Early Identiﬁcation of Autism Spectrum Disorder ... · of early signs of autism spectrum disorder...

Early Identification of Autism Spectrum Disorder:Recommendations for Practice and Research

abstractEarly identification of autism spectrum disorder (ASD) is essential toensure that children can access specialized evidence-based interven-tions that can help to optimize long-term outcomes. Early identificationalso helps shorten the stressful “diagnostic odyssey” that manyfamilies experience before diagnosis. There have been importantadvances in research into the early development of ASDs, incorpo-rating prospective designs and new technologies aimed at more pre-cisely delineating the early emergence of ASD. Thus, an updatedreview of the state of the science of early identification of ASD wasneeded to inform best practice. These issues were the focus of a mul-tidisciplinary panel of clinical practitioners and researchers whocompleted a literature review and reached consensus on currentevidence addressing the question “What are the earliest signs andsymptoms of ASD in children aged #24 months that can be used forearly identification?” Summary statements address current knowl-edge on early signs of ASD, potential contributions and limitationsof prospective research with high-risk infants, and priorities for pro-moting the incorporation of this knowledge into clinical practice andfuture research. Pediatrics 2015;136:S10–S40

AUTHORS: Lonnie Zwaigenbaum, MD,a Margaret L.Bauman, MD,b Wendy L. Stone, PhD,c Nurit Yirmiya, PhD,d

Annette Estes, PhD,e Robin L. Hansen, MD,f James C.McPartland, PhD,g Marvin R. Natowicz, MD, PhD,h RoulaChoueiri, MD,i Deborah Fein, PhD,j Connie Kasari, PhD,k

Karen Pierce, PhD,l Timothy Buie, MD,m Alice Carter, PhD,n

Patricia A. Davis, MD,o Doreen Granpeesheh, PhD, BCBA-D,p

Zoe Mailloux, OTD, OTR/L, FAOTA,q Craig Newschaffer, PhD,r

Diana Robins, PhD,r Susanne Smith Roley, OTD, OTR/L,FAOTA,s Sheldon Wagner, PhD,t and Amy Wetherby, PhDu

aDepartment of Pediatrics, University of Alberta, Edmonton,Alberta, Canada; bDepartment of Anatomy and Neurobiology,Boston University School of Medicine, Boston, Massachusetts;Departments of cPsychology and eSpeech and Hearing Sciences,University of Washington, Seattle, Washington; dDepartment ofPsychology, Hebrew University of Jerusalem Mount Scopus,Jerusalem, Israel; fDepartment of Pediatrics, University ofCalifornia Davis MIND Institute, Sacramento, California; gYaleChild Study Center, New Haven, Connecticut; hGenomic MedicineInstitute, Cleveland Clinic, Cleveland, Ohio; iDivision ofDevelopmental and Behavioral Pediatrics, University ofMassachusetts Memorial Children’s Medical Center, Worcester,Massachusetts; jDepartment of Psychology, University ofConnecticut, Storrs, Connecticut; kGraduate School of Education& Information Studies, University of California Los Angeles, LosAngeles, California; lDepartment of Neurosciences, University ofCalifornia San Diego, La Jolla, California; mHarvard MedicalSchool and Massachusetts General Hospital for Children, Boston,Massachusetts; nDepartment of Psychology, University ofMassachusetts, Boston, Massachusetts; oIntegrated Center forChild Development, Newton, Massachusetts; pCenter for Autismand Related Disorders, Tarzana, California; qDepartment ofOccupational Therapy, Thomas Jefferson University, Philadelphia,Pennsylvania; rA.J. Drexel Autism Institute, Drexel University,Philadelphia, Pennsylvania; sUSC Mrs T.H. Chan Division ofOccupational Science and Occupational Therapy, Los Angeles,California; tBehavioral Development & Educational Services, NewBedford, Massachusetts; and uDepartment of Clinical Sciences,Florida State University College of Medicine, Tallahassee, Florida

ABBREVIATIONSASD—autism spectrum disorderIJA—initiating joint attentionMSEL—Mullen Scales of Early LearningRJA—responding to joint attention

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Despite efforts to increase awarenessof early signs of autism spectrumdisorder (ASD) and promote earlyscreening,1 as well as some evidenceof recent trends toward diagnosingyounger children (as reviewed byDaniels and Mandell2), several large-scale epidemiologic studies suggestthat the mean age of diagnosis inthe United States remains at ∼4 to5 years.3–5 Given that parents of chil-dren with ASD generally report initialconcerns before the child is aged 18 to24 months, considerable opportunityexists to shorten the stressful “di-agnostic odyssey” that many familiesexperience,6 maximize opportunitiesfor children with ASD to benefit fromearly intensive interventions, and fur-ther develop evidence-based interventionsfor this age group.7

For many years, much of what wasknown about the early signs of ASDwasinformed by parents’ descriptions oftheir initial concerns,8–10 as well asanalyses of early home videos.11–13

Rich insights from these data (com-plemented by experimental work thathelped delineate key foundational pro-cesses impaired in ASD, such as af-fect sharing and joint attention14,15)helped to inform the development ofASD-screening tools and surveillanceefforts by community health pro-fessionals.16 Over the past decade,important advances in research havebeen made into the early developmentof ASD, incorporating prospective re-search designs17 and new technologiesaimed at more precisely delineatingthe early emergence of ASD.18,19 Ad-vances have also been made in identi-fying potential biomarkers (eg, genetic,neuroimaging), although there areimportant clinical and ethical consid-erations regarding their potential ap-plication.20

These issues were the focus of an in-ternational, multidisciplinary panel ofclinical practitioners and researchers

with expertise in ASD and develop-mental disabilities that was con-vened inMarina del Rey, California, inOctober 2010. Aworking group (detailedin the Methods section) completeda literature review that informed therecommendations by the panel atthe meeting; these recommendationswere further refined by an updatedreview that was completed in December2013. The panel reached consensuson the following key question: “Whatare the earliest signs and symp-toms of ASD in children aged #24months that can be used for earlyidentification?”

METHODS

The Early Identification working groupcomprised Drs Stone, Yirmiya (co-chairs), Chawarska, Estes, Hansen,McPartland, and Natowicz. The work-ing group co-chairs and panel co-chairs (Drs Zwaigenbaum and Bauman)conducted a literature search onPubMed to identify relevant articles onearly features of ASD. The PubMedsearchwas conducted onJune 30, 2010,and used the search terms (“child de-velopmental disorders, pervasive” or“autistic disorder/” or autism [tw] orautistic [tw]) and (“early detection”or “early diagnosis”), with the agefilter “infant, birth–23 months” and lim-ited to English-language papers. Thissearch yielded 341 references, whichwere reviewed by Drs Zwaigenbaumand Bauman, who selected articlesthat focused on studies examining therelationship between early behavioralor biological markers in the first 24months of life and ASD diagnosis. Thesearch results were complemented byadditional publications identified byworking group members. Hence, al-though the search strategy was com-prehensive, selection of articles wasnot systematic, which is an importantlimitation. A scoping approach, withsome discretion by the multidisciplin-

ary expert working group, was usedinstead to select articles of highestrelevance and methodologic quality.

Members of the working group re-viewed the articles and evaluated theirmethodologic quality. In the absence ofa standard evaluative tool for suchresearch (eg, Grading of Recom-mendations Assessment, Developmentand Evaluation,21 which was used toevaluate the quality of evidence ofclinical intervention trials), assess-ment of evidence quality focused onstudy design (retrospective versusprospective), measurement (eg, use ofvalidated measures for both risk fac-tors and diagnostic outcomes), andwhether diagnostic outcomes weremeasured blinded to risk factor status.The working group also took intoconsideration whether findings werereplicated across independent lab-oratories. Panel recommendationswere based on this evaluative frame-work. During the conference, theworking group offered draft recom-mendations for discussion, modifica-tion, and ratification by all attendees.Electronic voting was used to expressopinions and guide consensus building.Amodified nominal group techniquewasused to review the recommendations,with consensus reached by$1 round ofvoting. The consensus statements anddiscussion were summarized as draftproceedings of the conference, whichwere subsequently edited by all partic-ipants. Some of the statements providedhere are intended to summarize thestate of the literature, whereas othersare in the form of recommendations forresearch needed to fill important gapsoraimed at addressing issues critical forclinical practice.

To ensure that the final article reflectedrecent literature, thesearchwasupdatedby using the same strategy to addarticles published to December 31,2013; this search yielded an additional202 references. Evidence tables and text

SUPPLEMENT ARTICLE

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references were updated with findingsfrom prospective studies on early be-havioral or biological markers. Theworking group reviewed and approvedthe final wording of the summary andrecommendations.

SUMMARY STATEMENTS

Statement 1: Evidence indicatessubstantial heterogeneity in thepresentation and natural history ofclinical features associated withASDs. This heterogeneity hasramifications for the interpretationof research literature as well asfor clinical practice.

There is heterogeneity not only inthe etiology, neurobiology, onset, andcourse of core clinical ASD symptomsbut also in the rates and levels ofcognitive and language development,adaptive functioning, and co-morbiditywith other disorders. Given the tre-mendous clinical diversity evidentamong subjects with ASD across thelife span, it is not surprising to findthat early manifestations and de-velopmental course vary as well. Somechildren with ASDs are described ashaving behavioral differences (eg, inreactivity and social orienting) from theearliest months of life, whereas otherspresentwith speechdelay in the secondyear, and still others are described asbecoming withdrawn and losing skillsafter a period of relatively typical de-velopment into the second year of life.22–24

There is also heterogeneity at an etio-logic level, with hundreds of suscepti-bility genes25 and potentially a widerange of environmental and/or epige-netic factors26–28 implicated in ASDcausation. The variability in behavioralprofiles, developmental course, andunderlying etiologic factors must betaken into account when synthesizingfindings across studies. There arealso methodologic differences thatmay affect comparability across stud-ies (eg, prospective versus retrospec-

tive designs, measurement strategies,ages at which early signs and out-comes are examined).

Statement 2: There is evidence thatreduced levels of social attentionand social communication, as wellas increased repetitive behaviorwith objects, are early markers ofASD between 12 and 24 months ofage. Additional potential markersinclude abnormal body movementsand temperament dysregulation.

ASD is not commonly diagnosed until3 to 4 years of age.29 However, manyparents express concerns to their pe-diatrician by the time their child isaged 18 months.30,31 In addition toparent reports, potential early mark-ers have been identified according toretrospective analyses of home videosand prospective longitudinal studies ofinfants in the general population, aswell as assessment of high-risk infantsand toddlers who have an older siblingwith ASD.

Studies directed toward the identifica-tion of early clinical diagnosticmarkersof ASD have examined atypicalities inthe core domains of social communi-cation and social interaction, as well asthe presence of repetitive behaviors.There is strong evidence (ie, replicationin multiple samples by independentgroups) to support impairments insocial attention and social communi-cation as potential markers of ASDbetween the ages of 12 and 24 months(Table 1)32–56 as well as evidence foratypical object use during this sameage period.57,58

When concern about any of thesebehaviors is conveyed by parents orobserved by other care professionals(eg, a health care provider such ascommunity physician or nurse, de-velopmental service provider, or earlychildhood educator), it is recommendedthat the child be referred for furtherautism screening and, as appropriate,

for a more comprehensive developmen-tal and diagnostic evaluation.

Early marker: reduced levels of socialattention and social communication

Social attention and social communi-cation behaviors indicative of ASD in-clude decreased response to one’sname being called (ie, “orienting toname”), reduced visual attention tosocially meaningful stimuli, and lessfrequent use of joint attention andcommunicative gestures.

