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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
(Continued on last page)
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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
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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
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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
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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
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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
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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
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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
ClinicalbestdiagnosisofAD
orPDD-NO
Sat$24
mobasedon
clinicalobservation,ADOS,
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
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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)
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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
Social/emotionalbehavioralm
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
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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
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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
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TABLE1
Continued
Reference
Findings
Type
ofStudy
Sample
Ascertainm
ent
Outcom
eDiagnosis
Comments
Language/com
municationbehavioralmarkers
(fromstudieswithoutoutcomeassessments)
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
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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
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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
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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
andStatisticalManualofM
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).
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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
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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
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TABLE2
Selected
Studiesof
PotentialMarkers
Identifying
ASDin
InfantsAged
12Months
FirstAuthorandYear
ofPublication
Findings
Type
ofStudy
Sample
Ascertainm
ent
Outcom
eDiagnosis
Comments
Social/emotionalbehavioralm
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
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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
ClinicalbestdiagnosisofAD
orPDD-NO
Sat24
mobasedon
clinicalobservation,ADOS,
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
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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
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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
Social/emotionalbehavioralm
arkers
(fromstudieswithoutoutcomeassessments)
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
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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
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TABLE2
Continued
FirstAuthorandYear
ofPublication
Findings
Type
ofStudy
Sample
Ascertainm
ent
Outcom
eDiagnosis
Comments
Language/com
municationbehavioralmarkers
(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
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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
•Significantlyfewer
consonant
types
•7with
ASD
•Discriminantfunction
