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Early Identication of Autism Spectrum Disorder:

Recommendations for Practice and Research


AUTHORS: Lonnie Zwaigenbaum, MD,a Margaret L.
abstract Bauman, MD,b Wendy L. Stone, PhD,c Nurit Yirmiya, PhD,d
Annette Estes, PhD,e Robin L. Hansen, MD,f James C.
Early identication of autism spectrum disorder (ASD) is essential to McPartland, PhD,g Marvin R. Natowicz, MD, PhD,h Roula
ensure that children can access specialized evidence-based interven- Choueiri, MD,i Deborah Fein, PhD,j Connie Kasari, PhD,k
tions that can help to optimize long-term outcomes. Early identication Karen Pierce, PhD,l Timothy Buie, MD,m Alice Carter, PhD,n
also helps shorten the stressful diagnostic odyssey that many Patricia A. Davis, MD,o Doreen Granpeesheh, PhD, BCBA-D,p
families experience before diagnosis. There have been important Zoe Mailloux, OTD, OTR/L, FAOTA,q Craig Newschaffer, PhD,r
Diana Robins, PhD,r Susanne Smith Roley, OTD, OTR/L,
advances in research into the early development of ASDs, incorpo-
FAOTA,s Sheldon Wagner, PhD,t and Amy Wetherby, PhDu
rating prospective designs and new technologies aimed at more pre- aDepartment of Pediatrics, University of Alberta, Edmonton,
cisely delineating the early emergence of ASD. Thus, an updated Alberta, Canada; bDepartment of Anatomy and Neurobiology,
review of the state of the science of early identication of ASD was Boston University School of Medicine, Boston, Massachusetts;
needed to inform best practice. These issues were the focus of a mul- Departments of cPsychology and eSpeech and Hearing Sciences,
University of Washington, Seattle, Washington; dDepartment of
tidisciplinary panel of clinical practitioners and researchers who Psychology, Hebrew University of Jerusalem Mount Scopus,
completed a literature review and reached consensus on current Jerusalem, Israel; fDepartment of Pediatrics, University of
evidence addressing the question What are the earliest signs and California Davis MIND Institute, Sacramento, California; gYale
Child Study Center, New Haven, Connecticut; hGenomic Medicine
symptoms of ASD in children aged #24 months that can be used for
Institute, Cleveland Clinic, Cleveland, Ohio; iDivision of
early identication? Summary statements address current knowl- Developmental and Behavioral Pediatrics, University of
edge on early signs of ASD, potential contributions and limitations Massachusetts Memorial Childrens Medical Center, Worcester,
of prospective research with high-risk infants, and priorities for pro- Massachusetts; jDepartment of Psychology, University of
Connecticut, Storrs, Connecticut; kGraduate School of Education
moting the incorporation of this knowledge into clinical practice and & Information Studies, University of California Los Angeles, Los
future research. Pediatrics 2015;136:S10S40 Angeles, California; lDepartment of Neurosciences, University of
California San Diego, La Jolla, California; mHarvard Medical
School and Massachusetts General Hospital for Children, Boston,
Massachusetts; nDepartment of Psychology, University of
Massachusetts, Boston, Massachusetts; oIntegrated Center for
Child Development, Newton, Massachusetts; pCenter for Autism
and Related Disorders, Tarzana, California; qDepartment of
Occupational Therapy, Thomas Jefferson University, Philadelphia,
Pennsylvania; rA.J. Drexel Autism Institute, Drexel University,
Philadelphia, Pennsylvania; sUSC Mrs T.H. Chan Division of
Occupational Science and Occupational Therapy, Los Angeles,
California; tBehavioral Development & Educational Services, New
Bedford, Massachusetts; and uDepartment of Clinical Sciences,
Florida State University College of Medicine, Tallahassee, Florida
ABBREVIATIONS
ASDautism spectrum disorder
IJAinitiating joint attention
MSELMullen Scales of Early Learning
RJAresponding to joint attention

(Continued on last page)

S10 ZWAIGENBAUM et al
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SUPPLEMENT ARTICLE

Despite efforts to increase awareness with expertise in ASD and develop- ary expert working group, was used
of early signs of autism spectrum mental disabilities that was con- instead to select articles of highest
disorder (ASD) and promote early vened in Marina del Rey, California, in relevance and methodologic quality.
screening,1 as well as some evidence October 2010. A working group (detailed Members of the working group re-
of recent trends toward diagnosing in the Methods section) completed viewed the articles and evaluated their
younger children (as reviewed by a literature review that informed the methodologic quality. In the absence of
Daniels and Mandell2), several large- recommendations by the panel at a standard evaluative tool for such
scale epidemiologic studies suggest the meeting; these recommendations research (eg, Grading of Recom-
that the mean age of diagnosis in were further rened by an updated mendations Assessment, Development
the United States remains at 4 to review that was completed in December and Evaluation,21 which was used to
5 years.35 Given that parents of chil- 2013. The panel reached consensus evaluate the quality of evidence of
dren with ASD generally report initial on the following key question: What clinical intervention trials), assess-
concerns before the child is aged 18 to are the earliest signs and symp- ment of evidence quality focused on
24 months, considerable opportunity toms of ASD in children aged #24 study design (retrospective versus
exists to shorten the stressful di- months that can be used for early prospective), measurement (eg, use of
agnostic odyssey that many families identication? validated measures for both risk fac-
experience,6 maximize opportunities tors and diagnostic outcomes), and
for children with ASD to benet from METHODS whether diagnostic outcomes were
early intensive interventions, and fur- measured blinded to risk factor status.
The Early Identication working group
ther develop evidence-based interventions The working group also took into
comprised Drs Stone, Yirmiya (co-
for this age group.7
chairs), Chawarska, Estes, Hansen, consideration whether ndings were
For many years, much of what was McPartland, and Natowicz. The work- replicated across independent lab-
known about the early signs of ASD was ing group co-chairs and panel co- oratories. Panel recommendations
informed by parents descriptions of chairs (Drs Zwaigenbaum and Bauman) were based on this evaluative frame-
their initial concerns,810 as well as conducted a literature search on work. During the conference, the
analyses of early home videos.1113 PubMed to identify relevant articles on working group offered draft recom-
Rich insights from these data (com- early features of ASD. The PubMed mendations for discussion, modica-
plemented by experimental work that search was conducted on June 30, 2010, tion, and ratication by all attendees.
helped delineate key foundational pro- and used the search terms (child de- Electronic voting was used to express
cesses impaired in ASD, such as af- velopmental disorders, pervasive or opinions and guide consensus building.
fect sharing and joint attention14,15) autistic disorder/ or autism [tw] or A modied nominal group technique was
helped to inform the development of autistic [tw]) and (early detection used to review the recommendations,
ASD-screening tools and surveillance or early diagnosis), with the age with consensus reached by $1 round of
efforts by community health pro- lter infant, birth23 months and lim- voting. The consensus statements and
fessionals.16 Over the past decade, ited to English-language papers. This discussion were summarized as draft
important advances in research have search yielded 341 references, which proceedings of the conference, which
been made into the early development were reviewed by Drs Zwaigenbaum were subsequently edited by all partic-
of ASD, incorporating prospective re- and Bauman, who selected articles ipants. Some of the statements provided
search designs17 and new technologies that focused on studies examining the here are intended to summarize the
aimed at more precisely delineating relationship between early behavioral state of the literature, whereas others
the early emergence of ASD.18,19 Ad- or biological markers in the rst 24 are in the form of recommendations for
vances have also been made in identi- months of life and ASD diagnosis. The research needed to ll important gaps
fying potential biomarkers (eg, genetic, search results were complemented by or aimed at addressing issues critical for
neuroimaging), although there are additional publications identied by clinical practice.
important clinical and ethical consid- working group members. Hence, al- To ensure that the nal article reected
erations regarding their potential ap- though the search strategy was com- recent literature, the search was updated
plication.20 prehensive, selection of articles was by using the same strategy to add
These issues were the focus of an in- not systematic, which is an important articles published to December 31,
ternational, multidisciplinary panel of limitation. A scoping approach, with 2013; this search yielded an additional
clinical practitioners and researchers some discretion by the multidisciplin- 202 references. Evidence tables and text