Reducedorienting toname is frequentlyidentified by parents of children withASD as 1 of their earliest concerns,8,59

and it has been identified in severalprospective studies of at-risk infantsas a robust early marker of the di-agnosis.32,38,42,45 There is some evidenceto suggest that decreased orienting toname can differentiate children witha later ASD diagnosis not only fromtypically developing children but alsofrom children with other developmentaldelays/disabilities.42,60

Toddlers with ASD also exhibit a re-duced tendency to visually examinesociallymeaningful stimuli. Eye-trackingtechnology provides a unique opportu-nity to understand visual attention inASD and can accurately measure pointof gaze with ,1 degree of error.Studies of toddlers with ASD reportreduced monitoring of social sceneseven with an explicit dyadic cue (ages13–25 months)61 and a preference forvisually examining geometric shapesrather than images of children (ages14–42 months).40

Attention in ASD is often abnormal notjust in terms of what toddlers with ASDprefer to look at but also how they at-tend to their world. “Joint attention”refers to the development of specificskills that enable sharing attentionwith others through pointing, showing,and coordinating looks between objectsand people; joint attention skills are as-sociated with language acquisition.47


TABLE1

Selected

Studiesof

PotentialMarkers

Identifying

ASDin

ChildrenAged

12to

24Months

Reference

Findings

Type

ofStudy

Sample

Ascertainm

ent

Outcom

eDiagnosis

Comments

Social/emotionalbehavioralm

arkers

(fromstudieswith

outcom

eassessments)

Bryson

etal,32

2007

Atages

12–24

mo,2broadly

definedASDsubgroups:

Prospective

case

series

9SIBS-Alaterdiagnosedwith

ASD

Recruitedfrom

multidisciplinaryautism

diagnosticandtreatm

ent

centers

Goldstandard

diagnostic

assessmentfor

ASDatage36

mousingADI-R,ADO

S,and

DSM-IV-TRcriteria

ClinicaldiagnosisofASDfor

4childrenat24

moandfor

3childrenat30

mo

Assessmentsevery6

mo

from

age6to24

mo,

including:

•Decrease

inIQfrom

average/

near

averagetosevere

cognitive

impairment,with

ASDsignsem

erging

earlier

ormorestriking

earlier

•AOSIand/or

ADOS

toassess

forASD

symptom

s

•Continuedaverageor

near

averageIQ

•BSID-IIto

assess

cognition

Inall9

subjects,social-

communicativeimpairments

coexistedwith

atypical

sensoryor

motor

behaviors

andtemperamentp

rofileof

irritability/distress

and

difficulties

with

self-or

other-

regulationofstate

•CDI-W

Gtoassess

gesturalandearly

language

developm

ent

•Infant

Temperament

Scaleor

Toddler

Behavior

Assessment

Questionnaire

toassess

temperament

•Semi-structured

interviewsregarding

parentalconcerns

Fodstadetal,33

2009

Atages

17–37

mo:

Prospective

•161childrenwith

ADEnrollees

instate-funded

early

interventionprogramfor

childrenwith

developm

ent

delayor

medicalcondition

likelytoresultin

adevelopm

entaldelay

DiagnosisofAD

orPDD-NO

Sbasedon

DSM-IV-TRcriteria,

M-CHAT,andBattelle

Developm

entalInventory–

2ndedition

•BISCUIT–Part1

(20-itemsocial/

nonverbal

communication

subscaleand7-item

communication

subscale)toassess

autismsymptom

sin

one-to-one

parent

interviewsalongwith

child

observation

•Deficitsincommunications

andsocialskillsmore

obviousandpronounced

inAD

versus

othergroups

•140childrenwith

PDD-NO

S

•GreaterdeficitsinPPD-NO

Sversus

controls

•585controls:childrenatrisk

forotherdevelopm

ental

delays

ortohave

disorder

such

asDownsyndromeand

cerebralpalsy

•5of20

itemson

socialization/

nonverbalcom

munication

subscalediscriminated

betweengroups

a

•5of7itemson

communication

subscaleweremost

predictiveofdiagnostic

groupb

Aged

17–37

mo

SUPPLEMENT ARTICLE


TABLE1

Continued

Reference

Findings

Type

ofStudy

Sample

Ascertainm

ent

Outcom

eDiagnosis

Comments

Garonetal,34

2009

At24

mo,childrenwith

later

diagnosisofASDwere

distinguishedfrom

non-ASD

siblings

andcontrolsby:

Prospective

•138high-riskinfants(SIBS-A)

Enrolledinlarger

study;

recruitedthroughautism

diagnosticandtreatm

ent

centers

Goldstandard

diagnostic

assessmentfor

ASDat36

mo

basedon

ADI-R,ADO

S,DSM-IV-TRcriteria

•TBAQ-Rto

assess

temperament

(parentreport)at

24mo

•Temperamentp

rofile

(“effortfulemotion

regulation”)oflower

positive

affect,highernegativeaffect,

anddifficulty

controlling

attentionandbehavior

Ongoing(N

=211

with

data

collected

atage24

mo)

•73

low-riskinfants(nofamily

historyofASD)

34of138SIBS-A(24.6%

)diagnosedwith

ASD

•MSELat24

and36

mo

•Lower

sensitivityto

social

rewardcues

(low

“behavioral

approach”)

84%and80%,respectively,

enrolledinstudyatage6mo;

restby

age12

mo

TwoASDsubgroups

distinguishedby

numberof

ASDsymptom

s,IQ,age

atdiagnosis,Behavioral

Approach

profile

Goldberg

etal,35

2005

Atages

14–19

mo,significant

groupdifferences

in3of4

socialandcommunication

behaviorsbetweenASDand

TDchildrenbutnotb

etween

ASDandSIBS-Achildren:

Prospective

•8childrendiagnosedwith

ADor

PPD-NO

Saged

21.0–33.0mo

From

larger

sampleoffamilies

participatinginautismstudy

atuniversitymedicalcenter;

controlsfrom

community

volunteersample

Forsubjectsrecruitedas

partof

largerstudy,ADI-R

andADOS-G

wereadministered;controls

werescreened

byusingCARS

ESCS

(abridgedversion)

structured

interactions

videotaped

and

codedtoassess

socialinteraction,

jointattention,and

behavioralregulation

•Responsesto

social

interactionbids:less

frequent

eyecontact,

gestures,and

turn-taking

(P,

.05)

•8SIBS-Aaged

14.0–19.0mo

•Initiationofjointattention:

fewer

nonverbalbehaviors

toinitiateshared

experiencesof

objectsor

events(P

,.001)

•9childrenwith

TDfrom

families

withoutASD

aged

10.0–19.0mo

•Differences

infrequency

ofrequestingbehaviors

(P,

.05)

•No

significant

differences

inresponsestoJA


TABLE1

Continued

Reference

Findings

Type

ofStudy

Sample

Ascertainm

ent

Outcom

eDiagnosis

Comments

Mosconietal,36

2009

In2-y-olds

with

AD:

Longitudinal

MRIstudy

•50

childrenwith

ADChildrenwith

ADrecruitedafter

receivingclinicaldiagnosisor

whileaw

aitingclinical

evaluation

DiagnosisofAD

confirm

edat2y

andreassessed

at4ybyu

sing

ADI-R,ADO

S,DSM-IV

criteria;

controlsscreened

with

CARS

•ADOS

sessions

videotaped

and

codedby

usinganew

scale(SOC-RS)

toratesocialorienting

andcommunications

behaviors,including

IJA,RJA,and

nonverbalgestures

•Am

ygdalaenlargem

entthat

persistedthroughage4y

(16%

larger

volumes

than

incontrols)

Ongoing

•33

controls(11with

developm

entaldelay

and22

with

TD)

Details

ofsubjectascertainment

describedinHazlettetal,3

7

2005

•RepetitiveBehavior

Scale–Revisedto

assess

specificityof

hypothesized

relationshipbetween

amygdalaandJA,

investigated

onlyin

childrenwith

AD

Aged

2y(18–35

mo)

Nadigetal,38

2007

Atage12

mo,failure

torespond

tonameishighlysuggestiveof

developm

entalabnormality

Prospective

longitudinal

study

•101at-riskinfants(SIBS-A)

Enrollees

inuniversity-based

study

ClinicalbestdiagnosisofAD

orPDD-NO

Sat24

mobasedon

clinicalobservation,ADOS,

andDSM-IV

criteria

•Subjectsfollowed

uptoage36

mo

•86%ofat-riskinfants

respondedtofirstorsecond

namecallvs100%

ofcontrols

Ongoing

•46

infantsatno

know

nrisk

(SIBS-TD)

12childrenwho

failedto

respondtonameat12

mo

have

outcom

edata:ADand

PDD-NO

Sin5,otherdelaysin4,

TDin3

•MSELtoassess

developm

ent

•Failure

torespondtonameat

age12

mohighlyspecificfor

24-mooutcom

eof

developm

entaldelay,

includingASD

Aged

12mo

•ADOS

tomeasure

socialand

communicative

behaviors

•Response-to-nam

eexperimentaltask

videotaped

at6and

12moandcodedfor

numberofcalls

ittook

forresponse

tochild’sname

SUPPLEMENT ARTICLE


TABLE1

Continued

Reference

Findings

Type

ofStudy

Sample

Ascertainm

ent

Outcom

eDiagnosis

Comments

Osterlingetal,39

2002

At1y,infantswith

ASD:

Retrospective

videostudy

•20

infantswith

laterdiagnosis

ofAD

(35%

ofsample)or

PPD-

NOS

Recruitedfrom

university

subjectpools,stateautism

society,Division

ofDevelopm

entalDisabilities,

localnew

spaper

andlocal

radioadvertisem

ents,local

schools

ADor

PPD-NO

Sdiagnosis

confirm

edatstudyentryon

basisofDSM

-III-R

plus

scoreof

$30

onCARS

Homevideos

offirst

birthday

parties

codedby

blindraters

onfrequenciesof

specificsocialand

communicative

behaviorsand

repetitivemotor

actions

•Look

atothers

less

frequently

•14

infantslaterdiagnosed

with

MR(withoutASD

and

withoutd

istinguishing

physicalanom

alies)

•Orient

totheirnames

less

frequentlythan

infantswith

mentalretardation:

•20

infantswith

TD

At1y,infantswith

ASDor

MR:

Aged

2.5–10

yat

timeofstudy

•Usegestures

less

frequently

•Look

toobjectsheldby

others

less

frequently

•Engage

inrepetitivemotor

actions

morefrequentlythan

infantswith

TDOzonoffetal,2

22010

Byage12

mo,significant

differencesbetweenASDandTD

groups

infrequencyofgazeto

facesanddirected

vocalizations

(although

notat6

mo)

Prospective

longitudinal

study

•25

high-riskinfantswith

later

diagnosisofAD

orPDD-NO

S(22wereSIBS-A)

Sampledraw

nfrom

larger

longitudinalstudy

Classificationas

ASDor

TDat36

moby

usingBaby

Siblings

Research

Consortium

definitions

(ADO

SandDSM-IV-

TRcriteriaforAD

orPDD-NO

S)

Assessmentsatages6,12,

18,24,and36

moof:

By18

mo,significant

group

differences

onallsocial

communicationvariables

(see

Comments)

•25

gender-matched

SIBS-TD

determ

ined

latertohave

TD•Frequenciesof6social

communication

behaviors(gazeto

faces,gazetoobjects,

smiles,nonverbal

vocalizations,single-

wordverbalizations,

phrase

vocalizations),

recorded

ontoDVDs

andcodedduringMSEL

visualreceptionsubtest

Between6and18

mo:

•Frequencyofinfant

socialengagement

ratedby

blind

exam

iners

•Decliningtrajectories

ofsocial

communicationbehavior

and

loss

ofskillsinmostinfants

with

laterASDdiagnosis

•MSELtoassess

cognitive

functioning

•Increase

incognitive

and

language

skills(M

SELraw

scores)over

timeinboth

groups,w

ithsignificantly

slow

ergrow

thinASD

startingat12

mo

•Symptom

onsetby

parent

reports


TABLE1

Continued

Reference

Findings

Type

ofStudy

Sample

Ascertainm

ent

Outcom

eDiagnosis

Comments

•Discrepancyinautism

symptom

onsetwith

parent

reports

Pierce

etal,40

2011

•Toddlerswith

anASDas

young

as14

mospentsignificantly

moretim

efixatingon

geom

etricimages

than

onsocialimages

Prospective

longitudinal

study

•37

with

ASD

Samplerecruitedfrom

general

populationscreening

approach

startingat

12mo

andcommunity

referral


orPDD-NO

Sat$24

mobasedon


andDSM-IV

criteria

•1-mineye-tracking

testused

tomeasure

visualattention

•Individualvisualfixationlevels

couldbe

used

todiagnosticallyclassify

atoddleras

having

ASDat

100%

accuracy

level

•22

with

DD•Diagnosisconfirm

edby

experienced

diagnostician

blindedto

eye-

tracking

testresults

•Toddlerswith

ASDwho

visually

exam

ined

geom

etricimages

exhibitedsignificantlyfewer

saccades

whenlookingat

geom

etricimages

than

other

toddlers

•51

with

TD•MSELandVABS

used

tomeasure

cognitive

andadaptive

behavior

Sullivanetal,41

2007

Byage14

mo,childrenlater

diagnosedwith

ASDor

broaderautismphenotype

haddeficitsinRJA

Prospective

51high-riskchildren(SIBS-A)

who

received

outcom

eassessments:

Subsam

pleofsubjectsoflarge

study;recruitedthroughASD

advocacy

group,schools,

wordofmouth

Outcom

eassessmentat30(n

=7)

or36

(n=44)mo;

diagnosisofAD

orPDD-NO

Sbasedon

ADOS,DSM

-IVcriteria;BAP=language

and/

orsocialdelays

withoutASD

diagnosis

RJAbids

werecoded

from

videotapes

of3measures

administeredatages

14and24

mo:

Between14

and24

mo,children

with

ASDhadminimal

improvem

entinRJA,unlike

with

BAPandnon-BAP

•AD

(n=13)orPDD-NO

S(n

=3)

•“Lookonly”trials

adaptedfrom

Butterworth

and

Jarrett,1991

97

Significant

(P,

.01)

group

differences

inRJAat24

mo

•BAP(n

=8)

•Look

+pointtrials

from

CSBS

DPRJAat

14mopredictedASD

outcom

e•Non-BAP(n

=27)

•RJAitemfrom

ADOS

Wetherbyetal,42

2004

During

second

year

oflife,9

prelinguistic

behaviorsserve

asredflagstodistinguishASD

from

DDandTD:

Prospective

•18

childrenwith

later

diagnosisofAD

orPDD-NO

SRecruitedtolarger

study

Best-estimatediagnosisofAD

orPDD-NO

Smadebetweenages

30moand5ybasedon

MSEL;

VABS,Interview

Edition,

Survey

Form

;and

ADOS

•Directobservation

withinstandardized

Behavior

Sample,

videotaped

and

scored

byusing

standard

CSBS

DPprocedures

•7relatedtosocialand

communicationsymptom

scOngoing

•18

with

DDwithoutASD

•Behavior

Sample

videotaperecodedby

usingSORF

scoring

•2relatedtorepetitive

movem

entswith

objectsand/

orbody

parts

•18

with

TD

Aged

13.0–26.9moat

Behavior

Sample

SUPPLEMENT ARTICLE


TABLE1

Continued

Reference

Findings

Type

ofStudy

Sample

Ascertainm

ent

Outcom

eDiagnosis

Comments

4additional“redflags”

differentiatedASDfrom

TDbutn

otfrom

DDd

Yoderetal,43

2009

Latersocialimpairmentand

laterASDdiagnosispredicted

by:

Prospective

longitudinal

correlational

design

•43

SIBS-A

Participantsofanotherstudy;

SIBS-Arecruitedfrom

university-based

autismand

speech-language

programs

andcommunity

agencies;

SIBS-TDthroughbirthrecord

database

andwordofmouth

ASDdiagnosisassessed

∼1.5y

afterstudyentry(ie,afterage

30mo)usingADOS,ADI-R,and

DSM-IV-TRcriteria

•Hierarchicallinear

modelingtoassess

grow

thinearlysocial

skills(ie,RJAand

WTC)aspredictors

ofsocialimpairmentin

SIBS-A

•InitiallevelofR

JA(atage

15mo)

•24

age-matched

SIBS-TDwho

provided

socialoutcom

ebenchm

arks

ASDdiagnosedin6(ADin3and

PDD-NO

Sin3)

•RJA

andWTC

assessed

at4tim

epoints4mo

apart;RJA,WTC,and

SBCassessed

attim

e5,6moafterfourth

measurement(ie,

afterage30

mo)

•Grow

thrateofweighted

triadiccommunication(from

ages

15–34

mo)

Aged

12–23

moatstudyentry

•Weightedfrequencyof

unprom

pted

triadic

communications

derivedfrom

STAT

At30

mo,delayinRJAandmore

generalsocialskills

inSIBS-A

butlarge

variationinsocial

outcom

escores

•Experimentaltask

describedin

Presmanes

etal,44

2007,toassess

RJA

•SBCtoassess

social

behaviorsby

parent

report

Zwaigenbaum

etal,45

2005

Byage12

mo,infantswith

later

diagnosisofautismmay

bedistinguishedfrom

other

siblings

andcontrolsby:

Prospective

longitudinal

study

•65

SIBS-A

Recruitedmainlyatage#6mo

from

autismdiagnosticand

treatm

entprogram

s;low-risk

infantsrecruitedfrom

nurseriesinsameregions

Form

alindependentdiagnostic

assessmentat36mobased

onDSM-IV

criteria,ADI-R,and

ADOS

•AOSIat6and12

moto

assess

autism-

specificbehaviors

•Behavior

markers

eOngoing(N

=88

followed

upto

age24

mo)

•23

low-riskinfants(nofirst-or

second-degreerelatives

with

ASD)

ClinicaldiagnosisofASDmadeat

24moinup

to7SIBS-Awho

metDSM-IV

criteria

(confirm

edby

usingADI-R

and

ADOS)

•ADIS(24mo)toassess

autism-related

social

communication

impairments

•Prolongedlatencyto

disengagevisualattention

(startingafter6mo)

“Roughly”matched

bygender,

birthorder,andage;Nvalues

varied

byassessment

•Computerizedvisual

orientingtask

(6and

12mo)

toassess

abilityto

disengage

from

1of2

competingvisual

stimuli(attentional

disengagem

ent)


TABLE1

Continued

Reference

Findings

Type

ofStudy

Sample

Ascertainm

ent

Outcom

eDiagnosis

Comments

•Temperamentp

rofilef

Available12-mooutcom

edata

for65

SIBS-A:

•IBQ(6and12

mo)

and

TBAQ

(24mo)

tomeasure

infant

temperament

•Delayedexpressive

and

receptivelanguage

•7with

AD•MSEL-ABS

edition

and

CDI-W

G(12mo)

toassess

language

and

cognitive

developm

ent

•12

with

ASDclassificationon

ADOS

•46

withoutASD


arkers

(fromstudieswithoutoutcomeassessments)

Macarietal,4

62012

Atage12

mo,lack

ofattention-

sharingbehaviors,including:

Prospective

•53

SIBS-A

Recruitedfrom

university

research

programs,Web

site,

advertising,wordofmouth

ProvisionalCBE

diagnosisatage

24mo

•ADOS-Tadministered

at12

and24

moand

analyzed

byusing

nonparam

etric

decision-tree

learning

algorithms

•Show

ing

•31

low-riskinfants(noASD

historyinfirst-or

second-

degree

relative)

Diagnosisnotd

oneat36

mo

•MSELto

assess

developm

entalstatus

•IJA

64%male,enrolledby

age6mo

CanpredictASD

orother

atypicaldevelopm

entatage

24mo

Variouscombinations

ofsocial

communicativefeatures

associated

with

ASD

presentationat24

mo

Presmanes

etal,44

2007

Insecond

year

oflife,SIBS-A

show

edimpaired

RJArelative

toSIBS-TDacross

rangeof

prom

pttypes

Prospective

•46

SIBS-A

SIBS-Arecruitedfrom

regional

multidisciplinaryevaluation

andspeech

language

centers,

statebirth-to-3service

network,autismparent

groups,and

university-based

autismserviceandoutreach

program;SIBS-TD

recruited

from

birthrecords

“Notyetavailable”

•RJAtask

administered

with

different

combinations

ofverbalandnonverbal

cues;w

hennumberof

attentionalcueswas

increased;andwhere

multipleobjectsor

eventscompetedfor

child’sattention

Attentiondisengagem

ent

similarfor2groups

Ongoing

•35

SIBS-TD

•20

RJAtrialsper

subjectw

ere

videotaped

andcoded

Aged

12–23

mo

•MSELcognitive

scales

administered

•STAT

toassess

social

communicative

behaviors

SUPPLEMENT ARTICLE


TABLE1

Continued

Reference

Findings

Type

ofStudy

Sample

Ascertainm

ent

Outcom

eDiagnosis

Comments

Stoneetal,47

2007

Atages

12–23

mo,weaker

performance

bySIBS-Ain:

Prospective

•64

SIBS-A

SIBS-Arecruitedfrom

university-

basedautismandspeech-

language

programsand

community

agencies;SIBS-TD

recruitedfrom

birthrecord

database,university-based

research

programs,and

community

agencies

Notknown

Child-based

andparent

reportmeasures:

•Nonverbalproblemsolving(ie,

visualreception)

•42

SIBS-TD

•MSELto

assess

cognitive

function

•Directingattention(ie,IJA)

Aged

12–23

mo(m

ean:16

mo)

•CARStoassess

autism

symptom

s•Understandingwords

and

phrases

•STAT

toassess

play,

requesting,directing

attention,andmotor

imitation

•Gestureuse

•MCDIquestionnaire

toassess

verbaland

nonverbal

understandingand

expression

•Socialcommunicative

interactions

with

parents

•DAISItoassess

social

engagement

behaviors

Increasedautismsymptom

sin

SIBS-A

Significant

correlations

betweenchild-based

measuresandparentreports

Yirm

iyaetal,48

2006

Atage14

mo,SIBS-A:

Prospective(N

=61

with

14-mo

assessments)

•30

SIBS-A

Sibs-Arecruitedfrom

treatm

ent

centers,specialschools,and

contactswith

families

ofchildrenwith

ASD

Atage14

mo,1subjectwas

suspectedofhaving

autism,

adiagnosisconfirm

edatages

24and36

moby

usingADI-R

andADOS-G

Measuresat

age4and

14mo:

•Initiated

fewer

nonverbal

requestinggestures

•31

SIBS-TD

Comparisongrouprecruited

from

hospitalm

aternity

wards

•BSID-IIto

assess

generaldevelopment

andlanguage

•Achieved

lower

language

scores

(accounted

forby

5-molanguage

delayin6SIBS-

A)than

SIBS-TD

Matched

on1-to-1basis

accordingtochronologicage,

gender,birth

order,number

ofchildreninfamily,and

Bayley

mentaland

motor

scales

•ICQtoassess

maternalperception

ofinfant

temperament

Communicationand

cognition

measures

atage14

mo:

Ingeneral,mostS

IBS-A

functionedwell

•ESCS

toassess

nonverbal

communicationskills

•CHAT

toassess

JAbehavior


TABLE1

Continued

Reference

Findings

Type

ofStudy

Sample

Ascertainm

ent

Outcom

eDiagnosis

Comments

Language/com

municationbehavioralmarkers

(fromstudieswith

outcom

eassessments)

Landaand

Garrett-M

ayer,49

2006

By14

moofage,significantly

worse

performance

infine

motor,gross

motor,and

receptiveandexpressive

language

(ASD

versus

unaffected)

Prospective

longitudinal

•24

childrenwith

later

diagnosisofASD

SIBS-ArecruitedthroughAutism

SocietyofAm

ericalocal

chapters

anduniversity-

basedcenter

forautism;

childrenatlowautismrisk

recruitedthroughlocal

physicianofficesand

caregiver/child

play

groups

ASDclassified

at24

mobasedon

PLS,ADOS,and

MCDI

•MSELto

assess

generaland

language

developm

entacross

5domains

ofnonsocial

developm

ent(gross

motor,fine

motor,

visualreception,

receptiveand

expressive

language);

administeredas

closeas

possibleto

ages

6,14,and

24mo

By24

mo,significantlyworse

performance

inall5

domains

(ASD

versus

unaffected)and

significantlyworse

performance

ingrossmotor,

fine

motor,and

receptive

language

(ASD

versus

LD)