analyses
included
only
childrenathigh
risk
•Significantlyfewer
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
andStatisticalManualofM
entalDisorders,Third
Edition,Revised;DSM
-IV,Diagnostic
andStatisticalManualofM
entalDisorders,FourthEdition;DSM
-IV-TR,Diagnostic
andStatisticalManualofM
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.
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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
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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
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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.
REFERENCES
1. Myers SM, Johnson CP; American Academyof Pediatrics Council on Children WithDisabilities. Management of children withautism spectrum disorders. Pediatrics. 2007;120(5):1162–1182
2. Daniels AM, Mandell DS. Explaining differ-ences in age at autism spectrum disorderdiagnosis: a critical review. Autism. 2014;18(5):583–597
3. Developmental Disabilities Monitoring Net-work Surveillance Year 2010 PrincipalInvestigators; Centers for Disease Controland Prevention (CDC). Prevalence of autismspectrum disorder among children aged8 years—autism and developmental dis-abilities monitoring network, 11 sites, UnitedStates, 2010. MMWR Surveill Summ. 2014;63(2):1–21
4. Fountain C, King MD, Bearman PS. Age of di-agnosis for autism: individual and communityfactors across 10 birth cohorts. J EpidemiolCommunity Health. 2011;65(6):503–510
5. Mandell DS, Morales KH, Xie M, Lawer LJ,Stahmer AC, Marcus SC. Age of diagnosis
among Medicaid-enrolled children withautism, 2001-2004. Psychiatr Serv. 2010;61(8):822–829
6. Shattuck PT, Grosse SD. Issues related tothe diagnosis and treatment of autismspectrum disorders. Ment Retard Dev Dis-abil Res Rev. 2007;13(2):129–135
7. Wallace KS, Rogers SJ. Intervening in in-fancy: implications for autism spectrumdisorders. J Child Psychol Psychiatry. 2010;51(12):1300–1320
8. De Giacomo A, Fombonne E. Parental rec-ognition of developmental abnormalities inautism. Eur Child Adolesc Psychiatry. 1998;7(3):131–136
9. Gillberg C, Ehlers S, Schaumann H, et al.Autism under age 3 years: a clinical studyof 28 cases referred for autistic symptomsin infancy. J Child Psychol Psychiatry. 1990;31(6):921–934
10. Rogers SJ, DiLalla DL. Age of symptom on-set in young children with pervasive de-velopmental disorders. J Am Acad ChildAdolesc Psychiatry. 1990;29(6):863–872
11. Adrien JL, Faure M, Perrot A, et al. Autismand family home movies: preliminary find-ings. J Autism Dev Disord. 1991;21(1):43–49
12. Mars AE, Mauk JE, Dowrick PW. Symptomsof pervasive developmental disorders asobserved in prediagnostic home videos ofinfants and toddlers. J Pediatr. 1998;132(3 pt 1):500–504
13. Maestro S, Casella C, Milone A, Muratori F,Palacio-Espasa F. Study of the onset of au-tism through home movies. Psychopathol-ogy. 1999;32(6):292–300
14. Loveland KA, Landry SH. Joint attention andlanguage in autism and developmentallanguage delay. J Autism Dev Disord. 1986;16(3):335–349
15. Kasari C, Sigman M, Mundy P, Yirmiya N.Affective sharing in the context of joint at-tention interactions of normal, autistic, andmentally retarded children. J Autism DevDisord. 1990;20(1):87–100
16. Filipek PA, Accardo PJ, Ashwal S, et al.Practice parameter: screening and di-agnosis of autism: report of the quality
SUPPLEMENT ARTICLE
PEDIATRICS Volume 136, Supplement 1, October 2015 S37 by guest on May 24, 2020www.aappublications.org/newsDownloaded from
standards subcommittee of the AmericanAcademy of Neurology and the Child Neu-rology Society. Neurology. 2000;55(4):468–479
17. Zwaigenbaum L, Thurm A, Stone W, et al.Studying the emergence of autism spec-trum disorders in high-risk infants: meth-odological and practical issues. J AutismDev Disord. 2007;37(3):466–480