PEDIATRICS Volume 136, Supplement 1, October 2015 S11


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references were updated with ndings tive designs, measurement strategies, for a more comprehensive developmen-
from prospective studies on early be- ages at which early signs and out- tal and diagnostic evaluation.
havioral or biological markers. The comes are examined).
working group reviewed and approved Early marker: reduced levels of social
the nal wording of the summary and Statement 2: There is evidence that attention and social communication
recommendations. reduced levels of social attention Social attention and social communi-
and social communication, as well cation behaviors indicative of ASD in-
SUMMARY STATEMENTS as increased repetitive behavior clude decreased response to ones
with objects, are early markers of name being called (ie, orienting to
Statement 1: Evidence indicates ASD between 12 and 24 months of
substantial heterogeneity in the name), reduced visual attention to
age. Additional potential markers
presentation and natural history of socially meaningful stimuli, and less
include abnormal body movements
clinical features associated with frequent use of joint attention and
and temperament dysregulation.
ASDs. This heterogeneity has communicative gestures.
ASD is not commonly diagnosed until
ramications for the interpretation Reduced orienting to name is frequently
of research literature as well as 3 to 4 years of age.29 However, many
identied by parents of children with
for clinical practice. parents express concerns to their pe-
ASD as 1 of their earliest concerns,8,59
diatrician by the time their child is and it has been identied in several
There is heterogeneity not only in
aged 18 months.30,31 In addition to prospective studies of at-risk infants
the etiology, neurobiology, onset, and
parent reports, potential early mark- as a robust early marker of the di-
course of core clinical ASD symptoms
ers have been identied according to agnosis.32,38,42,45 There is some evidence
but also in the rates and levels of
retrospective analyses of home videos to suggest that decreased orienting to
cognitive and language development,
and prospective longitudinal studies of name can differentiate children with
adaptive functioning, and co-morbidity
infants in the general population, as a later ASD diagnosis not only from
with other disorders. Given the tre-
well as assessment of high-risk infants typically developing children but also
mendous clinical diversity evident
and toddlers who have an older sibling from children with other developmental
among subjects with ASD across the
with ASD. delays/disabilities.42,60
life span, it is not surprising to nd
that early manifestations and de- Studies directed toward the identica- Toddlers with ASD also exhibit a re-
velopmental course vary as well. Some tion of early clinical diagnostic markers duced tendency to visually examine
children with ASDs are described as of ASD have examined atypicalities in socially meaningful stimuli. Eye-tracking
having behavioral differences (eg, in the core domains of social communi- technology provides a unique opportu-
reactivity and social orienting) from the cation and social interaction, as well as nity to understand visual attention in
earliest months of life, whereas others the presence of repetitive behaviors. ASD and can accurately measure point
present with speech delay in the second There is strong evidence (ie, replication of gaze with ,1 degree of error.
year, and still others are described as in multiple samples by independent Studies of toddlers with ASD report
becoming withdrawn and losing skills groups) to support impairments in reduced monitoring of social scenes
after a period of relatively typical de- social attention and social communi- even with an explicit dyadic cue (ages
velopment into the second year of life.2224 cation as potential markers of ASD 1325 months)61 and a preference for
There is also heterogeneity at an etio- between the ages of 12 and 24 months visually examining geometric shapes
logic level, with hundreds of suscepti- (Table 1)3256 as well as evidence for rather than images of children (ages
bility genes25 and potentially a wide atypical object use during this same 1442 months).40
range of environmental and/or epige- age period.57,58 Attention in ASD is often abnormal not
netic factors2628 implicated in ASD When concern about any of these just in terms of what toddlers with ASD
causation. The variability in behavioral behaviors is conveyed by parents or prefer to look at but also how they at-
proles, developmental course, and observed by other care professionals tend to their world. Joint attention
underlying etiologic factors must be (eg, a health care provider such as refers to the development of specic
taken into account when synthesizing community physician or nurse, de- skills that enable sharing attention
ndings across studies. There are velopmental service provider, or early with others through pointing, showing,
also methodologic differences that childhood educator), it is recommended and coordinating looks between objects
may affect comparability across stud- that the child be referred for further and people; joint attention skills are as-
ies (eg, prospective versus retrospec- autism screening and, as appropriate, sociated with language acquisition.47

S12 ZWAIGENBAUM et al
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TABLE 1 Selected Studies of Potential Markers Identifying ASD in Children Aged 12 to 24 Months
Reference Findings Type of Study Sample Ascertainment Outcome Diagnosis Comments
Social/emotional behavioral markers (from studies with outcome assessments)
Bryson et al,32 2007 At ages 1224 mo, 2 broadly Prospective 9 SIBS-A later diagnosed with Recruited from Gold standard diagnostic Assessments every 6 mo
dened ASD subgroups: case series ASD multidisciplinary autism assessment for ASD at age 36 from age 6 to 24 mo,
diagnostic and treatment mo using ADI-R, ADOS, and including:
Decrease in IQ from average/ centers DSM-IV-TR criteria AOSI and/or ADOS to
near average to severe Clinical diagnosis of ASD for assess for ASD
cognitive impairment, with 4 children at 24 mo and for symptoms
ASD signs emerging earlier 3 children at 30 mo
or more striking earlier
Continued average or near BSID-II to assess
average IQ cognition
In all 9 subjects, social- CDI-WG to assess
communicative impairments gestural and early

PEDIATRICS Volume 136, Supplement 1, October 2015


coexisted with atypical language
sensory or motor behaviors development
and temperament prole of Infant Temperament
irritability/distress and Scale or Toddler
difculties with self- or other- Behavior Assessment
regulation of state Questionnaire to
assess temperament
Semi-structured
interviews regarding
parental concerns
Fodstad et al,33 2009 At ages 1737 mo: Prospective 161 children with AD Enrollees in state-funded early Diagnosis of AD or PDD-NOS BISCUITPart 1
Decits in communications 140 children with PDD-NOS intervention program for based on DSM-IV-TR criteria, (20-item social/
and social skills more children with development M-CHAT, and Battelle nonverbal
obvious and pronounced in delay or medical condition Developmental Inventory communication
AD versus other groups likely to result in 2nd edition subscale and 7-item
Greater decits in PPD-NOS 585 controls: children at risk a developmental delay communication

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versus controls for other developmental subscale) to assess
5 of 20 items on socialization/ delays or to have disorder autism symptoms in
nonverbal communication such as Down syndrome and one-to-one parent
subscale discriminated cerebral palsy interviews along with
between groupsa child observation
5 of 7 items on communication Aged 1737 mo
subscale were most
predictive of diagnostic
groupb

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SUPPLEMENT ARTICLE
TABLE 1 Continued

S14
Reference Findings Type of Study Sample Ascertainment Outcome Diagnosis Comments
34
Garon et al, 2009 At 24 mo, children with later Prospective 138 high-risk infants (SIBS-A) Enrolled in larger study; Gold standard diagnostic TBAQ-R to assess
diagnosis of ASD were recruited through autism assessment for ASD at 36 mo temperament
distinguished from non-ASD diagnostic and treatment based on ADI-R, ADOS, (parent report) at
siblings and controls by: centers DSM-IV-TR criteria 24 mo
Temperament prole Ongoing (N = 211 73 low-risk infants (no family 34 of 138 SIBS-A (24.6%) MSEL at 24 and 36 mo

ZWAIGENBAUM et al
(effortful emotion with data history of ASD) diagnosed with ASD
regulation) of lower positive collected
affect, higher negative affect, at age 24 mo)
and difculty controlling
attention and behavior
Lower sensitivity to social 84% and 80%, respectively,
reward cues (low behavioral enrolled in study at age 6 mo;
approach) rest by age 12 mo
Two ASD subgroups
distinguished by number of
ASD symptoms, IQ, age at
diagnosis, Behavioral
Approach prole
Goldberg et al,35 2005 At ages 1419 mo, signicant Prospective 8 children diagnosed with From larger sample of families For subjects recruited as part of ESCS (abridged version)
group differences in 3 of 4 AD or PPD-NOS aged participating in autism study larger study, ADI-R and ADOS-G structured
social and communication 21.033.0 mo at university medical center; were administered; controls interactions
behaviors between ASD and controls from community were screened by using CARS videotaped and
TD children but not between volunteer sample coded to assess
ASD and SIBS-A children: social interaction,
Responses to social 8 SIBS-A aged 14.019.0 mo joint attention, and
interaction bids: less behavioral regulation
frequent eye contact,
gestures, and turn-taking
(P , .05)
Initiation of joint attention: 9 children with TD from

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fewer nonverbal behaviors to families without ASD aged
initiate shared experiences of 10.019.0 mo
objects or events (P , .001)
Differences in frequency
of requesting behaviors
(P , .05)
No signicant differences in
responses to JA
TABLE 1 Continued
Reference Findings Type of Study Sample Ascertainment Outcome Diagnosis Comments
36
Mosconi et al, 2009 In 2-y-olds with AD: Longitudinal 50 children with AD Children with AD recruited after Diagnosis of AD conrmed at 2 y ADOS sessions
MRI study receiving clinical diagnosis or and reassessed at 4 y by using videotaped and
while awaiting clinical ADI-R, ADOS, DSM-IV criteria; coded by using a new
evaluation controls screened with CARS scale (SOC-RS) to
rate social orienting
and communications
behaviors, including
IJA, RJA, and
nonverbal gestures
Amygdala enlargement that Ongoing 33 controls (11 with Details of subject ascertainment Repetitive Behavior
persisted through age 4 y developmental delay and 22 described in Hazlett et al,37 ScaleRevised to
(16% larger volumes than in with TD) 2005 assess specicity of
controls) Aged 2 y (1835 mo) hypothesized

PEDIATRICS Volume 136, Supplement 1, October 2015


relationship between
amygdala and JA,
investigated only in
children with AD
Nadig et al,38 2007 At age 12 mo, failure to respond Prospective 101 at-risk infants (SIBS-A) Enrollees in university-based Clinical best diagnosis of AD or Subjects followed up
to name is highly suggestive of longitudinal study PDD-NOS at 24 mo based on to age 36 mo
developmental abnormality study clinical observation, ADOS,
and DSM-IV criteria
86% of at-risk infants Ongoing 46 infants at no known risk 12 children who failed to MSEL to assess
responded to rst or second (SIBS-TD) respond to name at 12 mo development
name call vs 100% of controls have outcome data: AD and
Failure to respond to name at Aged 12 mo PDD-NOS in 5, other delays in 4, ADOS to measure
age 12 mo highly specic for TD in 3 social and
24-mo outcome of communicative
developmental delay, behaviors
including ASD Response-to-name

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experimental task
videotaped at 6 and
12 mo and coded for
number of calls it
took for response to
childs name

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SUPPLEMENT ARTICLE
TABLE 1 Continued

S16
Reference Findings Type of Study Sample Ascertainment Outcome Diagnosis Comments
39
Osterling et al, 2002 At 1 y, infants with ASD: Retrospective 20 infants with later diagnosis Recruited from university AD or PPD-NOS diagnosis Home videos of rst
video study of AD (35% of sample) or PPD- subject pools, state autism conrmed at study entry on birthday parties
NOS society, Division of basis of DSM-III-R plus score of coded by blind raters
Look at others less frequently 14 infants later diagnosed Developmental Disabilities, $30 on CARS on frequencies of
with MR (without ASD and local newspaper and local specic social and