•11

with

laterdiagnosisof

language

delay

•PLS-IIIor

PLS-IVat

24moforreceptive

andexpressive

standard

scores

and

ageequivalences

Slow

erdevelopm

ental

trajectory

inASDgroup

versus

othergroups,w

ithsignificant

declinebetween

firstand

second

birthdays

•52

classified

asunaffected

(at

24mo)

•CDIat14and24

moto

assess

child’s

understandingand

productionof

language

Enrollees

enteredstudyas

SIBS-

Aandinfantswith

nofamily

historyofidiopathicautism

Olleretal,50

2010

From

∼1yofage,vocalizations

from

childrenwith

autismor

language

delaycanbe

differentiatedfrom

children

with

TDby

automated

analysisofselected

acoustic

features

Prospective

•77

childrenaged

16–48

mo

with

ADor

PDD-NO

SRecruitedthrough

advertisem

ents

PhaseI:childrenwith

reported

diagnosisoflanguage

delay

evaluatedby

speech-

language

clinician.PhaseII:

documentationofdiagnosis

from

outsideclinician,plus

failure

onM-CHAT

•PhaseI(2006–2008)

andPhaseII(2009)

studiestoassess

automated

methodto

determ

inepresence

orabsenceof12

acousticparameters

onchild

vocalizations;

parametersreflect

rhythm

ic/syllabic

articulationand

voice

•49

childrenaged

10–44

mo

with

language

delaywithout

autism

•Analysisof1486

all-

dayrecordings

•106childrenaged

10–48

mo

with

TD

SUPPLEMENT ARTICLE


TABLE1

Continued

Reference

Findings

Type

ofStudy

Sample

Ascertainm

ent

Outcom

eDiagnosis

Comments

Language/com



Gamlieletal,5

12007

At14

and24

mo,cognitiveand/or

language

delays

($2SDs

belowaverageon

measures)

inSIBS-Asubsets,compared

with

otherSIBS-AandSIBS-TD

Prospective

•39

SIBS-A

Recruitedthroughtreatm

ent

centers,specialschools,

nationalautismorganization,

families

ofchildrenwith

autism;com

parisongroup

recruitedfrom

hospital

maternitywards

Notknown

•BSID-IIat

4,14,and

24motoassess

developm

ent

Atages

14–36

mo,cognitive

and/or

language

difficulties

in11

of39

SIBS-Avs

2SIBS-TD

Ongoing(N

=78

with

developm

ental

trajectories

toage

54mo)

•39

SIBS-TD

•RD

LS(24mo)

toassess

expressive

andverbal

comprehension

By54

mo,cognitive

differences

gone,butsomedifferences

inlanguage

ability(receptive

andexpressive)remained

Matched

atage4moon

1-to-1

basisaccordingto

chronologicage,gender,birth

order,numberofchildrenin

family,tem

peramentp

rofile,

andmentaland

motor

scales

•K-ABC(36and54

mo)

toassess

intelligence

Mostsiblings

with

language

impairmentsatage14

mo

functioning

wellat54mo

withoutintervention

•ClinicalEvaluationof

Language

Fundam

entals–

Preschool(36

and

54mo)

•Parent

questionnaire

regardingclinical

andeducational

services

(24,36,and

54mo)

•Thisisafollow-up

reportto

Yirm

iya

etal,48

2006

Markers

ofmotor

dysfunction(fromstudieswith

outcom

eassessments)

Esposito

and

Venuti,522008

Atage∼20

mo,boyswith

ADhad:

Retrospective

videostudy

•16boysmeanage20.2mowith

ADRecruitedfrom

referralsto

university-based

center

for

developm

entaldisabilities

ADdiagnosisbefore

study

confirm

edby

usingDSM-IV

criteriaandADOS

•Analysisofhome

videos

takenafter

6moofindependent

walking

•Different

distributions

inWOS

scores

from

othergroups

•10

boys

meanage21

mowith

mentalretardation

•WOS

used

tocode

videos

byassessing

gaiton

3axes:foot,

arm,and

global

movem

ents

•Different

gaitpatterns:

problemswith

heel-to-toe

pattern,moreasym

metric

postureofarmwhilewalking,

higher

frequencyofgeneral

movem

entanomalies(eg,

“waddlingwalk”)

•16boysmeanage20.5mowith

TDAD

andMRgroups

matched

bychronologicaland

developm

entalages

Esposito

etal,53

2011

Aged

,2y,significant(P#.001)

differences

ingaitpatternin

toddlers

with

ADversus

TDandDD

:

Retrospective

videostudy

•20

toddlers

with

ADRecruitedfrom

2nationw

ide

referralcentersfor

developm

entaldisabilities

ClinicaldiagnosisofAD

basedon

DSM-IV-Randconfirm

edby

usingADI-R,ADO

S-G,andCARS

Analysiswhentoddlers

werefirstw

alking

withoutassistance


TABLE1

Continued

Reference

Findings

Type

ofStudy

Sample

Ascertainm

ent

Outcom

eDiagnosis

Comments

•Higher

levelsofpostural

asym

metry

during

walking

•15

toddlers

with

nonautistic

DD•Homevideos

taken

whenchild

was

aged

,2y(plusallfootage

within2-hwindow)

•Someatypicalarmandfoot

movem

entsduring

walking

•20

toddlers

with

TD•WOS

tocode

videos

byassessinggaiton

3axes:foot,arm,and

globalmovem

ents

Meanages

12.9–14.2mowhen

firstwalking

without

assistance

•PPSW

toassess

static

anddynamical

symmetryduring

gait

Matsonetal,54

2009

Atages

17–37

mo:

Prospective

•140infantswith

ADEnrollees

ofstate-funded

early

interventionprogramforDD

sAD

andPDD-NO

Sdiagnoses

basedon

DSM-IV-TRcriteria,

M-CHAT,andBattelle

Developm

entalInventory–

Second

Edition

developm

entalprofile

•BISCUITPart1—

specifically

the

repetitivebehavior/

restricted

interests

subscale—toassess

forASDsymptom

s•Stereotypies

andrepetitive/

ritualistic

behaviorswere

mostcom

mon

inAD,followed

byPDD-NO

Sandthen

other

DDS

•121with

PDD-NO

S•Child

observationand

1-to-1parent

assessment;

administeredas

part

ofbatteryof

assessmentsof

physicalandsocial

developm

ent

•Striking

differences

across

groups

inlim

itednumberof

interests,engagesin

repetitivemotor

movem

ents

forno

reason,eye-to-eye

gaze,m

aintains

eyecontact

•499atrisk

forDD

butno

ASD

diagnosis

•BISCUITsubsetcould

accuratelypredictd

iagnostic

groupmem

bership

Aged

17–37

mo(m

ean:26.63

mo)

Ozonoffetal,57

2008

Atage12

mo:

Prospective

•35

SIBS-A

Recruitedfrom

SIBS-AandSIBS-

TDDiagnosisat24

(n=29)or

36(n

=37)mobasedon

ADOS,

SCQ,andDSM-IV

criteria

Mannerinwhich

infants

exploreobjectswas

exam

ined

intask

that

afforded

rangeof

repetitiveuses

•Atypicaluses

ofobjects

(spinning,rotating,and,

especially,unusualvisual

explorationofobjects)

significantly(P

#.005)more

frequent

ininfantswith

ASD

comparedwith

othergroups

•31

inSIBS-TD

For37

with

outcom

edataat24

and36

mo,31

(83.8%

)had

the

sameclassifications

atboth

ages;the

laterclassification

was

used

inanalyses

•Four

objects

presentedtothe

infant,1

atatim

e,for

30seach

•Repetitivebehaviors

significantlyrelatedto

Aged

12mo,with

following

outcom

es:

•Behavior

recorded

onDVD

•9with

ASDdiagnosis

SUPPLEMENT ARTICLE


TABLE1

Continued

Reference

Findings

Type

ofStudy

Sample

Ascertainm

ent

Outcom

eDiagnosis

Comments

cognitive

andsymptom

status

at36

mo

•8objectuses

codedby

blindedraters

aseither

frequencyor

duration;4

hypothesized

astypicaland

age-

appropriateand4as

atypicalh

•10

with

laterdiagnosisof

otherdelays

g

•47

with

noconcerns

(didnot

meetcriteriaforother

groups)

Ozonoffetal,55

2008

During

first2

yofage:

Retrospective

videostudy

•26

childrenaged

26–61

mo

with

nonregression-type

AD82

recruitedfrom

university-

basedrecruitm

entcoreand

localagenciesserving

individualswith

developm

entaldisabilities;21

recruitedinanothercityfrom

ongoingstudiesand

universitysubjectpool

DiagnosisofADorPDD-NO

Sinthe

community

confirm

edat

studyentry;AD

diagnosis

basedon

ADI-R

plus

ADOS;

regression

versus

noregression

subgroupsbased

onADI-R

•Participantsseen

atinitialenrollm

ent

(whenallhom

evideos

ofchild

from

birthto

age2ywere

collected)and1–2y

laterforassessment

batterythatwas

part

ofanotherstudy

•Neither

regression

nor

nonregressiontypesofAD

differedfrom

TDinratesof

movem

entabnormalities

orlack

ofprotectiveresponses

•28

childrenaged

26–61

mo

with

regression-type

AD•Videos

codedfor

motor

maturity,

protective

responses,and

movem

ent

abnorm

alities

byusingInfant

Motor

Maturity

and

Atypicality

Coding

Scales

•Toddlers

with

nonautistic

DDdisplayedhigher

ratesof

movem

entabnormalities

insittingandproneandfewer

protectiveresponsesin

craw

lingthan

othergroups

•25

with

nonautistic

DDmatched

forchronologicand

developm

entalage

•24

with

TD

Provostetal,56

2007

Atages

21–41

mo:

Prospective

•19

childrenaged

21–41

mo

with

ASD

Recruitedfrom

referralsto

university-based

early

childhood

evaluation

programfordevelopm

ental

disabilities

ASDdiagnosismadeby

study

team

evaluation

•BSID-IIMotor

Scaleto

assess

motor

skills

•Motor

dysfunctiontosome

degree

inallchildrenwith

ASD(delay

ingrossand/or

fine

motor

skills)

•19

with

otherDD

including

motor

delay

DiagnosisofAD

in18,PDD

-NOS

in1

•PDMS-2also

toassess

presence

anddegree

ofdelayinmotor

skills

•Significant

motor

impairmentsversus

those

with

developm

entalconcerns

withoutm

otor

delay

•18

with

developm

ental

concerns

(eg,speech

and

emotionalissues)butno

motor

delay

•No

significant

differencein

motor

scores

versus

children

with

DD

ASDandDD

groups

matched

ongender,cognitiveabilities

within3mo;ASDmatched

toDD

andno

motordelaygroups

onchronologicagewithin

3mo


TABLE1

Continued

Reference

Findings

Type

ofStudy

Sample

Ascertainm

ent

Outcom

eDiagnosis

Comments

Wattetal,5

82008

Atages

18–24

mo,childrenwith

ASDdemonstrated

significantlyhigher

frequencyandlonger

durationof:

Prospective

•50

childrenwith

ASD(ADor

PDD-NO

S)Recruitedthroughscreening

projectinvolving

general

populationsample;ASDand

DDparticipantswerein

bottom

10thpercentileon

$1

compositeofCSBS

Behavior

Sampleduring

second

yearof

life

Best-estimateassessmentof

ASDor

DDdiagnosisatage

$30

mobasedon

batteryof

testsincludingADOS

Insecond

year

oflife:

•RSBwith

objects

•25

with

developm

entaldelay

withoutASD

•CSBSBehavior

Sample

toassess

communication

behaviors;RSBcoded

from

Behavior

Samplevideotapes

•RSBwith

body

•50

with

TD•S

ymbolic

compositeof

Behavior

Sampleto

measure

developm

entallevel

•Sensorybehaviors

than

DDandTD

groups

Aged

18–24

mo;DD

group

matched

groupw

isetoASD

groupon

ageand

developm

entallevel;TD

groupmatched

individually

toASDgroupon

gender

and

chronologicage

•Socialcompositeof

Behavior

Sampleto

assess

social

competence

Infourth

year:

Inchildrenwith

ASDandthose

with

otherDD

s,RSBwith

objectspredicted

developm

entaloutcomes

and

severityofASDsymptom

sat3y

•MSELto

measure

developm

entallevel

•VABS

toassess

adaptivebehavior

•ADOS

tomeasure

autismsymptom

s

Studiesmay

evaluatemarkersin.1category(see

“Com

ments”).AD,autistic

disorder;ADI-R,AutismDiagnosticInterview–Revised;ADOS,AutismDiagnosticObservationSchedule;ADO

S-G,AutismDiagnosticObservationSchedule–Generic;ADOS-T,Autism

DiagnosticObservationSchedule–ToddlerModule;AOSI,AutismObservationScaleforInfants;BAP,broaderautismphenotype;BISCUIT,Baby

andInfantScaleforChildrenwith

AutismTraits;BSID-II,Bayley

Scales

ofInfantDevelopm

ent–2ndEdition;CARS,

Childhood

AutismRatingScale;CBE,clinicalbestestim

ate;CDI-W

G,MacArthur

CommunicativeDevelopm

entInventories–Words

andGestures;CSBSDP,Com

municationandBehavior

Scales

Developm

entalProfile;CHAT,Checklistfor

AutisminToddlers;

DAISI,DetectionofAutismby

InfantSociabilityInterview;DD,developm

entaldelay;DSM

-III-R,Diagnostic

andStatisticalManualofM

entalDisorders,Third

Edition,Revised;DSM

-IV,Diagnostic


entalDisorders,FourthEdition;DSM

-IV-TR,DiagnosticandStatisticalManualofM

entalDisorders,FourthEdition,TextRevision;ESCS,EarlySocialCommunicationScales;IBQ,InfantBehaviorQuestionnaire;JA,jointattention;K-ABC,Kaufman

AssessmentBatteryforChildren;LD,languagedelay;

MR,mentalretardation;PDD-NO

S,pervasivedevelopm

entaldisordernototherwisespecified;PDM

S-2,PeabodyDevelopm

entM

otor

Scales,SecondEdition;PLS,PreschoolLanguage

Scale;PPSW

,PositionalPatternforSymmetry

during

Walking;RDLS,

ReynellDevelopmentalLanguageScales;RSB,repetitive

andstereotypedbehavior;SBC,SocialBehaviorChecklist;SCQ,SocialCommunicationQuestionnaire;SIBS-A,siblings

ofchildrenwith

ASD;SIBS-TD,siblings

ofchildrenwith

typicaldevelopment;SOC-

RS,SocialOrientingContinuumandResponse

Scale;SORF,SystematicObservationofRedFlagsforASDinYoungChildren;STAT,Screening

ToolforAutisminTwo-Year-Olds;TBAQ,Toddler

Behavior

AssessmentQuestionnaire;TBAQ-R,ToddlerBehavior

AssessmentQuestionnaire–Revised;TD,typicaldevelopm

ent;VABS,VinelandAdaptiveBehavior

Scales;W

OS,Walking

ObservationScale;WTC,weightedtriadiccommunications

(child-initiated

communicationofmessage

aboutanobjectoreventtoanother

person,alsocalledIJAbutconsidered

tohave

imperativeas

wellasdeclarativefunctions).

aFodstadetal2009

33:Socialization/nonverbalcom

municationsubscaleitemsthatdiscriminated:intellectualabilities;shares

enjoym

ent,interests,orachievem

entw

ithothers;interestinparticipatinginsocialgames,sports,andactivities;use

oftoofew

ortoomanysocialgestures;and

developm

entofsocialrelationships.

bFodstadetal2009

33:Com

municationsubscaleitemsthatwerepredictive:age-appropriateself-helpandadaptiveskills;useoflanguage

tocommunicate;useoflanguage

inconversations

with

others;com

municates

effectively;andlanguage

developm

ent.

cWetherbyetal2004

42:Red

flagsdifferentiatingASDfrom

bothDD

andTD:lackofappropriategaze;lackofwarm,joyfulexpressions

with

gaze;lackofsharingenjoym

entorinterest;lackofresponse

toname;lack

ofcoordinationofgaze,facialexpression,

gesture,andsound;lack

ofshow

ing;andunusualprosody.

dWetherbyetal2004

42:Red

flagsdifferentiatingASDfrom

TDbutnotDD

werelack

ofresponse

tocontextualcues,lackofpointing,lack

ofvocalizations

with

consonants,and

lack

ofplayingwith

avarietyoftoys

conventionally.

eZw

aigenbaumetal2005

45:Behavioralm

arkers

distinguishing

autismby

age12

monthswereatypicaleyecontact,visualtracking,disengagementofvisualattention,orientingtoname,imitation,socialsm

iling,reactivity,socialinterestand

affect,and

sensory-oriented

behaviors.

fZw

aigenbaumetal2005

45:Tem

peramentm

arkedby

markedpassivity

anddecreasedactivity

levelat6

mo,followed

byextrem

estress

reactions,tendencytofixateon

particular

objectsinenvironm

ent,anddecreasedexpression

ofpositiveaffectby

12mo.

gOzonoffetal20085

7 :Otherdelays

weregeneraldevelopmentaldelay,speech/language

delay,markedhyperactivity,and

markedanxiety.

hOzonoffetal20085

7 :Behaviorshypothesized

astypical:shaking,banging,mouthing,throwing;behaviorshypothesized

asatypical:spinning,rolling,rotating,unusualvisualexploration(eg,engagesinprolongedvisualinspection,exam

ines

objectfrom

oddangles

orperipheralvision).

SUPPLEMENT ARTICLE


Some studies have reported group dif-ferences in both responding to jointattention (RJA) and initiating joint at-tention (IJA) between infants who re-ceive a later diagnosis of ASD andchildren who are not diagnosed. RJA,also called attention following, is in-dicated by the child’s shifting of at-tention in response to a cue, such assomeone’s gaze, head turn, point, orattention-directing utterance. Lowerlevels of RJA have been reported inchildrenwith ASD as early as 14 monthsin 2 prospective studies41,43 but not ina third.35 In 1 study,41 group differ-ences in RJA between high-risk siblingswith a later ASD diagnosis and high-risk siblings with later outcomes ofbroader autism phenotype or non–broader autism phenotype becameapparent at 24 months of age.

IJA behaviors, or directing attention,refer to a child’s integration of gestures,gaze shifts, utterances, and other cuesto initiate a shared experience ofobjects or events with others. As earlyas age 14 months, IJA behaviors havebeen found to be impaired in childrenwith ASD35 and younger siblings ofchildren with ASD47 compared withtypically developing children. ReducedIJA (at 18 months) also distinguishesyounger siblings who subsequentlydevelop ASD from those who do not,62

as does a slower growth trajectoryof IJA-related communication fromage 15 months.43 Other studies haveassessed the use of gestures moregenerally. During the second year oflife, a lower frequency of gesture usedifferentiated children with ASD fromtypically developing children35,63 andfrom children with other developmen-tal disorders.33,39

Early marker: repetitive behavior withobjects

As early as 12 months of age, infantswitha laterdiagnosisof ASDwere foundto exhibit atypical use of objects, such

as the spinning, lining up, rotating, andespecially visual exploration of objects,compared with infants with a later di-agnosis of other developmental orlanguage delays or no developmentalconcerns.57 These findings are con-sistent with other reports of repeti-tive behaviors associated with objectuse42,58,64 and prolonged visual fixationon objects32 or repetitive geometricshapes40 in infants who subsequentlydevelop ASD. In 2 samples, such re-petitive behaviors correlated withsubsequent diagnostic outcomes andother ASD symptoms.57,58,64

Potential early marker: atypical bodymovements and motor development

Evidence in this domain is less wellestablished, but research suggests thatatypicalities in body movements, whichcan encompass repetitive actions orposturing of the body, arms, hands, orfingers (including hand flapping, fingerflicking, and atypical arm and footmovements during walking), mayemerge as important early markers.Whether these atypical behaviors arenoted to emerge early or late duringthe second year of life seems to varydepending on the design of the study.

Prospective studies in children witha later diagnosis of ASD have shown ahigher frequencyand longerdurationofrepetitive stereotyped movements58,64

compared with typically developingor “unaffected” children, respectively.Similar findings have been reported inother prospective studies32,42,54,65 aswell as in retrospective studies.39,52,53

In contrast, 1 retrospective video studyof children with autistic disorder foundno differences from typically devel-oping children in rates of movementabnormalities.55

There is a growing interest as towhether atypicalities in developmentalmotor patterns may appear very earlyand possibly predate social and com-munication markers. General delays in

gross and/or fine motor skills havebeen reported in high-risk infants,49,66

and more recent research has sug-gested very early emerging abnormal-ities in motor control. For example, ina preliminary study of 40 high-risk in-fant siblings, Flanagan et al67 reportedthat head lag at 6 months was pre-dictive of a subsequent diagnosis ofASD at 30 to 36 months. In a relatedstudy,68 motor delays at 6 months werepredictive of social communicationdelays across the high-risk cohort.Bolton et al69 reported that fine motorbehaviors were among a larger set ofparent-report items on a general de-velopmental screening tool that wasinformative for risk of ASD at 6 monthsof age. Although these studies suggestthat, in some cases, delayed or atypicalmotor patterns may be predictive ofASD, definitive markers are not yetavailable. Certainly, children with atyp-ical motor development should beclosely monitored and followed up, notonly for ASD but also for other de-velopmental disorders. Further stud-ies of the association between infantmotor development and ASD risk arewarranted.

Potential early marker:temperamental profile

It has been reported that by 24 monthsof age, temperament profiles can dis-tinguish high-risk siblings with a laterdiagnosis of ASD from high-risk siblingswho do not receive an ASD diagnosisand siblings without a family history ofASD.34 One profile is characterized bylower sensitivity to social reward cues.A second profile, marked by negativeaffect and difficulty in controlling at-tention and behavior, can differentiatesiblings diagnosed later with ASD frominfants with no family history of ASD(low-risk infants). Two smaller caseseries by the same group identifiedtemperamental differences in childrenwith ASD as early as age 6 months.32,45


Clifford et al70 reported on the pres-ence of reduced positive affect andincreased perceptual sensitivity at7 months of age, as well as a pervasivepattern of emotional dysregulationand reduced attentional flexibility(consistent with findings from Garonet al34), features that were predictiveof ASD within a cohort of 54 high-riskinfants. Measures of temperamenthave not yet been reported by othergroups investigating infants at riskfor autism, suggesting that theseobservations need further study. Inaddition, temperamental features inlow-risk populations have not beeninvestigated as a potential risk markerfor ASD.

Statement 3: Reliable behavioralmarkers for ASD in children aged,12 months have not yet beenconsistently identified.

Many factors limit investigations intothe earliest age at which markers forASD can be identified, including: (1) thepresence of considerable individualdifferences and variability in cogni-tive and social development in younginfants; (2) the use of study designs thatlimit conclusions about whether dif-ferences are predictive of an ASD di-agnosis and/or are specific to ASD; (3)the possibility that behavioral symp-toms used in diagnosis are associatedwith neuronal circuitry that developsafter 12 months of age; and (4) thepossibility that early, prodromal symp-toms at the time of ASD diagnosis maydiffer from behaviors observed andmeasured later in development.