18. Jones W, Klin A. Attention to eyes is presentbut in decline in 2-6-month-old infants laterdiagnosed with autism. Nature. 2013;504(7480):427–431
19. Elsabbagh M, Fernandes J, Jane Webb S,Dawson G, Charman T, Johnson MH; BritishAutism Study of Infant Siblings Team. Dis-engagement of visual attention in infancy isassociated with emerging autism in tod-dlerhood. Biol Psychiatry. 2013;74(3):189–194
20. Walsh P, Elsabbagh M, Bolton P, Singh I. Insearch of biomarkers for autism: scientific,social and ethical challenges. Nat RevNeurosci. 2011;12(10):603–612
21. Guyatt GH, Oxman AD, Vist GE, et al; GRADEWorking Group. GRADE: an emerging con-sensus on rating quality of evidence andstrength of recommendations. BMJ. 2008;336(7650):924–926
22. Ozonoff S, Iosif AM, Baguio F, et al. Aprospective study of the emergence ofearly behavioral signs of autism. J AmAcad Child Adolesc Psychiatry. 2010;49(3):256–66.e1, 2
23. Zwaigenbaum L, Bryson S, Lord C, et al.Clinical assessment and management oftoddlers with suspected autism spectrumdisorder: insights from studies of high-riskinfants. Pediatrics. 2009;123(5):1383–1391
24. Zwaigenbaum L, Bryson S, Garon N. Earlyidentification of autism spectrum disorders.Behav Brain Res. 2013;251:133–146
25. Coe BP, Girirajan S, Eichler EE. The geneticvariability and commonality of neuro-developmental disease. Am J Med Genet CSemin Med Genet. 2012;160C(2):118–129
26. Carayol J, Schellenberg GD, Tores F, HagerJ, Ziegler A, Dawson G. Assessing the im-pact of a combined analysis of four com-mon low-risk genetic variants on autismrisk. Mol Autism. 2010;1(1):4
27. Hallmayer J, Cleveland S, Torres A, et al.Genetic heritability and shared environ-mental factors among twin pairs with au-tism. Arch Gen Psychiatry. 2011;68(11):1095–1102
28. Pierce K, Glatt SJ, Liptak GS, McIntyre LL.The power and promise of identifying au-tism early: insights from the search forclinical and biological markers. Ann ClinPsychiatry. 2009;21(3):132–147
29. Autism and Developmental DisabilitiesMonitoring Network Surveillance Year 2008Principal Investigators; Centers for DiseaseControl and Prevention. Prevalence ofautism spectrum disorders—Autism andDevelopmental Disabilities Monitoring Net-work, 14 sites, United States, 2008. MMWRSurveill Summ. 2012;61(3):1–19
30. Howlin P, Moore A. Diagnosis of autism:a survey of over 1200 patients in the UK.Autism. 1997;1(2):135–162
31. Siegel B, Pliner C, Eschler J, Elliott GR. Howchildren with autism are diagnosed: diffi-culties in identification of children withmultiple developmental delays. J Dev BehavPediatr. 1988;9(4):199–204
32. Bryson SE, Zwaigenbaum L, Brian J, et al. Aprospective case series of high-risk infantswho developed autism. J Autism Dev Dis-ord. 2007;37(1):12–24
33. Fodstad JC, Matson JL, Hess J, Neal D. So-cial and communication behaviours ininfants and toddlers with autism and per-vasive developmental disorder–not other-wise specified. Dev Neurorehabil. 2009;12(3):152–157
34. Garon N, Bryson SE, Zwaigenbaum L, et al.Temperament and its relationship to au-tistic symptoms in a high-risk infant sibcohort. J Abnorm Child Psychol. 2009;37(1):59–78
35. Goldberg WA, Jarvis KL, Osann K, et al. Briefreport: early social communication behav-iors in the younger siblings of childrenwith autism. J Autism Dev Disord. 2005;35(5):657–664
36. Mosconi MW, Cody-Hazlett H, Poe MD, GerigG, Gimpel-Smith R, Piven J. Longitudinalstudy of amygdala volume and joint atten-tion in 2- to 4-year-old children with autism.Arch Gen Psychiatry. 2009;66(5):509–516
37. Hazlett HC, Poe M, Gerig G, et al. Magneticresonance imaging and head circumfer-ence study of brain size in autism: birththrough age 2 years. Arch Gen Psychiatry.2005;62(12):1366–1376
38. Nadig AS, Ozonoff S, Young GS, Rozga A,Sigman M, Rogers SJ. A prospective studyof response to name in infants at risk forautism. Arch Pediatr Adolesc Med. 2007;161(4):378–383