ZWAIGENBAUM et al
without distinguishing radio advertisements, local communicative
physical anomalies) schools behaviors and
Orient to their names less 20 infants with TD repetitive motor
frequently than infants with actions
mental retardation:
At 1 y, infants with ASD or MR: Aged 2.510 y at time of study
Use gestures less frequently
Look to objects held by others
less frequently
Engage in repetitive motor
actions more frequently than
infants with TD
Ozonoff et al,22 2010 By age 12 mo, signicant Prospective 25 high-risk infants with later Sample drawn from larger Classication as ASD or TD at 36 Assessmentsatages6,12,
differences between ASD and TD longitudinal diagnosis of AD or PDD-NOS longitudinal study mo by using Baby Siblings 18, 24, and 36 mo of:
groups in frequency of gaze to study (22 were SIBS-A) Research Consortium
faces and directed vocalizations denitions (ADOS and DSM-IV-
(although not at 6 mo) TR criteria for AD or PDD-NOS)
By 18 mo, signicant group 25 gender-matched SIBS-TD Frequencies of 6 social
differences on all social determined later to have TD communication
communication variables behaviors (gaze to
(see Comments) faces, gaze to objects,
smiles, nonverbal
vocalizations, single-
word verbalizations,
phrase vocalizations),

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recorded onto DVDs
and coded during MSEL
visual reception subtest
Between 6 and 18 mo: Frequency of infant
social engagement
rated by blind
examiners
Declining trajectories of social MSEL to assess
communication behavior and cognitive functioning
loss of skills in most infants
with later ASD diagnosis
Increase in cognitive and Symptom onset by
language skills (MSEL raw parent reports
scores) over time in both
groups, with signicantly
slower growth in ASD
starting at 12 mo
TABLE 1 Continued
Reference Findings Type of Study Sample Ascertainment Outcome Diagnosis Comments
Discrepancy in autism
symptom onset with parent
reports
Pierce et al,40 2011 Toddlers with an ASD as young Prospective 37 with ASD Sample recruited from general Clinical best diagnosis of AD or 1-min eye-tracking
as 14 mo spent signicantly longitudinal population screening PDD-NOS at $24 mo based on test used to measure
more time xating on study approach starting at 12 mo clinical observation, ADOS, visual attention
geometric images than on and community referral and DSM-IV criteria
social images
Individual visual xation levels 22 with DD Diagnosis conrmed
could be used to by experienced
diagnostically classify diagnostician
a toddler as having ASD at blinded to eye-
100% accuracy level tracking test results

PEDIATRICS Volume 136, Supplement 1, October 2015


Toddlers with ASD who visually 51 with TD MSEL and VABS used
examined geometric images to measure cognitive
exhibited signicantly fewer and adaptive
saccades when looking at behavior
geometric images than other
toddlers
Sullivan et al,41 2007 By age 14 mo, children later Prospective 51 high-risk children (SIBS-A) Subsample of subjects of large Outcome assessment at 30 (n = RJA bids were coded
diagnosed with ASD or who received outcome study; recruited through ASD 7) or 36 (n = 44) mo; from videotapes of
broader autism phenotype assessments: advocacy group, schools, diagnosis of AD or PDD-NOS 3 measures
had decits in RJA word of mouth based on ADOS, DSM-IV administered at ages
criteria; BAP = language and/ 14 and 24 mo:
Between 14 and 24 mo, children AD (n = 13) or PDD-NOS (n = 3) or social delays without ASD Look only trials
with ASD had minimal diagnosis adapted from
improvement in RJA, unlike Butterworth and
with BAP and non-BAP Jarrett, 199197
Signicant (P , .01) group BAP (n = 8) Look + point trials

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differences in RJA at 24 mo from CSBS DP
RJA at 14 mo predicted ASD Non-BAP (n = 27) RJA item from ADOS
outcome
Wetherby et al,42 2004 During second year of life, 9 Prospective 18 children with later Recruited to larger study Best-estimate diagnosis of AD or Direct observation
prelinguistic behaviors serve diagnosis of AD or PDD-NOS PDD-NOS made between ages within standardized
as red ags to distinguish ASD 30 mo and 5 y based on MSEL; Behavior Sample,
from DD and TD: VABS, Interview Edition, videotaped and
Survey Form; and ADOS scored by using
standard CSBS DP
procedures
7 related to social and Ongoing 18 with DD without ASD Behavior Sample
communication symptomsc videotape recoded by
2 related to repetitive 18 with TD using SORF scoring
movements with objects and/
or body parts
Aged 13.026.9 mo at Behavior
Sample

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TABLE 1 Continued

S18
Reference Findings Type of Study Sample Ascertainment Outcome Diagnosis Comments
4 additional red ags
differentiated ASD from TD
but not from DDd
Yoder et al,43 2009 Later social impairment and Prospective 43 SIBS-A Participants of another study; ASD diagnosis assessed 1.5 y Hierarchical linear
later ASD diagnosis predicted longitudinal SIBS-A recruited from after study entry (ie, after age modeling to assess

ZWAIGENBAUM et al
by: correlational university-based autism and 30 mo) using ADOS, ADI-R, and growth in early social
design speech-language programs DSM-IV-TR criteria skills (ie, RJA and
and community agencies; WTC) as predictors of
SIBS-TD through birth record social impairment in
database and word of mouth SIBS-A
Initial level of RJA (at age 15 24 age-matched SIBS-TD who ASD diagnosed in 6 (AD in 3 and RJA and WTC assessed
mo) provided social outcome PDD-NOS in 3) at 4 time points 4 mo
benchmarks apart; RJA, WTC, and
SBC assessed at time
5, 6 mo after fourth
measurement (ie,
after age 30 mo)
Growth rate of weighted Aged 1223 mo at study entry Weighted frequency of
triadic communication (from unprompted triadic
ages 1534 mo) communications
derived from STAT
At 30 mo, delay in RJA and more Experimental task
general social skills in SIBS-A described in
but large variation in social Presmanes et al,44
outcome scores 2007, to assess RJA
SBC to assess social
behaviors by parent
report
Zwaigenbaum By age 12 mo, infants with later Prospective 65 SIBS-A Recruited mainly at age #6 mo Formal independent diagnostic AOSI at 6 and 12 mo to
et al,45 2005 diagnosis of autism may be longitudinal from autism diagnostic and assessment at 36 mo based assess autism-

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distinguished from other study treatment programs; low-risk on DSM-IV criteria, ADI-R, and specic behaviors
siblings and controls by: infants recruited from ADOS
Behavior markerse Ongoing (N = 88 23 low-risk infants (no rst- or nurseries in same regions Clinical diagnosis of ASD made at ADIS (24 mo) to assess
followed up to second-degree relatives with 24 mo in up to 7 SIBS-A who autism-related social
age 24 mo) ASD) met DSM-IV criteria communication
(conrmed by using ADI-R and impairments
Prolonged latency to Roughly matched by gender, ADOS) Computerized visual
disengage visual attention birth order, and age; N values orienting task (6 and
(starting after 6 mo) varied by assessment 12 mo) to assess
ability to disengage
from 1 of 2
competing visual
stimuli (attentional
disengagement)
TABLE 1 Continued
Reference Findings Type of Study Sample Ascertainment Outcome Diagnosis Comments
f
Temperament prole Available 12-mo outcome data IBQ (6 and 12 mo) and
for 65 SIBS-A: TBAQ (24 mo) to
measure infant
temperament
Delayed expressive and 7 with AD MSEL-ABS edition and
receptive language 12 with ASD classication on CDI-WG (12 mo) to
ADOS assess language and
46 without ASD cognitive
development
Social/emotional behavioral markers (from studies without outcome assessments)
Macari et al,46 2012 At age 12 mo, lack of attention- Prospective 53 SIBS-A Recruited from university Provisional CBE diagnosis at age ADOS-T administered
sharing behaviors, including: research programs, Web site, 24 mo at 12 and 24 mo and
advertising, word of mouth analyzed by using

PEDIATRICS Volume 136, Supplement 1, October 2015


nonparametric
decision-tree
learning algorithms
Showing 31 low-risk infants (no ASD Diagnosis not done at 36 mo MSEL to assess
history in rst- or second- developmental status
degree relative)
IJA 64% male, enrolled by age 6 mo
Can predict ASD or other
atypical development at age
24 mo
Various combinations of social
communicative features
associated with ASD
presentation at 24 mo
Presmanes In second year of life, SIBS-A Prospective 46 SIBS-A SIBS-A recruited from regional Not yet available RJA task administered
et al,44 2007 showed impaired RJA relative multidisciplinary evaluation with different

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to SIBS-TD across range of and speech language centers, combinations of
prompt types state birth-to-3 service verbal and nonverbal
network, autism parent cues; when number of
groups, and university-based attentional cues was
autism service and outreach increased; and where
program; SIBS-TD recruited multiple objects or
from birth records events competed for
childs attention
Attention disengagement Ongoing 35 SIBS-TD 20 RJA trials per
similar for 2 groups subject were
videotaped and coded
Aged 1223 mo MSEL cognitive scales
administered
STAT to assess social
communicative
behaviors

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TABLE 1 Continued

S20
Reference Findings Type of Study Sample Ascertainment Outcome Diagnosis Comments
47
Stone et al, 2007 At ages 1223 mo, weaker Prospective 64 SIBS-A SIBS-A recruited from university- Not known Child-based and parent
performance by SIBS-A in: based autism and speech- report measures:
Nonverbal problem solving (ie, 42 SIBS-TD language programs and MSEL to assess
visual reception) community agencies; SIBS-TD cognitive function
Directing attention (ie, IJA) Aged 1223 mo (mean: 16 mo) recruited from birth record CARS to assess autism

ZWAIGENBAUM et al
database, university-based symptoms
Understanding words and research programs, and STAT to assess play,
phrases community agencies requesting, directing
attention, and motor
imitation
Gesture use MCDI questionnaire to
assess verbal and
nonverbal
understanding and
expression
Social communicative DAISI to assess social
interactions with parents engagement
Increased autism symptoms in behaviors
SIBS-A
Signicant correlations
between child-based
measures and parent reports
Yirmiya et al,48 2006 At age 14 mo, SIBS-A: Prospective (N = 61 30 SIBS-A Sibs-A recruited from treatment At age 14 mo, 1 subject was Measures at age 4 and
with 14-mo centers, special schools, and suspected of having autism, 14 mo:
assessments) contacts with families of a diagnosis conrmed at ages
children with ASD 24 and 36 mo by using ADI-R
Initiated fewer nonverbal 31 SIBS-TD Comparison group recruited and ADOS-G BSID-II to assess
requesting gestures from hospital maternity general development
wards and language
Achieved lower language Matched on 1-to-1 basis ICQ to assess