Table 2 summarizes studies inwhich emerging markers over thefirst 12 months of life were as-sessed.22,32,38,45,46,48,49,71–78 Some re-searchers reported no behavioraldifferences at the age of 6 months insocial communication behaviors22 or inlanguage or motor development49,66

between infants who were later di-

agnosed with ASD and those witha later diagnosis of typical develop-ment. Other studies, which have alsoincluded outcome measures, suggestthat there may be differences duringthe age range of 6 to 12 months insocial attention (social gaze or ori-enting to name being called),32,74

atypical sensory behaviors,32 repetitiveor otherwise atypical motor behaviors,and nonverbal communication (differ-ences in gesture use).77 Addition-al similar studies during the first6 months of life have suggested dif-ferences in responding to social stim-uli72 and “at least some suggestion of”more difficult temperaments, char-acterized by marked irritability, in-tolerance to intrusions, and beingprone to distress/negative affect.32

Jones and Klin18 recently completeda landmark study that incorporatedeye-tracking technology to assess ahigh-risk sibling sample. They re-ported that infants later diagnosedwith ASD exhibited diminished orient-ing to the eye region of the face overtime, specifically from 2 to 6 months ofage. Cross-sectional group differencesemerged later in the first year. How-ever, these differences in orienting ofvisual attention, as measured by usingthe eye tracker, did not have straight-forward behavioral correlates thatwere detected by either clinicians orparents.

Studies of younger siblings of childrenwith ASD without a known diagnosticoutcome have reported either no dif-ferences in specific social behaviors48

or differences in visual fixation73;orienting to nonsocial versus socialstimuli76; and prespeech vocalizations.78

However, the predictive validity ofthese differences cannot be inter-preted in the absence of outcomedata.

To summarize, no definitive behavioralor diagnostic markers for ASD haveyet been identified in infants aged

,12 months. Replication of findingsacross research groups is needed.Nevertheless, caregivers are encour-aged to be mindful of early devel-opmental milestones (in social andemotional development, as well asmotor, language, and problem-solvingskills) and to raise questions if theyhave concerns that developmentalgoals are not being met.79

Statement 4: Developmentaltrajectories may also serve as riskindicators of ASD.

The term “trajectory” encompasses thedegree, rate, and direction of changesin the behaviors and/or developmentalmilestones being studied. An assess-ment of the time course of specificbehaviors and patterns of developmentmay be more sensitive than single-point, or “snapshot,” measures. Spe-cifically, there is evidence that bothearly development (eg, language, non-verbal cognition) and social commu-nication behaviors may follow atypicaltrajectories in children with ASDascertained from high-risk infant sib-ling cohorts.

Atypical trajectory of early languageand nonverbal development in ASD

Scores on standardized measures ofearly development reflect the slowing inacquisition of new skills over the first2 years of life. Prospective studies havereported atypical trajectories of earlyverbal and nonverbal skills, with rela-tively typical development during thefirst year followed by declining stan-dard scores corresponding with slow-ing of the acquisition of new skillsduring the second year of life. In aconsecutive case series,32 7 of 9 high-risk infants with a later diagnosis ofASD had average cognitive scores atthe age of 12 months based on eitherthe Bayley Scales of Infant Developmentor the Mullen Scales of Early Learning(MSEL). However, over the next 12 to

SUPPLEMENT ARTICLE


TABLE2

Selected

Studiesof

PotentialMarkers

Identifying

ASDin

InfantsAged

12Months

FirstAuthorandYear

ofPublication

Findings

Type

ofStudy

Sample

Ascertainm

ent

Outcom

eDiagnosis

Comments


arkers

(fromstudieswith

outcom

eassessment)

Bryson

etal,32

2007

Betweenages

6and12

mo,in

subsetofsiblingswith

change

incognitive

developm

ent

between12

and24

mo,5of6

infantswere“m

oredifficultto

engage

socially”(“less

…eye

contact,no

orvery

little

socialsm

iling,and

little

interestor

pleasure

ininteractingwith

others”);

minimalexplorationoftoys;

atypicalsensorybehavior

(strikingvisualfixation);

repetitive/atypicalmotor

behaviors

Prospective

case

series

9SIBS-Alaterdiagnosed

with

ASD

Recruitedfrom

multidisciplinaryautism

diagnosticandtreatm

ent

centers

Goldstandard

diagnostic

assessmentforASDatage

36moby

usingADI-R,ADO

S,andDSM-IV-TRcriteria

Assessmentsevery6mo

from

age6–24

mo,

including:

ClinicaldiagnosisofASDfor4

childrenat24

moandfor3at

30mo

•AOSIand/or

ADOS

toassess

forASDsymptom

s•BSID-IItoassess

cognition

•CDI-W

Gtoassess

gestural

andearlylanguage

developm

ent

•InfantTemperamentScale

orToddlerBehavior

Assessment

Questionnaire

toassess

temperament

Semi-structuredinterviews

regardingparental

concerns

Maestro

etal,71

2005

•Betweenages

0and6mo,

significant

groupdifferences

insocialattention(high

scores

insocialversus

nonsocialstim

uliin“typical”

infants)

Retrospective

videostudy

•15

childrenaged

3.5–5.2y

with

ADdiagnosis

Subjectswith

ADrecruited

from

community

sources

referred

topublic

academ

ichospital;

controlswere

kindergarten

attendees

Diagnosismadeatstudyentry

throughsymptom

checklist

basedon

DSM-IV

plus

$30

scoreon

CARS

•From

each

group,home

movieslastingatleast

10mincodedby

blinded

observersforfrequency

ofbehaviorsviaan

8-item

“grid”

forassessmentof

socialandnonsocial

attention

•Betweenages

7and12

mo,no

groupdifferences

insocialor

nonsocialattention;but

behaviorsregarding

attentiontononsocialstim

uli

increasedinboth

ADand

typicalgroupsbut“more

evident”intheform

er

•13

“typical”childrenwith

meanageof4.7y

•Socialattentionbehaviors

assessed:looking

atpeople,orientingtoward

people,smiling

atpeople,

vocalizingtopeople

•Nonsocialattention

behaviorsassessed:

lookingatobjects,

orientingtowardobjects,

smiling

atobjects,

vocalizingtoobjects


TABLE2

Continued

FirstAuthorandYear

ofPublication

Findings

Type

ofStudy

Sample

Ascertainm

ent

Outcom

eDiagnosis

Comments

Maestro

etal,72

2002

Betweenages

0and6mo,

significant

groupdifferences

insocialattentionandsocial

behavior,including:

Retrospective

videostudy

•15

childrenaged

3.5–5.6

(mean:4.1)

ywith

diagnosisofAD

(n=7)or

PPD-NO

S(n

=8)

Controlswerekindergarten

attendees

Diagnosismadeatstudyentry

throughsymptom

checklist

basedon

DSM-IV

plus

scoreof

$30

onCARS

•Homemovieslastingatleast

10minforeach

subject

duringage0–6mowere

ratedby

blindedobservers

forfrequencyofbehaviors

byusing13-item

“grid”

covering3developm

ental

areasofsocialattention

(eg,lookingatpeople),

socialbehavior(eg,

anticipatingtheother’s

aim),andnonsocial

attention(eg,“explorative

activity

with

object”)

•Less

frequent

lookingat

people(P

,.001)

•15“typical”“normal”children

with

meanageof4.7

y•Less

frequent

vocalizingto

people(P

,.001)

Matched

forgenderandage

inhomevideos

•Less

frequent

orienting

towardpeople(P

..01)

Nogroupdifferences

initems

referringtointerestand

attentionversus

nonsocial

stimuli

Macarietal,4

62012

At12

mo,7ADOS-Titems

optim

ized

classificationof

childrenwith

andwithoutASD

at24

mo

Prospective

longitudinalstudy

•53

at-riskinfants(SIBS-A);

13diagnosedwith

ASDat

24mo

Recruitedfrom

multiple

sources(existing

research

programs,Web

site,advertising,and

wordofmouth)

ClinicalbestdiagnosisofASDat

24mobasedon

developm

entaland

medical

history,developm

entaland

language

assessmentsand

ADOS,and

DSM-IV

criteria

•Subjectsassessed

at12

moandfollowed

upto

24mo

•11

of13

childrenwith

ASDand

68of71

childrenwithoutASD

correctly

classified

Ongoing

•31

infantsatno

know

nrisk

(SIBS-TD)

•MSELtoassess

developm

ent

Theseitemsincluded:levelof

engagement,am

ount

ofrequesting,imitation,

fussiness,show

ing,gestures,

andintonation

•ADOS-Ttomeasure

social

andcommunicative

behaviors

•Item-levelanalysisof

ADOS-T,“decisiontree”

procedures

tooptim

ize

predictionofASD

Nadigetal,38

2007

At6mo,nonsignificanttrendfor

controlsto

requirefewer

numberofcalls

torespondto

name

Prospective

longitudinal

study

•55

at-riskinfants(SIBS-A)

Enrolledinuniversity-based

study


orPDD-NO

Sat24

mobasedon


DSM-IV

criteria

•Subjectsfollowed

upto

age36

mo

•82%ofcontrolsrespondedon

firstor

second

callofname

vs.66%

ofSIBS-A

Ongoing

•43

infantsatno

know

nrisk

(SIBS-TD)

•MSELtoassess

developm

ent

Aged

6mo

•ADOStomeasuresocialand

communicativebehaviors

•Response-to-nam

eexperimentaltask

videotaped

at6and

12moandcodedfor

numberofcalls

ittook

for

response

tochild’sname

•Samesampleas

inMerin

etal,73

2007

SUPPLEMENT ARTICLE


TABLE2

Continued

FirstAuthorandYear

ofPublication

Findings

Type

ofStudy

Sample

Ascertainm

ent

Outcom

eDiagnosis

Comments

Ozonoffetal,22

2010

At6mo:

Prospective

longitudinal

study

•25

high-riskinfantswith

laterdiagnosisofAD

orPDD-NO

S(22wereSIBS-A)

Sampledraw

nfrom

larger

longitudinalstudy

Classificationas

ASDor

TDat36

mousingBaby

Siblings

Research

Consortium

definitions

(ADO

SandDSM-IV-

TRcriteriaforAD

orPDD-NO

S)

Assessmentsat

ages

6,12,

18,24,and36

moof:

•No

groupdifferences

insocial

communicationbehaviors

(including

frequencyofgaze

tofaces,shared

smiles,and

vocalizations

toothers)

•25

gender-matched

SIBS-TDdeterm

ined

later

tohave

TD

•Frequenciesof6social

communication

behaviors(gazeto

faces,

gaze

toobjects,sm

iles,

nonverbalvocalizations,

single-word

verbalizations,phrase

vocalizations),recorded

ontoDVDs

andcoded

during

MSELVisual

Receptionsubtest

•Better

(NS)

social

communicationbehaviorsfor

ASDversus

TDoutcom

egroup“onallvariables”

•Frequencyofinfant

social

engagementrated

byblindexam

iners

•MSELtoassess

cognitive

functioning

•Symptom

onsetb

yparent

reports

Werneretal,74

2000

At8–10

mo,significant(P,

.05)

maineffectofdiagnostic

groupforsocialbehaviors,

afterchildrenwith

late-onset

ASD(n

=3)

wereremoved

from

analysis

Retrospective

videostudy

•15

infantslaterdiagnosed

with

AD(n

=8)

orPPD-

NOS(n

=7)

Participantsofearlierstudy

plus

additionalrecruits

from

universityinfant

research

pool

Confirm

ationofAD

orPPD-NO

Sbasedon

DSM-III-R

plus

$30

scoreon

CARS

•Homevideos

between

ages

8–10

mocodedfor

presence

orabsenceof

behaviorscategorizedas

social(e.g.,lookingat

others,orientingtoname

beingcalled),

communication

(vocalizations),and

repetitive

•Infantswith

ASD“m

uchless

likely”(P,

.005)thaninfants

with

TDtoorient

whentheir

namewas

called

•15

childrenwith

TD

Youngetal,75

2009

•NoinfantinMerinetal,732007,

who

show

edabnorm

algaze

behavior

(decreased

eye

contact)at

6mohadany

signsofautismatoutcom

e

Prospective

•33

high-riskinfants

(SIBS-A)