39. Osterling JA, Dawson G, Munson JA. Earlyrecognition of 1-year-old infants with au-tism spectrum disorder versus mental re-tardation. Dev Psychopathol. 2002;14(2):239–251
40. Pierce K, Conant D, Hazin R, Stoner R,Desmond J. Preference for geometric pat-terns early in life as a risk factor for au-tism. Arch Gen Psychiatry. 2011;68(1):101–109
41. Sullivan M, Finelli J, Marvin A, Garrett-Mayer E, Bauman M, Landa R. Response tojoint attention in toddlers at risk for autismspectrum disorder: a prospective study.J Autism Dev Disord. 2007;37(1):37–48
42. Wetherby AM, Woods J, Allen L, Cleary J,Dickinson H, Lord C. Early indicators ofautism spectrum disorders in the secondyear of life. J Autism Dev Disord. 2004;34(5):473–493
43. Yoder P, Stone WL, Walden T, Malesa E.Predicting social impairment and ASD di-agnosis in younger siblings of childrenwith autism spectrum disorder. J AutismDev Disord. 2009;39(10):1381–1391
44. Presmanes AG, Walden TA, Stone WL, YoderPJ. Effects of different attentional cues onresponding to joint attention in youngersiblings of children with autism spectrumdisorders. J Autism Dev Disord. 2007;37(1):133–144
45. Zwaigenbaum L, Bryson S, Rogers T, Rob-erts W, Brian J, Szatmari P. Behavioralmanifestations of autism in the first year oflife. Int J Dev Neurosci. 2005;23(2–3):143–152
46. Macari SL, Campbell D, Gengoux GW, SaulnierCA, Klin AJ, Chawarska K. Predicting de-velopmental status from 12 to 24 months ininfants at risk for autism spectrum disorder:a preliminary report. J Autism Dev Disord.2012;42(12):2636–2647
47. Stone WL, McMahon CR, Yoder PJ, WaldenTA. Early social-communicative and cogni-tive development of younger siblings ofchildren with autism spectrum disorders.Arch Pediatr Adolesc Med. 2007;161(4):384–390
48. Yirmiya N, Gamliel I, Pilowsky T, Feldman R,Baron-Cohen S, Sigman M. The develop-ment of siblings of children with autismat 4 and 14 months: social engagement,communication, and cognition. J Child Psy-chol Psychiatry. 2006;47(5):511–523
49. Landa R, Garrett-Mayer E. Development ininfants with autism spectrum disorders:a prospective study. J Child Psychol Psy-chiatry. 2006;47(6):629–638
50. Oller DK, Niyogi P, Gray S, et al. Automatedvocal analysis of naturalistic recordingsfrom children with autism, language delay,and typical development. Proc Natl AcadSci USA. 2010;107(30):13354–13359
51. Gamliel I, Yirmiya N, Sigman M. The devel-opment of young siblings of children withautism from 4 to 54 months. J Autism DevDisord. 2007;37(1):171–183
52. Esposito G, Venuti P. Analysis of toddlers’gait after six months of independent walkingto identify autism: a preliminary study. Per-cept Mot Skills. 2008;106(1):259–269
S38 ZWAIGENBAUM et al by guest on May 24, 2020www.aappublications.org/newsDownloaded from
53. Esposito G, Venuti P, Apicella F, Muratori F.Analysis of unsupported gait in toddlerswith autism. Brain Dev. 2011;33(5):367–373
54. Matson JL, Dempsey T, Fodstad JC. Stereo-typies and repetitive/restrictive behavioursin infants with autism and pervasive de-velopmental disorder. Dev Neurorehabil.2009;12(3):122–127
55. Ozonoff S, Young GS, Goldring S, et al. Grossmotor development, movement abnormali-ties, and early identification of autism.J Autism Dev Disord. 2008;38(4):644–656
56. Provost B, Lopez BR, Heimerl S. A compar-ison of motor delays in young children:autism spectrum disorder, developmentaldelay, and developmental concerns. J Au-tism Dev Disord. 2007;37(2):321–328
57. Ozonoff S, Macari S, Young GS, Goldring S,Thompson M, Rogers SJ. Atypical objectexploration at 12 months of age is associ-ated with autism in a prospective sample.Autism. 2008;12(5):457–472
58. Watt N, Wetherby AM, Barber A, Morgan L.Repetitive and stereotyped behaviors inchildren with autism spectrum disordersin the second year of life. J Autism DevDisord. 2008;38(8):1518–1533