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scores (accounted for by 5- according to chronologic age, maternal perception
mo language delay in 6 SIBS- gender, birth order, number of infant
A) than SIBS-TD of children in family, and temperament
Bayley mental and motor Communication and
scales cognition measures
at age 14 mo:
In general, most SIBS-A ESCS to assess
functioned well nonverbal
communication skills
CHAT to assess JA
behavior
TABLE 1 Continued
Reference Findings Type of Study Sample Ascertainment Outcome Diagnosis Comments
Language/communication behavioral markers (from studies with outcome assessments)
Landa and By 14 mo of age, signicantly Prospective 24 children with later SIBS-A recruited through Autism ASD classied at 24 mo based on MSEL to assess
Garrett-Mayer,49 worse performance in ne longitudinal diagnosis of ASD Society of America local PLS, ADOS, and MCDI general and
2006 motor, gross motor, and chapters and university- language
receptive and expressive based center for autism; development across
language (ASD versus children at low autism risk 5 domains of
unaffected) recruited through local nonsocial
physician ofces and development (gross
caregiver/child play groups motor, ne motor,
visual reception,
receptive and
expressive
language);

PEDIATRICS Volume 136, Supplement 1, October 2015


administered as
close as possible to
ages 6, 14, and 24 mo
By 24 mo, signicantly worse 11 with later diagnosis of PLS-III or PLS-IV at
performance in all 5 domains language delay 24 mo for receptive
(ASD versus unaffected) and and expressive
signicantly worse standard scores and
performance in gross motor, age equivalences
ne motor, and receptive
language (ASD versus LD)
Slower developmental 52 classied as unaffected (at CDI at 14 and 24 mo to
trajectory in ASD group 24 mo) assess childs
versus other groups, with Enrollees entered study as SIBS- understanding and
signicant decline between A and infants with no family production of
rst and second birthdays history of idiopathic autism language
Oller et al,50 2010 From 1 y of age, vocalizations Prospective 77 children aged 1648 mo Recruited through Phase I: children with reported Phase I (20062008)

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from children with autism or with AD or PDD-NOS advertisements diagnosis of language delay and Phase II (2009)
language delay can be evaluated by speech- studies to assess
differentiated from children language clinician. Phase II: automated method to
with TD by automated documentation of diagnosis determine presence
analysis of selected acoustic from outside clinician, plus or absence of 12
features failure on M-CHAT acoustic parameters
on child
vocalizations;
parameters reect
rhythmic/syllabic
articulation and
voice
49 children aged 1044 mo Analysis of 1486 all-
with language delay without day recordings
autism
106 children aged 1048 mo
with TD

S21
SUPPLEMENT ARTICLE
TABLE 1 Continued

S22
Reference Findings Type of Study Sample Ascertainment Outcome Diagnosis Comments
Language/communication behavioral markers (from studies without outcome assessments)
Gamliel et al,51 2007 At 14 and 24 mo, cognitive and/or Prospective 39 SIBS-A Recruited through treatment Not known BSID-II at 4, 14, and
language delays ($2 SDs centers, special schools, 24 mo to assess
below average on measures) national autism organization, development
in SIBS-A subsets, compared families of children with

ZWAIGENBAUM et al
with other SIBS-A and SIBS-TD autism; comparison group
At ages 1436 mo, cognitive Ongoing (N = 78 with 39 SIBS-TD recruited from hospital RDLS (24 mo) to
and/or language difculties developmental maternity wards assess expressive
in 11 of 39 SIBS-A vs 2 SIBS-TD trajectories to age and verbal
54 mo) comprehension
By 54 mo, cognitive differences Matched at age 4 mo on 1-to-1 K-ABC (36 and 54 mo)
gone, but some differences in basis according to to assess intelligence
language ability (receptive chronologic age, gender, birth
and expressive) remained order, number of children in
Most siblings with language family, temperament prole, Clinical Evaluation of
impairments at age 14 mo and mental and motor scales Language
functioning well at 54 mo Fundamentals
without intervention Preschool (36 and
54 mo)
Parent questionnaire
regarding clinical
and educational
services (24, 36, and
54 mo)
This is a follow-up
report to Yirmiya
et al,48 2006
Markers of motor dysfunction (from studies with outcome assessments)
Esposito and At age 20 mo, boys with AD had: Retrospective 16 boys mean age 20.2 mo with Recruited from referrals to AD diagnosis before study Analysis of home
Venuti,52 2008 video study AD university-based center for conrmed by using DSM-IV videos taken after

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developmental disabilities criteria and ADOS 6 mo of independent
walking
Different distributions in WOS 10 boys mean age 21 mo with WOS used to code
scores from other groups mental retardation videos by assessing
Different gait patterns: 16 boys mean age 20.5 mo with gait on 3 axes: foot,
problems with heel-to-toe TD arm, and global
pattern, more asymmetric AD and MR groups matched by movements
posture of arm while walking, chronological and
higher frequency of general developmental ages
movement anomalies (eg,
waddling walk)
Esposito et al,53 2011 Aged ,2 y, signicant (P #.001) Retrospective 20 toddlers with AD Recruited from 2 nationwide Clinical diagnosis of AD based on Analysis when toddlers
differences in gait pattern in video study referral centers for DSM-IV-R and conrmed by were rst walking
toddlers with AD versus TD developmental disabilities using ADI-R, ADOS-G, and CARS without assistance
and DD:
TABLE 1 Continued
Reference Findings Type of Study Sample Ascertainment Outcome Diagnosis Comments
Higher levels of postural 15 toddlers with nonautistic Home videos taken
asymmetry during walking DD when child was aged
,2 y (plus all footage
within 2-h window)
Some atypical arm and foot 20 toddlers with TD WOS to code videos by
movements during walking assessing gait on
3 axes: foot, arm, and
global movements
Mean ages 12.914.2 mo when PPSW to assess static
rst walking without and dynamical
assistance symmetry during gait
Matson et al,54 2009 At ages 1737 mo: Prospective 140 infants with AD Enrollees of state-funded early AD and PDD-NOS diagnoses BISCUIT Part 1
intervention program for DDs based on DSM-IV-TR criteria, specically the

PEDIATRICS Volume 136, Supplement 1, October 2015


M-CHAT, and Battelle repetitive behavior/
Developmental Inventory restricted interests
Second Edition subscaleto assess
developmental prole for ASD symptoms
Stereotypies and repetitive/ 121 with PDD-NOS Child observation and
ritualistic behaviors were 1-to-1 parent
most common in AD, followed assessment;
by PDD-NOS and then other administered as part
DDS of battery of
Striking differences across 499 at risk for DD but no ASD assessments of
groups in limited number of diagnosis physical and social
interests, engages in development
repetitive motor movements
for no reason, eye-to-eye
gaze, maintains eye contact
BISCUIT subset could Aged 1737 mo (mean: 26.63

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accurately predict diagnostic mo)
group membership
Ozonoff et al,57 2008 At age 12 mo: Prospective 35 SIBS-A Recruited from SIBS-A and SIBS- Diagnosis at 24 (n = 29) or 36 Manner in which infants
TD (n = 37) mo based on ADOS, explore objects was
SCQ, and DSM-IV criteria examined in task that
afforded range of
repetitive uses
Atypical uses of objects 31 in SIBS-TD For 37 with outcome data at 24 Four objects
(spinning, rotating, and, and 36 mo, 31 (83.8%) had the presented to the
especially, unusual visual same classications at both infant, 1 at a time, for
exploration of objects) ages; the later classication 30 s each
signicantly (P # .005) more was used in analyses
frequent in infants with ASD
compared with other groups
Repetitive behaviors Aged 12 mo, with following Behavior recorded on
signicantly related to outcomes: DVD
9 with ASD diagnosis

S23
SUPPLEMENT ARTICLE
TABLE 1 Continued

S24
Reference Findings Type of Study Sample Ascertainment Outcome Diagnosis Comments
cognitive and symptom 10 with later diagnosis of 8 object uses coded by
status at 36 mo other delaysg blinded raters as
47 with no concerns (did not either frequency or
meet criteria for other duration; 4
groups) hypothesized as

ZWAIGENBAUM et al
typical and age-
appropriate and 4 as
atypicalh
Ozonoff et al,55 2008 During rst 2 y of age: Retrospective 26 children aged 2661 mo 82 recruited from university- Diagnosis of AD or PDD-NOS in the Participants seen at
video study with nonregression-type AD based recruitment core and community conrmed at initial enrollment
local agencies serving study entry; AD diagnosis (when all home
individuals with based on ADI-R plus ADOS; videos of child from
developmental disabilities; 21 regression versus no birth to age 2 y were
recruited in another city from regression subgroups based collected) and 12 y
ongoing studies and on ADI-R later for assessment
university subject pool battery that was part
of another study
Neither regression nor 28 children aged 2661 mo Videos coded for
nonregression types of AD with regression-type AD motor maturity,
differed from TD in rates of protective
movement abnormalities or responses, and
lack of protective responses movement
Toddlers with nonautistic DD 25 with nonautistic DD abnormalities by
displayed higher rates of matched for chronologic and using Infant Motor
movement abnormalities in developmental age Maturity and
sitting and prone and fewer 24 with TD Atypicality Coding
protective responses in Scales
crawling than other groups
Provost et al,56 2007 At ages 2141 mo: Prospective 19 children aged 2141 mo Recruited from referrals to ASD diagnosis made by study BSID-II Motor Scale to
with ASD university-based early team evaluation assess motor skills