RefertoMerinetal,73

2007

(below

)Clinicaldiagnosisofautismat18

and/or

24mobasedon

ADOS-

Gsupplementedby

M-CHAT

andMSEL

•Longitudinalfollow-upfor

sampleinMerinetal,73

2007

•The3infantsinsamplewho

werediagnosedwith

autism

by24

modidnotexhibit

abnorm

algaze

patterns

at6

moandhadtypicalaffective

responsesat6mo

•25

infant

SIBS-TD

Clinicaloutcom

edataavailable

on49

infants

•Assessm

entat6

moofeye-

tracking

dataand

behavioraldataduring

livemother–infant

interaction


TABLE2

Continued

FirstAuthorandYear

ofPublication

Findings

Type

ofStudy

Sample

Ascertainm

ent

Outcom

eDiagnosis

Comments

•MSELto

assess

developm

entat6,12,18,

and24

mo

•VABS

toassess

social,

communication,and

motor

skillsat12,18,and

24mo

•CDItoassess

language

developm

entat18

and

24mo

Zwaigenbaumetal,45

2005

At6mo,siblings

with

later

diagnosisofASDshow

ed:

Prospective

longitudinal

study

•44

SIBS-A

Recruitedmainlyatage#6

mofrom

autism

diagnosticandtreatm

ent

programs;low-risk

infantsrecruitedfrom

nurseriesinsame

regions

Form

alindependentd

iagnostic

assessmentat36

mobased

onDSM-IV

criteria,ADI-R,and

ADOS

•AOSIat6and12

moto

assess

autism-specific

behaviors

•No

differenceinnumberof

risk

markers

measuredby

usingAOSI

Ongoing

(N=88

followed

uptoage24

mo;

6-modataavailable

on44

SIBS-A)

•15

low-riskinfants(no

first-or

second-degree

relatives

with

ASD)

ClinicaldiagnosisofASD

madeat

24moinup

to7SIBS-Awho

metDSM-IV

criteria

(confirm

edby

usingADI-R

and

ADOS)

•Computerizedvisual

orientingtask

at6and12

motoassess

abilityto

disengagefrom

1of2

competingvisualstimuli

(attentional

disengagem

ent)

•No

difference(P

=.12)

indisengagem

entofvisual

attention

“Roughly”matched

accordingtogender,

birthorder,andage;

Nvalues

varied

byassessment

•IBQat6and12

moto

measure

infant

temperament

•Temperamentcharacterized

bymarkedpassivity

and

decreasedactivity

level

(P=.019)

Available6-mooutcom

edata

for44

SIBS-A:

•MSELandCDI-W

Gat12

mo

toassess

language

and

cognitive

developm

ent

Comparedwith

non-ASD

siblings

andcontrols

•4with

AD

Behavioralobservations

at6mo

donotpredictlaterdiagnosis

•8with

ASDclassification

onADOS

•32

withoutASD


arkers


Merinetal,73

2007

At6mo,diminishedgaze

tomother’s

eyes

relativeto

mouth

(10of11

infantswith

thisfindingwereinat-risk

group)

Prospective

•31

at-riskinfants(SIBS-A)

Recruitedby

usingresearch

institutedatabase

and

wordofmouth

Notd

one

•Visualfixationassessment

during

reciprocalsocial

interaction,conductedat

age6moviaeyetracking

during

modified

still-face

paradigm

SUPPLEMENT ARTICLE


TABLE2

Continued

FirstAuthorandYear

ofPublication

Findings

Type

ofStudy

Sample

Ascertainm

ent

Outcom

eDiagnosis

Comments

•24

with

anoldersibling

withoutautism

•Samesampleas

inNadig

etal,38

2007

Noland

etal,76

2010

At6.5–9mo,higher

working

mem

oryscores

forSIBS-A

versus

SIBS-TDfornonsocial

stimuli;no

groupdifference

forsocialstimuli

Prospective

•25

SIBS-A

SIBS-Arecruitedprimarily

throughuniversity-based

serviceandASDoutreach

program;SIBS-TD

recruitedfrom

telephone

contactsby

usingstate

birthrecord

database

Notd

one

•Trialsatage6.5moand/or

9moinvolvingtasks

relatingtoorienting

towardsocialand

nonsocialtargets

(stim

uli);correct

response

was

infantgaze

towardlocationwhere

targetmostrecently

appeared

•30

SIBS-TD

•Trialsvideotaped,coded

forcorrectfi

rstlooks

Yirm

iyaetal,48

2006

At4mo:

Prospective

•21

dyadsofmothers

and

infantswho

wereSIBS-A

Comparisongroup

recruitedfrom

hospital

maternitywards

Atage14

mo,1subjectw

assuspectedofhaving

autism,

adiagnosisconfirm

edatages

24and36

moby

usingADI-R

andADOS-G

Measuresatage4and

14mo:

•No

significant

group

differenceinmother–infant

synchrony,although

SIBS-A

exhibitedweakersynchrony

during

infant-ledinteractions

Ongoing(N

=42

with

4-moassessments)

•21

dyadsandinfantswho

wereSIBS-TD

•BSID-IItoassess

general

developm

entand

language

•No

significant

group

differenceininfant

gaze

behavior

during

still-face

procedurebutm

oreneutral

affectandless

upsetw

ithSIBS-A

Matched

on1-to-1basis

accordingtochronologic

age,gender,birth

order,

numberofchildrenin

family,and

Bayley

mental

andmotor

scales

•ICQtoassess

maternal

perceptionofinfant

temperament

•SignificantlymoreSIBS-A

respondedto

namebeing

calledby

motherthan

SIBS-TD

Socialengagement

measuresat4mo:

•Synchronyduring

mother–child

free

play

interaction

•Infant

gaze

andaffect

during

still-face

paradigm

•Procedureto

assess

responsiveness

toname

beingcalled


TABLE2

Continued

FirstAuthorandYear

ofPublication

Findings

Type

ofStudy

Sample

Ascertainm

ent

Outcom

eDiagnosis

Comments

Language/com


(fromstudieswith

outcom

eassessment)

Colgan

etal,77

2006

At9–12

mo,decreasedvarietyin

typesofsocialinteraction

gestures

used

was

significantlyassociated

with

autismstatus

Retrospective

videostudy

•21

childrenlater

diagnosedwith

ADRecruitedthroughmailings

tochild

care

centersand

developm

entalevaluation

centers;parent

advocacy

groupmeetings;hospital

clinics;university-based

autismsubjectregistry

ClinicaldiagnosisofAD

made

accordingto

timeofstudy

recruitm

ent(preschoolage),

byusingDSM-III-R

orDSM-IV

criteriaand,for11

subjects,

score.30

onCARS

Homevideotapes

from

ages

9–12

mocollected;edited

footagetotaling5min

andincludingsocial

scenes,com

parable

across

groups,w

ere

codedforuseofgestures

•Othermeasureswerenot

associated

with

anAD

diagnosis:totalnum

berof

socialinteractiongestures,

numberofchild-initiated

socialinteractiongestures

•14

childrenwith

TD•Onlygestures

definedas

socialinteractionwere

used

inthisstudy

(“gesturalactu

sedto

attractormaintain

attentionofanotherfor

socialpurposes”;eg,

wavinghello

orgood-bye,

shakinghead

yesor

no)

Landaand

Garrett-M

ayer,49

2006

At6mo,no

significant

group

differences

indomains

ofmotor,visualreception,and

language

developm

ent

Prospective

longitudinal

•24

childrenwith

later

diagnosisofASD

SIBS-Arecruitedthrough

AutismSocietyofAmerica

localchaptersand

university-based

center

forautism;childrenatlow

autismrisk

recruited

throughlocalphysician

officesandcaregiver-

child

play

groups

ASDclassified

at24

mobasedon

PLS,ADOS,and

CDI

MSELtoassessgeneraland

language

developm

ent

across

5domains

ofnonsociald

evelopment

(gross

motor,fine

motor,visualreception,

receptiveand

expressive

language);

administeredas

close

aspossibletoages

6,14,

and24

mo

•11

with

laterdiagnosisof

language

delay

•52classified

asunaffected

(at24mo)

58SIBS-Aandinfantswith

nofamily

historyof

autismevaluatedat6mo

SUPPLEMENT ARTICLE


TABLE2

Continued

FirstAuthorandYear

ofPublication

Findings

Type

ofStudy

Sample

Ascertainm

ent

Outcom

eDiagnosis

Comments

Pauletal,78

2011

Atage6–12

mo,group

differences

forcertain

prelinguistic

vocalbehaviors

Prospective

cross-sectional

design

•28–38

high-riskinfants

(SIB-A)

Recruitedfrom

university

research

pool;also

referralsfrom

local

pediatricpractices,local

autismadvocacy

groups,

wordofmouth,

advertisinginparenting

media

Provisionaldiagnoses

at24

mo

basedon

clinical

observations,ADO

S-T,and

MSEL

•Vocalizationsamples

collected

atage6,9,and

12moduring

play

with

motherandstandard

set

oftoys

•Significantlyfewer

speech-like

vocalizations

andmore

nonspeechvocalization

Ongoing(N

=43

who

have

participated

in24-mofollow-up)

•20–31

low-riskinfants(no

siblingwith

ASD

diagnosis)

Ofthe24

high-risksubjectswho

madea24-movisit:

•Detailedanalysisofvocal

production(eg,for

consonantinventory,

presence

ofcanonical

syllables)and

developm

entof

prespeechvocalization


consonant

types

•7with

ASD

•Discriminantfunction

analyses

included

only

childrenathigh

risk


canonical

syllableshapes

•6with

symptom

swithout

meetingfullBAPcriteria

Differences

invocalproduction

infirstyearoflifeassociated

with

“outcomes

interm

sof

autistic

symptom

s”insecond

year

forchildrenathigh

risk

•1with

nonautistic

developm

entaldelay

•10

withouta

clinicaldiagnosis

Studiesmay

evaluatemarkersin.1category(see

“Com

ments”).AD,autistic

disorder;ADI-R,AutismDiagnosticInterview–Revised;ADOS,AutismDiagnosticObservationSchedule;ADO

S-G,AutismDiagnosticObservationSchedule–Generic;ADOS-T,Autism

Diagnostic

ObservationSchedule–ToddlerModule;AOSI,Autism

ObservationScaleforInfants;BAP,broaderautism

phenotype;

BSID-II,Bayley

Scales

ofInfant

Developm

ent–2ndedition;CARS,Childhood

Autism

RatingScale;CDI-W

G,MacArthur

CommunicativeDevelopm

entInventories–Words

andGestures;DSM

-III-R,Diagnostic


entalDisorders,Third

Edition,Revised;DSM

-IV,Diagnostic


entalDisorders,FourthEdition;DSM

-IV-TR,Diagnostic


entalDisorders,FourthEdition,TextRevision;DVD,digitalvideo

disc

(high-capacityopticaldisk);IBQ,InfantBehavior

Questionnaire;ICQ,InfantCharacteristicsQuestionnaire;M

-CHAT,Modified

Checklistfor

AutisminToddlers;

PLS,PreschoolLanguageScale;PDD-NO

S,pervasivedevelopm

entaldisordernototherwisespecified;SIBS-A,youngersiblings

ofchildrenwith

ASD;SIBS-TD,youngersiblings

ofchildrenwith

typicaldevelopment;TD,typicaldevelopm

ent;VABS,Vineland

AdaptiveBehavior

Scales.


24months, 4 of these 7 subjects (all boys)exhibited dramatic declines in IQ intothe severe impairment range. In a sec-ond study comparing 50 infants aged6 to 36 months who received a laterdiagnosis of ASD or typical develop-ment,22 MSEL scores increased overtime for all, but starting at 12months ofage, the ASD group exhibited slowernonverbal cognitive/language growth.Similarly, Landa and Garrett-Mayer49

reported that 24 children with ASD,ascertained from a group of 87 high-risk infants, demonstrated reducedlanguage and motor skills by age 14months and reduced skills in all areasat age 24 months on the MSEL, com-pared with high-risk siblings who weredeveloping typically. More recently,Landa et al66,80 have provided evidencethat declining trajectories in languageand nonverbal cognitive skills (asindexed by using the MSEL) in high-riskinfants are strongly associated witha later diagnosis of ASD. Althoughthere may be uncertainty with regardto what is being measured by “cog-nitive” assessments at young ages,the measurement equivalence ofverbal and nonverbal indices over thefirst few years of life (ie, whethermeasures are tapping the same de-velopmental constructs at differentages), and the extent to which socialand attentional abilities may be con-tributing to children’s performance,the findings of declining trajectorieson standardized measures may nev-ertheless provide important predictiveinformation.