59. Coonrod EE, Stone WL. Early concerns ofparents of children with autistic and non-autistic disorders. Infants Young Child.2004;17(3):258–268
60. Baranek GT, Barnett CR, Adams EM, WolcottNA, Watson LR, Crais ER. Object play ininfants with autism: methodological issuesin retrospective video analysis. Am J OccupTher. 2005;59(1):20–30
61. Chawarska K, Macari S, Shic F. Contextmodulates attention to social scenes intoddlers with autism. J Child Psychol Psy-chiatry. 2012;53(8):903–913
62. Cornew L, Dobkins KR, Akshoomoff N,McCleery JP, Carver LJ. Atypical social ref-erencing in infant siblings of children withautism spectrum disorders. J Autism DevDisord. 2012;42(12):2611–2621
63. Mitchell S, Brian J, Zwaigenbaum L, et al.Early language and communication devel-opment of infants later diagnosed withautism spectrum disorder. J Dev BehavPediatr. 2006;27(2 suppl):S69–S78
64. Barber AB, Wetherby AM, Chambers NW.Brief report: repetitive behaviors in youngchildren with autism spectrum disorderand developmentally similar peers: a followup to Watt et al. (2008). J Autism Dev Dis-ord. 2012;42(9):2006–2012
65. Loh A, Soman T, Brian J, et al. Stereotypedmotor behaviors associated with autism inhigh-risk infants: a pilot videotape analysisof a sibling sample. J Autism Dev Disord.2007;37(1):25–36
66. Landa RJ, Gross AL, Stuart EA, Bauman M.Latent class analysis of early developmentaltrajectory in baby siblings of children withautism. J Child Psychol Psychiatry. 2012;53(9):986–996
67. Flanagan JE, Landa R, Bhat A, Bauman M.Head lag in infants at risk for autism:a preliminary study. Am J Occup Ther. 2012;66(5):577–585
68. Bhat AN, Galloway JC, Landa RJ. Relationbetween early motor delay and later com-munication delay in infants at risk for au-tism. Infant Behav Dev. 2012;35(4):838–846
69. Bolton PF, Golding J, Emond A, Steer CD.Autism spectrum disorder and autistictraits in the Avon Longitudinal Study ofParents and Children: precursors and earlysigns. J Am Acad Child Adolesc Psychiatry.2012;51(3):249–260.e25
70. Clifford SM, Hudry K, Elsabbagh M, Charman T,Johnson MH; BASIS Team. Temperament in thefirst 2 years of life in infants at high-riskfor autism spectrum disorders. J AutismDev Disord. 2013;43(3):673–686
71. Maestro S, Muratori F, Cavallaro MC, et al.How young children treat objects andpeople: an empirical study of the first yearof life in autism. Child Psychiatry Hum Dev.2005;35(4):383–396
72. Maestro S, Muratori F, Cavallaro MC, et al.Attentional skills during the first 6 monthsof age in autism spectrum disorder. J AmAcad Child Adolesc Psychiatry. 2002;41(10):1239–1245
73. Merin N, Young GS, Ozonoff S, Rogers SJ.Visual fixation patterns during reciprocalsocial interaction distinguish a subgroup of6-month-old infants at-risk for autism fromcomparison infants. J Autism Dev Disord.2007;37(1):108–121
74. Werner E, Dawson G, Osterling J, Dinno N.Brief report: recognition of autism spec-trum disorder before one year of age:a retrospective study based on home vid-eotapes. J Autism Dev Disord. 2000;30(2):157–162
75. Young GS, Merin N, Rogers SJ, Ozonoff S.Gaze behavior and affect at 6 months:predicting clinical outcomes and languagedevelopment in typically developing infantsand infants at risk for autism. Dev Sci.2009;12(5):798–814
76. Noland JS, Steven Reznick J, Stone WL,Walden T, Sheridan EH. Better workingmemory for non-social targets in infantsiblings of children with autism spectrumdisorder. Dev Sci. 2010;13(1):244–251
77. Colgan SE, Lanter E, McComish C, WatsonLR, Crais ER, Baranek GT. Analysis of socialinteraction gestures in infants with autism.Child Neuropsychol. 2006;12(4-5):307–319
78. Paul R, Fuerst Y, Ramsay G, Chawarska K,Klin A. Out of the mouths of babes: vocalproduction in infant siblings of childrenwith ASD. J Child Psychol Psychiatry. 2011;52(5):588–598