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Motor dysfunction to some 19 with other DD including childhood evaluation Diagnosis of AD in 18, PDD-NOS PDMS-2 also to assess
degree in all children with motor delay program for developmental in 1 presence and degree
ASD (delay in gross and/or disabilities of delay in motor
ne motor skills) skills
Signicant motor 18 with developmental
impairments versus those concerns (eg, speech and
with developmental concerns emotional issues) but no
without motor delay motor delay
No signicant difference in ASD and DD groups matched on
motor scores versus children gender, cognitive abilities
with DD within 3 mo; ASD matched to
DD and no motor delay groups
on chronologic age within
3 mo
TABLE 1 Continued
Reference Findings Type of Study Sample Ascertainment Outcome Diagnosis Comments
58
Watt et al, 2008 At ages 1824 mo, children with Prospective 50 children with ASD (AD or Recruited through screening Best-estimate assessment of In second year of life:
ASD demonstrated PDD-NOS) project involving general ASD or DD diagnosis at age
signicantly higher population sample; ASD and $30 mo based on battery of
frequency and longer DD participants were in tests including ADOS
duration of: bottom 10th percentile on $1
RSB with objects 25 with developmental delay composite of CSBS Behavior CSBS Behavior Sample
without ASD Sample during second year of to assess
life communication
behaviors; RSB coded
from Behavior
Sample videotapes
RSB with body 50 with TD Symbolic composite of
Behavior Sample to

PEDIATRICS Volume 136, Supplement 1, October 2015


measure
developmental level
Sensory behaviors Aged 1824 mo; DD group Social composite of
than DD and TD groups matched groupwise to ASD Behavior Sample to
group on age and assess social
developmental level; TD competence
group matched individually In fourth year:
In children with ASD and those to ASD group on gender and MSEL to measure
with other DDs, RSB with chronologic age developmental level
objects predicted VABS to assess
developmental outcomes and adaptive behavior
severity of ASD symptoms ADOS to measure
at 3 y autism symptoms
Studies may evaluate markers in .1 category (see Comments). AD, autistic disorder; ADI-R, Autism Diagnostic InterviewRevised; ADOS, Autism Diagnostic Observation Schedule; ADOS-G, Autism Diagnostic Observation ScheduleGeneric; ADOS-T, Autism
Diagnostic Observation ScheduleToddler Module; AOSI, Autism Observation Scale for Infants; BAP, broader autism phenotype; BISCUIT, Baby and Infant Scale for Children with Autism Traits; BSID-II, Bayley Scales of Infant Development2nd Edition; CARS,
Childhood Autism Rating Scale; CBE, clinical best estimate; CDI-WG, MacArthur Communicative Development InventoriesWords and Gestures; CSBS DP, Communication and Behavior Scales Developmental Prole; CHAT, Checklist for Autism in Toddlers;

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DAISI, Detection of Autism by Infant Sociability Interview; DD, developmental delay; DSM-III-R, Diagnostic and Statistical Manual of Mental Disorders, Third Edition, Revised; DSM-IV, Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition; DSM-
IV-TR, Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision; ESCS, Early Social Communication Scales; IBQ, Infant Behavior Questionnaire; JA, joint attention; K-ABC, Kaufman Assessment Battery for Children; LD, language delay;
MR, mental retardation; PDD-NOS, pervasive developmental disorder not otherwise specied; PDMS-2, Peabody Development Motor Scales, Second Edition; PLS, Preschool Language Scale; PPSW, Positional Pattern for Symmetry during Walking; RDLS,
Reynell Developmental Language Scales; RSB, repetitive and stereotyped behavior; SBC, Social Behavior Checklist; SCQ, Social Communication Questionnaire; SIBS-A, siblings of children with ASD; SIBS-TD, siblings of children with typical development; SOC-
RS, Social Orienting Continuum and Response Scale; SORF, Systematic Observation of Red Flags for ASD in Young Children; STAT, Screening Tool for Autism in Two-Year-Olds; TBAQ, Toddler Behavior Assessment Questionnaire; TBAQ-R, Toddler Behavior
Assessment QuestionnaireRevised; TD, typical development; VABS, Vineland Adaptive Behavior Scales; WOS, Walking Observation Scale; WTC, weighted triadic communications (child-initiated communication of message about an object or event to another
person, also called IJA but considered to have imperative as well as declarative functions).
a Fodstad et al 200933: Socialization/nonverbal communication subscale items that discriminated: intellectual abilities; shares enjoyment, interests, or achievement with others; interest in participating in social games, sports, and activities; use of too few

or too many social gestures; and development of social relationships.


b Fodstad et al 200933: Communication subscale items that were predictive: age-appropriate self-help and adaptive skills; use of language to communicate; use of language in conversations with others; communicates effectively; and language development.
c Wetherby et al 200442: Red ags differentiating ASD from both DD and TD: lack of appropriate gaze; lack of warm, joyful expressions with gaze; lack of sharing enjoyment or interest; lack of response to name; lack of coordination of gaze, facial expression,

gesture, and sound; lack of showing; and unusual prosody.


d Wetherby et al 200442: Red ags differentiating ASD from TD but not DD were lack of response to contextual cues, lack of pointing, lack of vocalizations with consonants, and lack of playing with a variety of toys conventionally.
e Zwaigenbaum et al 200545: Behavioral markers distinguishing autism by age 12 months were atypical eye contact, visual tracking, disengagement of visual attention, orienting to name, imitation, social smiling, reactivity, social interest and affect, and

sensory-oriented behaviors.
f Zwaigenbaum et al 200545: Temperament marked by marked passivity and decreased activity level at 6 mo, followed by extreme stress reactions, tendency to xate on particular objects in environment, and decreased expression of positive affect by 12 mo.
g Ozonoff et al 200857: Other delays were general developmental delay, speech/language delay, marked hyperactivity, and marked anxiety.
h Ozonoff et al 200857: Behaviors hypothesized as typical: shaking, banging, mouthing, throwing; behaviors hypothesized as atypical: spinning, rolling, rotating, unusual visual exploration (eg, engages in prolonged visual inspection, examines object from

odd angles or peripheral vision).

S25
SUPPLEMENT ARTICLE
Some studies have reported group dif- as the spinning, lining up, rotating, and gross and/or ne motor skills have
ferences in both responding to joint especially visual exploration of objects, been reported in high-risk infants,49,66
attention (RJA) and initiating joint at- compared with infants with a later di- and more recent research has sug-
tention (IJA) between infants who re- agnosis of other developmental or gested very early emerging abnormal-
ceive a later diagnosis of ASD and language delays or no developmental ities in motor control. For example, in
children who are not diagnosed. RJA, concerns.57 These ndings are con- a preliminary study of 40 high-risk in-
also called attention following, is in- sistent with other reports of repeti- fant siblings, Flanagan et al67 reported
dicated by the childs shifting of at- tive behaviors associated with object that head lag at 6 months was pre-
tention in response to a cue, such as use42,58,64 and prolonged visual xation dictive of a subsequent diagnosis of
someones gaze, head turn, point, or on objects32 or repetitive geometric ASD at 30 to 36 months. In a related
attention-directing utterance. Lower shapes40 in infants who subsequently study,68 motor delays at 6 months were
levels of RJA have been reported in develop ASD. In 2 samples, such re- predictive of social communication
children with ASD as early as 14 months petitive behaviors correlated with delays across the high-risk cohort.
in 2 prospective studies41,43 but not in subsequent diagnostic outcomes and Bolton et al69 reported that ne motor
a third.35 In 1 study,41 group differ- other ASD symptoms.57,58,64 behaviors were among a larger set of
ences in RJA between high-risk siblings parent-report items on a general de-
with a later ASD diagnosis and high- Potential early marker: atypical body velopmental screening tool that was
risk siblings with later outcomes of movements and motor development informative for risk of ASD at 6 months
broader autism phenotype or non Evidence in this domain is less well of age. Although these studies suggest
broader autism phenotype became established, but research suggests that that, in some cases, delayed or atypical
apparent at 24 months of age. atypicalities in body movements, which motor patterns may be predictive of
IJA behaviors, or directing attention, can encompass repetitive actions or ASD, denitive markers are not yet
refer to a childs integration of gestures, posturing of the body, arms, hands, or available. Certainly, children with atyp-
gaze shifts, utterances, and other cues ngers (including hand apping, nger ical motor development should be
to initiate a shared experience of icking, and atypical arm and foot closely monitored and followed up, not
objects or events with others. As early movements during walking), may only for ASD but also for other de-
as age 14 months, IJA behaviors have emerge as important early markers. velopmental disorders. Further stud-
been found to be impaired in children Whether these atypical behaviors are ies of the association between infant
with ASD35 and younger siblings of noted to emerge early or late during motor development and ASD risk are
children with ASD47 compared with the second year of life seems to vary warranted.
typically developing children. Reduced depending on the design of the study.
IJA (at 18 months) also distinguishes Prospective studies in children with Potential early marker:
younger siblings who subsequently a later diagnosis of ASD have shown a temperamental prole
develop ASD from those who do not,62 higher frequency and longer duration of It has been reported that by 24 months
as does a slower growth trajectory repetitive stereotyped movements58,64 of age, temperament proles can dis-
of IJA-related communication from compared with typically developing tinguish high-risk siblings with a later
age 15 months.43 Other studies have or unaffected children, respectively. diagnosis of ASD from high-risk siblings
assessed the use of gestures more Similar ndings have been reported in who do not receive an ASD diagnosis
generally. During the second year of other prospective studies32,42,54,65 as and siblings without a family history of
life, a lower frequency of gesture use well as in retrospective studies.39,52,53 ASD.34 One prole is characterized by
differentiated children with ASD from In contrast, 1 retrospective video study lower sensitivity to social reward cues.
typically developing children35,63 and of children with autistic disorder found A second prole, marked by negative
from children with other developmen- no differences from typically devel- affect and difculty in controlling at-
tal disorders.33,39 oping children in rates of movement tention and behavior, can differentiate
abnormalities.55 siblings diagnosed later with ASD from
Early marker: repetitive behavior with There is a growing interest as to infants with no family history of ASD
objects whether atypicalities in developmental (low-risk infants). Two smaller case
As early as 12 months of age, infants motor patterns may appear very early series by the same group identied
with a later diagnosis of ASD were found and possibly predate social and com- temperamental differences in children
to exhibit atypical use of objects, such munication markers. General delays in with ASD as early as age 6 months.32,45