Atypical trajectory of early socialcommunication skills in ASD

The atypical trajectory of early socialcommunication skills in ASD includedecreased social gaze, social smiles,and vocalizations between 6 and 12 to18months of age. Ozonoff et al22 reportedon the emergence of social behavioralsigns in 25 high-risk siblings with a

later diagnosis of ASD and 25 low-riskchildren matched according to genderand later determined to have typicaldevelopment. There were no groupdifferences at age 6 months, but a de-clining trajectory of specific behaviorsover the next 12 months was noted inthe high-risk group. Group differencesin gaze to faces and directed vocal-izations were significant by age12 months and in social smiling by18 months; these findings persistedthrough to 36 months. Similarly, ina cohort of 125 high-risk infants, re-duced social smiling, eye contact, so-cial interest, affect, and responseto name at 12 months (but not at6 months) were predictive of diagnosticoutcomes at 24 months.45 Decliningtrajectories of social communicativebehaviors associated with subse-quent ASD diagnoses have also beenreported in another cohort of 204high-risk infants.80 Yoder et al43 alsoreported declining rates of joint at-tention behaviors in high-risk infantssubsequently diagnosed with ASD.As previously noted, Jones and Klin18

reported that a decline in the relativeamount of time that high-risk infantsaged 2 to 6 months spent orienting tothe eyes versus mouth of a highlyengaging adult shown on video waspredictive of ASD.

Thus, the monitoring of developmentover time may prove important inassessing ASD risk, consistent with theAmerican Academy of Pediatrics’ rec-ommendations for systematic surveil-lance during well-child visits.79

Statement 5: Caution should beexercised in drawing conclusionsabout early risk markers of ASDfrom studies that do not includeindividual-level outcome data.

Studies comparing behavior profilesacross high- and low-risk groups cancontribute to our understanding ofearly emerging features as well as the

extent of the broader ASD phenotype(milder constellation of behavioral,cognitive, and other developmentalcharacteristics that present in somerelatives of individuals with ASD).However, group-level correlations donot always reflect individual-level cor-relations. Although some high-risksiblings will go on to receive a diagno-sis of ASD, otherswill be diagnosedwithother disorders, and most will not.Therefore, prevalence of an early be-havioral marker in a group known tohave elevated ASD risk should not betaken as evidence that the markerpredicts risk at the individual levelwithout knowing the outcome status ofindividuals.

Statement 6: Caution should beexercised in generalizing findingsfrom studies of high-risk infants.

Even when individual-level data on riskmarkers and ASD outcomes are avail-able in high-risk samples and markerspredictive of ASD are reported, suchfindings might not generalize to thegeneral population. High-risk siblingcohortsareunique in that theiroutcomerisk is many times greater than otherpopulations. In light of this finding andthe accepted substantive involvement ofgenetic susceptibility factors in ASDetiology, it is plausible to suspect thatunique risk mechanisms could beoperating in this group. For example,initial reports suggested that abnor-malities in DNA copy number varia-tion in children with ASD were morecommon in simplex families thanin multiplex families.81 More recentarray- and exome-based studies result-ing from more advanced sequencingmethods have not confirmed a higheroverall burden of genetic variants insimplex families, although these stud-ies continue to highlight the tremen-dous genetic diversity among andwithin families.82,83 Variations in ge-netic mechanisms and the brain

SUPPLEMENT ARTICLE


networks to which theymapmight alsocorrelate with variation in early be-havior profiles,83 thus potentiallylimiting the extent to which riskmarkers seen in high-risk cohortsapply to other samples. Although it ispremature to assume that findingsfrom high-risk groups do not gener-alize more broadly, until more is knownabout underlying causal mechanismsand their relationship to phenotypicprofiles, ample caution should beexercised.

Statement 7: Research about earlymarkers of ASD should includediverse high- and low-risk samples.

Studies that examine cohorts at higherrisk for ASD extending beyond infantsibling cohorts may offer some addi-tional advantages in ASD research.First, these groups (eg, infants bornprematurely or infants born to olderparents)might be easier to assemblein large sample sizes. Moreover, suchcohorts will also prove useful forassessing the generalizability of earlyrisk marker profiles because they willhave a mix of genetic susceptibilityfactors different from high-risk sib-ling cohorts yet still have elevatedoutcome rates comparedwith generalpopulation samples. Follow-up stud-ies involving these cohorts may alsocreate opportunities to studywhetherearly behavioral markers for ASD areASD-specific or also predict other de-velopmental endpoints that occur (eg,intellectual disabilities). This point isparticularly critical because in theabsence of such comparison groups,we cannot conclude that behavioralmarkers associated with later di-agnosis in high-risk infant siblingsamples would be specific to ASDsin community samples that includethe full spectrum of developmentaland mental health disorders of earlyonset.

Statement 8: Future efforts shouldaim to identify: (1) early markersthat can be measured in routineclinical practice, involving directobservation and parental report;(2) early biological processesmeasurable concurrently with, orbefore, overt behavioral markers;and (3) combined approaches.

Markers measurable in routineclinical practice

Many measures currently used in earlyidentification research involve videocoding of discrete behaviors, eye track-ing, and/or the development of study-specific cutoffs that are of limitedutility for present-day clinical prac-tice. Efforts should be directed to-ward the development and validationof easy-to-administer, reliable toolsfor measuring potential behavioralmarkers within the context of routineclinical assessments; examples in-clude coding smiling during cognitiveassessment22 or the assessment ofhead lag at 6 months,67 especially inhigh-risk infants. Methods should bedeveloped for gathering informationfrom caregivers and from direct ob-servation and interaction with thechild, and for integrating thesesources of information to informclinical judgment. In a recent study,2 prospective measures of emergingsymptoms of ASD were found to cor-relate highly: (1) frequency of specificsocial behaviors as coded from video-tape; and (2) independent examinerratings of the frequency of social en-gagement behaviors in a different set-ting.22 This type of study design mayaccelerate the development of mea-sures that would be valid as well asmore easily integrated into everydaypractice.

Early neurobiological processes

Progress has also been made instudying and integrating biologicaldata, such as brain volume and func-

tional imaging (eg, from electrophysi-ological measurements) indices, withbehavioral measures of ASD. For ex-ample, enlarged brain volumes in-cluding both gray and white matterhave been reported in MRI studies oftoddlers with ASD.37,84–89 Enlargementhas been noted in the frontal andtemporal lobes37,90 and in specificsubcortical structures, such as theamygdala.36,91 Enlargement has beenobserved in children as young as age12 months andmay be accompanied byan increase in extra-axial fluid.87 Headcircumference, which is a crude proxyfor brain size, is generally consistentwith brain enlargement in ASD,84 al-though a recent review has raisedquestions as to whether ASD-relatedincreases in head circumference havebeen largely driven by comparisonwithoutdated population-based norms.92 Assuch, MRI is the gold standard forindexing structural brain develop-ment in ASD.

In some MRI studies, brain overgrowthwas found to correlate with behavioralmarkers at later ages. For example,amygdala sizewas correlatedwith jointattention ability measured at age4 years36 and with severity of socialand communicative impairments mea-sured at age 5 years.91 In another re-cent study,93 aberrant development ofwhite matter pathways was found be-tween 6 and 24 months of age in high-risk infants symptomatic for ASD at24 months. Atypical neural responses,as indexed by event-related potentials,at age 6 to 10 months to viewingfaces (specifically, the contrast betweenviewing faces whose eye gaze was di-rected toward, versus away from, theinfant) have also been reported to re-late to risk of ASD among high-riskinfants.19 Using functional MRI duringnatural sleep, a new study showed thatthe superior temporal gyrus (known tobe involved in language processing)was less activated in toddlers with


ASD relative to typically developingpeers while listening to a simple bed-time story. Notably, these toddlers withASD were referred from the communityrather than being identified froma high-risk sibling sample.94 Anotherfunctional MRI study, also with ASDtoddlers from the general population,found reduced correlation between theright and left hemispheres in brainregions key for language and socialprocessing.95 Moreover, the levels ofabnormal interhemispheric correla-tion could be used to distinguish tod-dlers with ASD from control subjects atan individual level, with a sensitivity of72% and a specificity of 84%. Thesereports encourage the search forneurologic biomarkers or others thatmay reflect underlying pathologic pro-cesses in ASD and possibly precedeand/or predict behavioral changes.

Cumulative risk indices

Researchers have not found a singlebehavioral sign or a single develop-

mental trajectory that is predictive ofall diagnoses of ASD. Given the het-erogeneity of ASD expression, it isunlikely that a single behavior will befound universally across all childrenor will serve as the defining markerfor a later emerging ASD. Future re-search may improve ASD risk pre-diction by examining combinations ofsymptomatic abnormalities (both ina cross-sectional manner and overtime) that constitute cumulative riskindices.96 Moreover, such a risk-profiling approach could incorporateboth behavioral and biological mark-ers24 and thus offer the possibility ofmore reliable identification of infantsat very high risk who could benefitfrom early intervention and/or pre-ventive approaches to mitigate symp-tom development. It is also essentialthat future studies report individual-level data and adopt more consistentmeasures of relevant constructs toallow for accurate estimates of sen-sitivity and specificity of precise risk

markers, aswell asmeta-analysis acrossstudies.

ACKNOWLEDGMENTSThe conference chairs and workinggroups acknowledge the precon-ference contributions of KatarzynaChawarska, PhD, whowas unable to at-tend the conference. We also acknowl-edge the efforts of Katherine F. Murray,BSN, RN, Massachusetts General Hos-pital for Children, in coordinating theforum and subsequent conferencereport process, and Sifor Ng in theconference report process.

The meeting and consensus reportwere sponsored by the Autism Forum.An important goal of the forum is toidentify early indicators of ASDs thatmay lead to effective health care ser-vices. Autism Forum programs are de-veloped under the guidance of itsparent organization, the NorthwestAutism Foundation. For this project,the Autism Research Institute pro-vided financial support.

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(Continued from first page)

Drs Zwaigenbaum and Bauman initiated a literature review, co-chaired the meeting that generated the consensus recommendations outlined in this article, anddrafted the initial manuscript; Drs Stone and Yirmiya co-chaired the working group that conducted the detailed literature review, generated initial recommen-dations that were discussed at the consensus meeting, and provided critical input to subsequent drafts of the manuscript; Drs Estes, Hansen, McPartland, andNatowicz were members of the working group that reviewed selected publications, contributed to initial recommendations that were reviewed at the consensusmeeting, and critically reviewed the manuscript; Drs Choueiri, Fein, Kasari, Pierce, Buie, Carter, Davis, Granpeesheh, Mailloux, Newschaffer, Robins, Smith Roley, andWetherby contributed to the consensus meeting that formed the basis for the manuscript and critically reviewed the manuscript; and all authors approved the finalmanuscript as submitted.

www.pediatrics.org/cgi/doi/10.1542/peds.2014-3667C

doi:10.1542/peds.2014-3667C

Accepted for publication Aug 3, 2015

Address correspondence to Lonnie Zwaigenbaum, MD, Autism Research Center, Glenrose Rehabilitation Hospital, Room E209, 10230 111 Ave, Edmonton, AB, CanadaT5G 0B7. E-mail: [email protected]

PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275).

Copyright © 2015 by the American Academy of Pediatrics

FINANCIAL DISCLOSURE: Dr Zwaigenbaum was the site Principal Investigator of a study sponsored by SynapDx (he received operating funds but no honoraria).Drs Fein and Robins are co-owners of M-CHAT, LLC, which licenses use of the Modified Checklist for Autism in Toddlers in electronic products. Dr Stone is theauthor of the Screening Tool for Autism in Two-Year-Olds and receives a share of royalties from sales of this instrument. The authors received an honorariumas well as travel expenses from Autism Forum for contributing to the expert panels.

FUNDING: Sponsored by the Autism Forum under the guidance of the Northwest Autism Foundation and with the support of the Autism Research Institute.

POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose.


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