2)62








J




social perception


communication








communication





processing






processing)

83-85


84







lt



group




1

Comprehensive

ABA-based

EIBI Young

children

(usually aged

lt5 years)

Low or

moderate89









developmental and


Floor-time)

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children


Moderate or

insufficient88 for


Floor-time










interactions)91






ltlt




2 Comprehensive

structuredteaching

TEACCH Children







3

Targeted

skill-based

intervention

PECS Non-verbal

individuals







mind and functional

communication


but potentially

effective95





emotion recognition



and systems)

Children

adolescents

and adults

Not established

but potentially

effective99-101



99) or Lego

therapy101


(≧6 years)

Low or

moderate89






lt

children

adolescents

and adults


autonomy

Children






4 Targeted

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intervention for

anxiety and

aggression

CBT ABA Children

adolescents

and adults












5 Parent-mediated

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communication109 or

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children

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low112








lt=

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Drugs

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drugs



Children



effect and high

for adverse

effect113

adolescents and

adults

insufficient but

might have effects

as in children114




2



Children

adolescents

and adults

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effect and adverse

effect113-115





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screening measure



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th f i th ti ) h b







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eff ectiveness





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Seminar






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2011 395 419























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min



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years)






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_tests






individuals




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above-average

intelligence)




individuals

Public domain


_tests



(RAADS-R )56

gt18 years (with

average or

above-average

intelligence)






Mental age gt2years







K


Disorders (DISCO)58

chronological

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measure




ADOS-2)61





necessary




CARS-2)62








J




social perception


communication








communication





processing






processing)

83-85


84







lt



group




1

Comprehensive

ABA-based

EIBI Young

children

(usually aged

lt5 years)

Low or

moderate89









developmental and


Floor-time)

Young

children


Moderate or

insufficient88 for


Floor-time










interactions)91






ltlt




2 Comprehensive

structuredteaching

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3

Targeted

skill-based

intervention

PECS Non-verbal

individuals







mind and functional

communication


but potentially

effective95





emotion recognition



and systems)

Children

adolescents

and adults

Not established

but potentially

effective99-101



99) or Lego

therapy101


(≧6 years)

Low or

moderate89






lt

children

adolescents

and adults


autonomy

Children






4 Targeted

behavioural

intervention for

anxiety and

aggression

CBT ABA Children

adolescents

and adults












5 Parent-mediated

early

intervention

Training for joint


interaction and

communication109 or

models like pivotal

response training

Young

children

Insufficient or

low112








lt=

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Than Words111

Drugs

1 Antipsychotic

drugs



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effect and high

for adverse

effect113

adolescents and

adults

insufficient but

might have effects

as in children114




2



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adolescents

and adults

Insufficient for

effect and adverse

effect113-115





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th f i th ti ) h b







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eff ectiveness





aged lt5 years)









aged lt5 years)



floortime













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th t t ti l d i t f


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adverse eff ect



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and adults











Seminar






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2011 395 419























lt

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contexts













abilities2














affected

Comments

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compliance10




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(CHAT)41




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years)






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_tests






individuals




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gt18 years (with

average or

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processing






processing)

83-85


84







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group




1

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(usually aged

lt5 years)

Low or

moderate89









developmental and


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children


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insufficient88 for


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ltlt




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structuredteaching

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3

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skill-based

intervention

PECS Non-verbal

individuals







mind and functional

communication


but potentially

effective95





emotion recognition



and systems)

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and adults

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but potentially

effective99-101



99) or Lego

therapy101


(≧6 years)

Low or

moderate89






lt

children

adolescents

and adults


autonomy

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4 Targeted

behavioural

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anxiety and

aggression

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Young

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effect and high

for adverse

effect113

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as in children114




2



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eff ectiveness





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Acknowledgments


















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2011 395 419























lt

$amp )+- amp01 23 424$5-6





contexts













abilities2














affected

Comments

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categories








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compliance10




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or bullied39




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(CHAT)41




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min



Toddlers (M-CHAT)44



Public domain









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_tests



(STAT)48







adolescents



years)






H











_tests






individuals




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years

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intelligence)




individuals

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_tests



(RAADS-R )56

gt18 years (with

average or

above-average

intelligence)






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ADOS-2)61





necessary




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J




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processing






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83-85


84







lt



group




1

Comprehensive

ABA-based

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(usually aged

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moderate89









developmental and


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children


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insufficient88 for


Floor-time










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ltlt




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structuredteaching

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3

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individuals







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communication


but potentially

effective95





emotion recognition



and systems)

Children

adolescents

and adults

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but potentially

effective99-101



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(≧6 years)

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moderate89






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processing)

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Comprehensive

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insufficient88 for


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emotion recognition



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children

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effect and high

for adverse

effect113

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emotion recognition



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99) or Lego

therapy101


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moderate89






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adolescents

and adults


autonomy

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aggression

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adolescents

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early

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but potentially

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emotion recognition



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but potentially

effective99-101



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therapy101


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Low or

moderate89






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adolescents

and adults


autonomy

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aggression

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and adults












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and adults

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emotion recognition



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moderate89






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individuals




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individuals

Public domain


_tests



(RAADS-R )56

gt18 years (with

average or

above-average

intelligence)






Mental age gt2years







K


Disorders (DISCO)58

chronological

and mental ages










measure




ADOS-2)61





necessary




CARS-2)62








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processing)

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84







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group




1

Comprehensive

ABA-based

EIBI Young

children

(usually aged

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Low or

moderate89









developmental and


Floor-time)

Young

children


Moderate or

insufficient88 for


Floor-time










interactions)91






ltlt




2 Comprehensive

structuredteaching

TEACCH Children







3

Targeted

skill-based

intervention

PECS Non-verbal

individuals







mind and functional

communication


but potentially

effective95





emotion recognition



and systems)

Children

adolescents

and adults

Not established

but potentially

effective99-101



99) or Lego

therapy101


(≧6 years)

Low or

moderate89






lt

children

adolescents

and adults


autonomy

Children






4 Targeted

behavioural

intervention for

anxiety and

aggression

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adolescents

and adults












5 Parent-mediated

early

intervention

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communication109 or

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Drugs

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effect and high

for adverse

effect113

adolescents and

adults

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as in children114




2



Children

adolescents

and adults

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effect and adverse

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adolescents

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but potentially

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therapy101


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Low or

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autonomy

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effect and high

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adolescents

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2014 Lancet Autism Seminar & Appendix

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Transcript of 2014 Lancet Autism Seminar & Appendix