S26 ZWAIGENBAUM et al
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SUPPLEMENT ARTICLE

Clifford et al70 reported on the pres- agnosed with ASD and those with ,12 months. Replication of ndings
ence of reduced positive affect and a later diagnosis of typical develop- across research groups is needed.
increased perceptual sensitivity at ment. Other studies, which have also Nevertheless, caregivers are encour-
7 months of age, as well as a pervasive included outcome measures, suggest aged to be mindful of early devel-
pattern of emotional dysregulation that there may be differences during opmental milestones (in social and
and reduced attentional exibility the age range of 6 to 12 months in emotional development, as well as
(consistent with ndings from Garon social attention (social gaze or ori- motor, language, and problem-solving
et al34), features that were predictive enting to name being called),32,74 skills) and to raise questions if they
of ASD within a cohort of 54 high-risk atypical sensory behaviors,32 repetitive have concerns that developmental
infants. Measures of temperament or otherwise atypical motor behaviors, goals are not being met.79
have not yet been reported by other and nonverbal communication (differ-
groups investigating infants at risk ences in gesture use).77 Addition- Statement 4: Developmental
for autism, suggesting that these al similar studies during the rst trajectories may also serve as risk
observations need further study. In 6 months of life have suggested dif- indicators of ASD.
addition, temperamental features in ferences in responding to social stim- The term trajectory encompasses the
low-risk populations have not been uli72 and at least some suggestion of degree, rate, and direction of changes
investigated as a potential risk marker more difcult temperaments, char- in the behaviors and/or developmental
for ASD. acterized by marked irritability, in- milestones being studied. An assess-
tolerance to intrusions, and being ment of the time course of specic
Statement 3: Reliable behavioral prone to distress/negative affect.32 behaviors and patterns of development
markers for ASD in children aged Jones and Klin18 recently completed may be more sensitive than single-
,12 months have not yet been a landmark study that incorporated point, or snapshot, measures. Spe-
consistently identied. eye-tracking technology to assess a cically, there is evidence that both
Many factors limit investigations into high-risk sibling sample. They re- early development (eg, language, non-
the earliest age at which markers for ported that infants later diagnosed verbal cognition) and social commu-
ASD can be identied, including: (1) the with ASD exhibited diminished orient- nication behaviors may follow atypical
presence of considerable individual ing to the eye region of the face over trajectories in children with ASD
differences and variability in cogni- time, specically from 2 to 6 months of ascertained from high-risk infant sib-
tive and social development in young age. Cross-sectional group differences ling cohorts.
infants; (2) the use of study designs that emerged later in the rst year. How-
limit conclusions about whether dif- ever, these differences in orienting of Atypical trajectory of early language
ferences are predictive of an ASD di- visual attention, as measured by using and nonverbal development in ASD
agnosis and/or are specic to ASD; (3) the eye tracker, did not have straight- Scores on standardized measures of
the possibility that behavioral symp- forward behavioral correlates that early development reect the slowing in
toms used in diagnosis are associated were detected by either clinicians or acquisition of new skills over the rst
with neuronal circuitry that develops parents. 2 years of life. Prospective studies have
after 12 months of age; and (4) the Studies of younger siblings of children reported atypical trajectories of early
possibility that early, prodromal symp- with ASD without a known diagnostic verbal and nonverbal skills, with rela-
toms at the time of ASD diagnosis may outcome have reported either no dif- tively typical development during the
differ from behaviors observed and ferences in specic social behaviors48 rst year followed by declining stan-
measured later in development. or differences in visual xation73 ; dard scores corresponding with slow-
Table 2 summarizes studies in orienting to nonsocial versus social ing of the acquisition of new skills
which emerging markers over the stimuli76; and prespeech vocalizations.78 during the second year of life. In a
rst 12 months of life were as- However, the predictive validity of consecutive case series,32 7 of 9 high-
sessed.22,32,38,45,46,48,49,7178 Some re- these differences cannot be inter- risk infants with a later diagnosis of
searchers reported no behavioral preted in the absence of outcome ASD had average cognitive scores at
differences at the age of 6 months in data. the age of 12 months based on either
social communication behaviors22 or in To summarize, no denitive behavioral the Bayley Scales of Infant Development
language or motor development49,66 or diagnostic markers for ASD have or the Mullen Scales of Early Learning
between infants who were later di- yet been identied in infants aged (MSEL). However, over the next 12 to

PEDIATRICS Volume 136, Supplement 1, October 2015 S27


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TABLE 2 Selected Studies of Potential Markers Identifying ASD in Infants Aged 12 Months

S28
First Author and Year Findings Type of Study Sample Ascertainment Outcome Diagnosis Comments
of Publication
Social/emotional behavioral markers (from studies with outcome assessment)
Bryson et al,32 2007 Between ages 6 and 12 mo, in Prospective 9 SIBS-A later diagnosed Recruited from Gold standard diagnostic Assessments every 6 mo
subset of siblings with change case series with ASD multidisciplinary autism assessment for ASD at age from age 624 mo,
in cognitive development diagnostic and treatment 36 mo by using ADI-R, ADOS, including:

ZWAIGENBAUM et al
between 12 and 24 mo, 5 of 6 centers and DSM-IV-TR criteria
infants were more difcult to Clinical diagnosis of ASD for 4 AOSI and/or ADOS to
engage socially (less eye children at 24 mo and for 3 at assess for ASD symptoms
contact, no or very little 30 mo BSID-II to assess cognition
social smiling, and little CDI-WG to assess gestural
interest or pleasure in and early language
interacting with others); development
minimal exploration of toys; Infant Temperament Scale
atypical sensory behavior or Toddler Behavior
(striking visual xation); Assessment
repetitive/atypical motor Questionnaire to assess
behaviors temperament
Semi-structured interviews
regarding parental
concerns
Maestro et al,71 2005 Between ages 0 and 6 mo, Retrospective 15 children aged 3.55.2 y Subjects with AD recruited Diagnosis made at study entry From each group, home
signicant group differences video study with AD diagnosis from community sources through symptom checklist movies lasting at least
in social attention (high referred to public based on DSM-IV plus $30 10 min coded by blinded
scores in social versus academic hospital; score on CARS observers for frequency
nonsocial stimuli in typical controls were of behaviors via an 8-item
infants) kindergarten attendees grid for assessment of
social and nonsocial
attention
Between ages 7 and 12 mo, no 13 typical children with Social attention behaviors
group differences in social or mean age of 4.7 y assessed: looking at

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nonsocial attention; but people, orienting toward
behaviors regarding people, smiling at people,
attention to nonsocial stimuli vocalizing to people
increased in both AD and Nonsocial attention
typical groups but more behaviors assessed:
evident in the former looking at objects,
orienting toward objects,
smiling at objects,
vocalizing to objects
TABLE 2 Continued
First Author and Year Findings Type of Study Sample Ascertainment Outcome Diagnosis Comments
of Publication
Maestro et al,72 2002 Between ages 0 and 6 mo, Retrospective 15 children aged 3.55.6 Controls were kindergarten Diagnosis made at study entry Home movies lasting at least
signicant group differences video study (mean: 4.1) y with attendees through symptom checklist 10 min for each subject
in social attention and social diagnosis of AD (n = 7) or based on DSM-IV plus score of during age 06 mo were
behavior, including: PPD-NOS (n = 8) $30 on CARS rated by blinded observers
Less frequent looking at 15 typical normal children for frequency of behaviors
people (P , .001) with mean age of 4.7 y by using 13-item grid
Less frequent vocalizing to Matched for gender and age covering 3 developmental
people (P , .001) in home videos areas of social attention
Less frequent orienting (eg, looking at people),
toward people (P . .01) social behavior (eg,
No group differences in items anticipating the others
referring to interest and aim), and nonsocial

PEDIATRICS Volume 136, Supplement 1, October 2015


attention versus nonsocial attention (eg, explorative
stimuli activity with object)
Macari et al,46 2012 At 12 mo, 7 ADOS-T items Prospective 53 at-risk infants (SIBS-A); Recruited from multiple Clinical best diagnosis of ASD at Subjects assessed at
optimized classication of longitudinal study 13 diagnosed with ASD at sources (existing 24 mo based on 12 mo and followed up to
children with and without ASD 24 mo research programs, Web developmental and medical 24 mo
at 24 mo site, advertising, and history, developmental and
11 of 13 children with ASD and Ongoing 31 infants at no known word of mouth) language assessments and MSEL to assess
68 of 71 children without ASD risk (SIBS-TD) ADOS, and DSM-IV criteria development
correctly classied
These items included: level of ADOS-T to measure social
engagement, amount of and communicative
requesting, imitation, behaviors
fussiness, showing, gestures, Item-level analysis of
and intonation ADOS-T, decision tree
procedures to optimize
prediction of ASD

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Nadig et al,38 2007 At 6 mo, nonsignicant trend for Prospective 55 at-risk infants (SIBS-A) Enrolled in university-based Clinical best diagnosis of AD or Subjects followed up to
controls to require fewer longitudinal study PDD-NOS at 24 mo based on age 36 mo
number of calls to respond to study clinical observation, ADOS,
name DSM-IV criteria
82% of controls responded on Ongoing 43 infants at no known MSEL to assess
rst or second call of name risk (SIBS-TD) development
vs. 66% of SIBS-A Aged 6 mo ADOS to measure social and
communicative behaviors
Response-to-name
experimental task
videotaped at 6 and
12 mo and coded for
number of calls it took for
response to childs name
Same sample as in Merin
et al,73 2007

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SUPPLEMENT ARTICLE
TABLE 2 Continued