79. Johnson CP, Myers SM; American Academyof Pediatrics Council on Children With Dis-abilities. Identification and evaluation ofchildren with autism spectrum disorders.Pediatrics. 2007;120(5):1183–1215
80. Landa RJ, Gross AL, Stuart EA, Faherty A.Developmental trajectories in children withand without autism spectrum disorders:the first 3 years. Child Dev. 2013;84(2):429–442
81. Sebat J, Lakshmi B, Malhotra D, et al.Strong association of de novo copy numbermutations with autism. Science. 2007;316(5823):445–449
82. Griswold AJ, Ma D, Cukier HN, et al. Evalu-ation of copy number variations revealsnovel candidate genes in autism spectrumdisorder-associated pathways. Hum MolGenet. 2012;21(15):3513–3523
83. Pinto D, Delaby E, Merico D, et al. Conver-gence of genes and cellular pathways dys-regulated in autism spectrum disorders. AmJ Hum Genet. 2014;94(5):677–694
84. Courchesne E, Mouton PR, Calhoun ME,et al. Neuron number and size in prefrontalcortex of children with autism. JAMA. 2011;306(18):2001–2010
85. Carper RA, Moses P, Tigue ZD, CourchesneE. Cerebral lobes in autism: early hyper-plasia and abnormal age effects. Neuro-image. 2002;16(4):1038–1051
86. Sparks BF, Friedman SD, Shaw DW, et al.Brain structural abnormalities in youngchildren with autism spectrum disorder.Neurology. 2002;59(2):184–192
87. Shen MD, Nordahl CW, Young GS, et al. Earlybrain enlargement and elevated extra-axialfluid in infants who develop autism spec-trum disorder. Brain. 2013;136(pt 9):2825–2835
88. Hazlett HC, Poe MD, Gerig G, et al. Earlybrain overgrowth in autism associatedwith an increase in cortical surface areabefore age 2 years. Arch Gen Psychiatry.2011;68(5):467–476
89. Schumann CM, Bloss CS, Barnes CC, et al.Longitudinal magnetic resonance imagingstudy of cortical development throughearly childhood in autism. J Neurosci. 2010;30(12):4419–4427
90. Carper RA, Courchesne E. Localized en-largement of the frontal cortex in earlyautism. Biol Psychiatry. 2005;57(2):126–133
91. Schumann CM, Barnes CC, Lord C, Courch-esne E. Amygdala enlargement in toddlerswith autism related to severity of social
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PEDIATRICS Volume 136, Supplement 1, October 2015 S39 by guest on May 24, 2020www.aappublications.org/newsDownloaded from
and communication impairments. BiolPsychiatry. 2009;66(10):942–949
92. Raznahan A, Wallace GL, Antezana L, et al.Compared to what? Early brain overgrowthin autism and the perils of populationnorms. Biol Psychiatry. 2013;74(8):563–575
93. Wolff JJ, Gu H, Gerig G, et al; IBIS Network.Differences in white matter fiber tract de-velopment present from 6 to 24 months in
infants with autism. Am J Psychiatry. 2012;169(6):589–600
94. Eyler LT, Pierce K, Courchesne E. A failure ofleft temporal cortex to specialize for languageis an early emerging and fundamental prop-erty of autism. Brain. 2012;135(pt 3):949–960
95. Dinstein I, Pierce K, Eyler L, et al. Disruptedneural synchronization in toddlers withautism. Neuron. 2011;70(6):1218–1225
96. Yirmiya N, Charman T. The prodrome ofautism: early behavioral and biologicalsigns, regression, peri- and post-natal de-velopment and genetics. J Child PsycholPsychiatry. 2010;51(4):432–458
97. Butterworth G, Jarrett N. What minds havein common is space: Spatial mechanismsserving joint visual attention in infancy.Br J Dev Psychol. 1991;9:55–72
(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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DOI: 10.1542/peds.2014-3667C2015;136;S10Pediatrics
Susanne Smith Roley, Sheldon Wagner and Amy WetherbyDavis, Doreen Granpeesheh, Zoe Mailloux, Craig Newschaffer, Diana Robins,
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Early Identification of Autism Spectrum Disorder: Recommendations for
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DOI: 10.1542/peds.2014-3667C2015;136;S10Pediatrics
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