S30
First Author and Year Findings Type of Study Sample Ascertainment Outcome Diagnosis Comments
of Publication
Ozonoff et al,22 2010 At 6 mo: Prospective 25 high-risk infants with Sample drawn from larger Classication as ASD or TD at 36 Assessments at ages 6, 12,
longitudinal later diagnosis of AD or longitudinal study mo using Baby Siblings 18, 24, and 36 mo of:
study PDD-NOS (22 were SIBS-A) Research Consortium
No group differences in social 25 gender-matched denitions (ADOS and DSM-IV- Frequencies of 6 social

ZWAIGENBAUM et al
communication behaviors SIBS-TD determined later TR criteria for AD or PDD-NOS) communication
(including frequency of gaze to have TD behaviors (gaze to faces,
to faces, shared smiles, and gaze to objects, smiles,
vocalizations to others) nonverbal vocalizations,
single-word
verbalizations, phrase
vocalizations), recorded
onto DVDs and coded
during MSEL Visual
Reception subtest
Better (NS) social Frequency of infant social
communication behaviors for engagement rated by
ASD versus TD outcome blind examiners
group on all variables MSEL to assess cognitive
functioning
Symptom onset by parent
reports
Werner et al,74 2000 At 810 mo, signicant (P , .05) Retrospective 15 infants later diagnosed Participants of earlier study Conrmation of AD or PPD-NOS Home videos between
main effect of diagnostic video study with AD (n = 8) or PPD- plus additional recruits based on DSM-III-R plus $30 ages 810 mo coded for
group for social behaviors, NOS (n = 7) from university infant score on CARS presence or absence of
after children with late-onset research pool behaviors categorized as
ASD (n = 3) were removed social (e.g., looking at
from analysis others, orienting to name
Infants with ASD much less 15 children with TD being called),
likely (P , .005) than infants communication

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with TD to orient when their (vocalizations), and
name was called repetitive
Young et al,75 2009 No infant in Merin et al,73 2007, Prospective 33 high-risk infants Refer to Merin et al,73 2007 Clinical diagnosis of autism at 18 Longitudinal follow-up for
who showed abnormal gaze (SIBS-A) (below) and/or 24 mo based on ADOS- sample in Merin et al,73
behavior (decreased eye G supplemented by M-CHAT 2007
contact) at 6 mo had any and MSEL
signs of autism at outcome
The 3 infants in sample who 25 infant SIBS-TD Clinical outcome data available Assessment at 6 mo of eye-
were diagnosed with autism on 49 infants tracking data and
by 24 mo did not exhibit behavioral data during
abnormal gaze patterns at 6 live motherinfant
mo and had typical affective interaction
responses at 6 mo
TABLE 2 Continued
First Author and Year Findings Type of Study Sample Ascertainment Outcome Diagnosis Comments
of Publication
MSEL to assess
development at 6, 12, 18,
and 24 mo
VABS to assess social,
communication, and
motor skills at 12, 18, and
24 mo
CDI to assess language
development at 18 and
24 mo
Zwaigenbaum et al,45 2005 At 6 mo, siblings with later Prospective 44 SIBS-A Recruited mainly at age #6 Formal independent diagnostic AOSI at 6 and 12 mo to
diagnosis of ASD showed: longitudinal mo from autism assessment at 36 mo based assess autism-specic

PEDIATRICS Volume 136, Supplement 1, October 2015


study diagnostic and treatment on DSM-IV criteria, ADI-R, and behaviors
programs; low-risk ADOS
No difference in number of Ongoing 15 low-risk infants (no infants recruited from Clinical diagnosis of ASD made at Computerized visual
risk markers measured by (N = 88 followed rst- or second- degree nurseries in same 24 mo in up to 7 SIBS-A who orienting task at 6 and 12
using AOSI up to age 24 mo; relatives with ASD) regions met DSM-IV criteria mo to assess ability to
6-mo data available (conrmed by using ADI-R and disengage from 1 of 2
on 44 SIBS-A) ADOS) competing visual stimuli
(attentional
disengagement)
No difference (P = .12) in Roughly matched IBQ at 6 and 12 mo to
disengagement of visual according to gender, measure infant
attention birth order, and age; temperament
N values varied by
assessment
Temperament characterized Available 6-mo outcome data MSEL and CDI-WG at 12 mo
by marked passivity and for 44 SIBS-A: to assess language and

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decreased activity level cognitive development
(P = .019)
Compared with non-ASD 4 with AD
siblings and controls
Behavioral observations at 6 mo 8 with ASD classication
do not predict later diagnosis on ADOS
32 without ASD
Social/emotional behavioral markers (from studies without outcome assessments)
Merin et al,73 2007 At 6 mo, diminished gaze to Prospective 31 at-risk infants (SIBS-A) Recruited by using research Not done Visual xation assessment
mothers eyes relative to institute database and during reciprocal social
mouth (10 of 11 infants with word of mouth interaction, conducted at
this nding were in at-risk age 6 mo via eye tracking
group) during modied still-face
paradigm

S31
SUPPLEMENT ARTICLE
TABLE 2 Continued

S32
First Author and Year Findings Type of Study Sample Ascertainment Outcome Diagnosis Comments
of Publication
24 with an older sibling Same sample as in Nadig
without autism et al,38 2007
Noland et al,76 2010 At 6.59 mo, higher working Prospective 25 SIBS-A SIBS-A recruited primarily Not done Trials at age 6.5 mo and/or
memory scores for SIBS-A through university-based 9 mo involving tasks

ZWAIGENBAUM et al
versus SIBS-TD for nonsocial service and ASD outreach relating to orienting
stimuli; no group difference program; SIBS-TD toward social and
for social stimuli recruited from telephone nonsocial targets
contacts by using state (stimuli); correct
birth record database response was infant gaze
toward location where
target most recently
appeared
30 SIBS-TD Trials videotaped, coded
for correct rst looks
Yirmiya et al,48 2006 At 4 mo: Prospective 21 dyads of mothers and Comparison group At age 14 mo, 1 subject was Measures at age 4 and
infants who were SIBS-A recruited from hospital suspected of having autism, 14 mo:
No signicant group Ongoing (N = 42 with 21 dyads and infants who maternity wards a diagnosis conrmed at ages BSID-II to assess general
difference in motherinfant 4-mo assessments) were SIBS-TD 24 and 36 mo by using ADI-R development and
synchrony, although SIBS-A and ADOS-G language
exhibited weaker synchrony
during infant-led interactions
No signicant group Matched on 1-to-1 basis ICQ to assess maternal
difference in infant gaze according to chronologic perception of infant
behavior during still-face age, gender, birth order, temperament
procedure but more neutral number of children in
affect and less upset with family, and Bayley mental
SIBS-A and motor scales
Signicantly more SIBS-A Social engagement
responded to name being measures at 4 mo:

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called by mother than Synchrony during
SIBS-TD motherchild free play
interaction
Infant gaze and affect
during still-face
paradigm
Procedure to assess
responsiveness to name
being called
TABLE 2 Continued
First Author and Year Findings Type of Study Sample Ascertainment Outcome Diagnosis Comments
of Publication
Language/communication behavioral markers (from studies with outcome assessment)
Colgan et al,77 2006 At 912 mo, decreased variety in Retrospective 21 children later Recruited through mailings Clinical diagnosis of AD made Home videotapes from ages
types of social interaction video study diagnosed with AD to child care centers and according to time of study 912 mo collected; edited
gestures used was developmental evaluation recruitment (preschool age), footage totaling 5 min
signicantly associated with centers; parent advocacy by using DSM-III-R or DSM-IV and including social
autism status group meetings; hospital criteria and, for 11 subjects, scenes, comparable
clinics; university-based score .30 on CARS across groups, were
autism subject registry coded for use of gestures
Other measures were not 14 children with TD Only gestures dened as
associated with an AD social interaction were
diagnosis: total number of used in this study
social interaction gestures, (gestural act used to

PEDIATRICS Volume 136, Supplement 1, October 2015


number of child-initiated attract or maintain
social interaction gestures attention of another for
social purposes; eg,
waving hello or good-bye,
shaking head yes or no)
Landa and At 6 mo, no signicant group Prospective 24 children with later SIBS-A recruited through ASD classied at 24 mo based on MSEL to assess general and
Garrett-Mayer,49 2006 differences in domains of longitudinal diagnosis of ASD Autism Society of America PLS, ADOS, and CDI language development
motor, visual reception, and 11 with later diagnosis of local chapters and across 5 domains of
language development language delay university-based center nonsocial development
52 classied as unaffected forautism; children at low (gross motor, ne
(at 24 mo) autism risk recruited motor, visual reception,
58 SIBS-A and infants with through local physician receptive and
no family history of ofces and caregiver- expressive language);
autism evaluated at 6 mo child play groups administered as close
as possible to ages 6, 14,
and 24 mo

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S33
SUPPLEMENT ARTICLE
TABLE 2 Continued

S34
First Author and Year Findings Type of Study Sample Ascertainment Outcome Diagnosis Comments
of Publication
Paul et al,78 2011 At age 612 mo, group Prospective 2838 high-risk infants Recruited from university Provisional diagnoses at 24 mo Vocalization samples
differences for certain cross-sectional (SIB-A) research pool; also based on clinical collected at age 6, 9, and
prelinguistic vocal behaviors design referrals from local observations, ADOS-T, and 12 mo during play with
pediatric practices, local MSEL mother and standard set

ZWAIGENBAUM et al
autism advocacy groups, of toys
Signicantly fewer speech-like Ongoing (N = 43 who 2031 low-risk infants (no word of mouth, Of the 24 high-risk subjects who Detailed analysis of vocal
vocalizations and more have participated in sibling with ASD advertising in parenting made a 24-mo visit: production (eg, for
nonspeech vocalization 24-mo follow-up) diagnosis) media consonant inventory,
presence of canonical
syllables) and
development of
prespeech vocalization
Signicantly fewer consonant 7 with ASD Discriminant function
types analyses included only
Signicantly fewer canonical 6 with symptoms without children at high risk
syllable shapes meeting full BAP criteria
Differences in vocal production 1 with nonautistic
in rst year of life associated developmental delay
with outcomes in terms of 10 without a clinical diagnosis
autistic symptoms in second
year for children at high risk
Studies may evaluate markers in .1 category (see Comments). AD, autistic disorder; ADI-R, Autism Diagnostic InterviewRevised; ADOS, Autism Diagnostic Observation Schedule; ADOS-G, Autism Diagnostic Observation ScheduleGeneric; ADOS-T, Autism
Diagnostic Observation ScheduleToddler Module; AOSI, Autism Observation Scale for Infants; BAP, broader autism phenotype; BSID-II, Bayley Scales of Infant Development2nd edition; CARS, Childhood Autism Rating Scale; CDI-WG, MacArthur
Communicative Development InventoriesWords and Gestures; DSM-III-R, Diagnostic and Statistical Manual of Mental Disorders, Third Edition, Revised; DSM-IV, Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition; DSM-IV-TR, Diagnostic
and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision; DVD, digital video disc (high-capacity optical disk); IBQ, Infant Behavior Questionnaire; ICQ, Infant Characteristics Questionnaire; M-CHAT, Modied Checklist for Autism in Toddlers;
PLS, Preschool Language Scale; PDD-NOS, pervasive developmental disorder not otherwise specied; SIBS-A, younger siblings of children with ASD; SIBS-TD, younger siblings of children with typical development; TD, typical development; VABS, Vineland
Adaptive Behavior Scales.

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SUPPLEMENT ARTICLE

24 months, 4 of these 7 subjects (all boys) later diagnosis of ASD and 25 low-risk extent of the broader ASD phenotype
exhibited dramatic declines in IQ into children matched according to gender (milder constellation of behavioral,
the severe impairment range. In a sec- and later determined to have typical cognitive, and other developmental
ond study comparing 50 infants aged development. There were no group characteristics that present in some
6 to 36 months who received a later differences at age 6 months, but a de- relatives of individuals with ASD).
diagnosis of ASD or typical develop- clining trajectory of specic behaviors However, group-level correlations do
ment,22 MSEL scores increased over over the next 12 months was noted in not always reect individual-level cor-
time for all, but starting at 12 months of the high-risk group. Group differences relations. Although some high-risk
age, the ASD group exhibited slower in gaze to faces and directed vocal- siblings will go on to receive a diagno-
nonverbal cognitive/language growth. izations were signicant by age sis of ASD, others will be diagnosed with
Similarly, Landa and Garrett-Mayer49 12 months and in social smiling by other disorders, and most will not.
reported that 24 children with ASD, 18 months; these ndings persisted Therefore, prevalence of an early be-
ascertained from a group of 87 high- through to 36 months. Similarly, in havioral marker in a group known to
risk infants, demonstrated reduced a cohort of 125 high-risk infants, re- have elevated ASD risk should not be
language and motor skills by age 14 duced social smiling, eye contact, so- taken as evidence that the marker
months and reduced skills in all areas cial interest, affect, and response predicts risk at the individual level
at age 24 months on the MSEL, com- to name at 12 months (but not at without knowing the outcome status of
pared with high-risk siblings who were 6 months) were predictive of diagnostic individuals.
developing typically. More recently, outcomes at 24 months.45 Declining
Landa et al66,80 have provided evidence trajectories of social communicative Statement 6: Caution should be
that declining trajectories in language behaviors associated with subse- exercised in generalizing ndings
and nonverbal cognitive skills (as quent ASD diagnoses have also been from studies of high-risk infants.
indexed by using the MSEL) in high-risk reported in another cohort of 204 Even when individual-level data on risk
infants are strongly associated with high-risk infants.80 Yoder et al43 also markers and ASD outcomes are avail-
a later diagnosis of ASD. Although reported declining rates of joint at- able in high-risk samples and markers
there may be uncertainty with regard tention behaviors in high-risk infants predictive of ASD are reported, such
to what is being measured by cog- subsequently diagnosed with ASD. ndings might not generalize to the
nitive assessments at young ages, As previously noted, Jones and Klin18 general population. High-risk sibling
the measurement equivalence of reported that a decline in the relative cohorts are unique in that their outcome
verbal and nonverbal indices over the amount of time that high-risk infants risk is many times greater than other
rst few years of life (ie, whether aged 2 to 6 months spent orienting to populations. In light of this nding and
measures are tapping the same de- the eyes versus mouth of a highly the accepted substantive involvement of
velopmental constructs at different engaging adult shown on video was genetic susceptibility factors in ASD
ages), and the extent to which social predictive of ASD. etiology, it is plausible to suspect that
and attentional abilities may be con- Thus, the monitoring of development unique risk mechanisms could be
tributing to childrens performance, over time may prove important in operating in this group. For example,
the ndings of declining trajectories assessing ASD risk, consistent with the initial reports suggested that abnor-
on standardized measures may nev- American Academy of Pediatrics rec- malities in DNA copy number varia-
ertheless provide important predictive ommendations for systematic surveil- tion in children with ASD were more
information. lance during well-child visits.79 common in simplex families than
in multiplex families.81 More recent
Atypical trajectory of early social Statement 5: Caution should be array- and exome-based studies result-
communication skills in ASD exercised in drawing conclusions ing from more advanced sequencing
The atypical trajectory of early social about early risk markers of ASD methods have not conrmed a higher
communication skills in ASD include from studies that do not include overall burden of genetic variants in
decreased social gaze, social smiles, individual-level outcome data. simplex families, although these stud-
and vocalizations between 6 and 12 to Studies comparing behavior proles ies continue to highlight the tremen-
18 months of age. Ozonoff et al22 reported across high- and low-risk groups can dous genetic diversity among and
on the emergence of social behavioral contribute to our understanding of within families. 82,83 Variations in ge-
signs in 25 high-risk siblings with a early emerging features as well as the netic mechanisms and the brain

PEDIATRICS Volume 136, Supplement 1, October 2015 S35


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networks to which they map might also Statement 8: Future efforts should tional imaging (eg, from electrophysi-
correlate with variation in early be- aim to identify: (1) early markers ological measurements) indices, with
havior proles,83 thus potentially that can be measured in routine behavioral measures of ASD. For ex-
limiting the extent to which risk clinical practice, involving direct ample, enlarged brain volumes in-
markers seen in high-risk cohorts observation and parental report; cluding both gray and white matter
(2) early biological processes have been reported in MRI studies of
apply to other samples. Although it is
measurable concurrently with, or
premature to assume that ndings toddlers with ASD.37,8489 Enlargement
before, overt behavioral markers; has been noted in the frontal and
from high-risk groups do not gener- and (3) combined approaches.
alize more broadly, until more is known temporal lobes 37,90 and in specic
about underlying causal mechanisms Markers measurable in routine subcortical structures, such as the
and their relationship to phenotypic clinical practice amygdala.36,91 Enlargement has been
proles, ample caution should be Many measures currently used in early observed in children as young as age
exercised. identication research involve video 12 months and may be accompanied by
coding of discrete behaviors, eye track- an increase in extra-axial uid.87 Head
Statement 7: Research about early ing, and/or the development of study- circumference, which is a crude proxy
markers of ASD should include specic cutoffs that are of limited for brain size, is generally consistent
diverse high- and low-risk samples. utility for present-day clinical prac- with brain enlargement in ASD,84 al-
tice. Efforts should be directed to- though a recent review has raised
Studies that examine cohorts at higher
ward the development and validation questions as to whether ASD-related
risk for ASD extending beyond infant
of easy-to-administer, reliable tools increases in head circumference have
sibling cohorts may offer some addi-
for measuring potential behavioral been largely driven by comparison with
tional advantages in ASD research.
markers within the context of routine outdated population-based norms.92 As
First, these groups (eg, infants born
clinical assessments; examples in- such, MRI is the gold standard for
prematurely or infants born to older
clude coding smiling during cognitive indexing structural brain develop-
parents) might be easier to assemble
assessment22 or the assessment of ment in ASD.
in large sample sizes. Moreover, such
head lag at 6 months,67 especially in In some MRI studies, brain overgrowth
cohorts will also prove useful for
high-risk infants. Methods should be was found to correlate with behavioral
assessing the generalizability of early
developed for gathering information markers at later ages. For example,
risk marker proles because they will
from caregivers and from direct ob- amygdala size was correlated with joint
have a mix of genetic susceptibility
servation and interaction with the attention ability measured at age
factors different from high-risk sib-
child, and for integrating these 4 years36 and with severity of social
ling cohorts yet still have elevated
sources of information to inform and communicative impairments mea-
outcome rates compared with general clinical judgment. In a recent study, sured at age 5 years.91 In another re-
population samples. Follow-up stud- 2 prospective measures of emerging cent study,93 aberrant development of
ies involving these cohorts may also symptoms of ASD were found to cor- white matter pathways was found be-
create opportunities to study whether relate highly: (1) frequency of specic tween 6 and 24 months of age in high-
early behavioral markers for ASD are social behaviors as coded from video- risk infants symptomatic for ASD at
ASD-specic or also predict other de- tape; and (2) independent examiner 24 months. Atypical neural responses,
velopmental end points that occur (eg, ratings of the frequency of social en- as indexed by event-related potentials,
intellectual disabilities). This point is gagement behaviors in a different set- at age 6 to 10 months to viewing
particularly critical because in the ting.22 This type of study design may faces (specically, the contrast between
absence of such comparison groups, accelerate the development of mea- viewing faces whose eye gaze was di-
we cannot conclude that behavioral sures that would be valid as well as rected toward, versus away from, the
markers associated with later di- more easily integrated into everyday infant) have also been reported to re-
agnosis in high-risk infant sibling practice. late to risk of ASD among high-risk
samples would be specic to ASDs infants.19 Using functional MRI during
in community samples that include Early neurobiological processes natural sleep, a new study showed that
the full spectrum of developmental Progress has also been made in the superior temporal gyrus (known to
and mental health disorders of early studying and integrating biological be involved in language processing)
onset. data, such as brain volume and func- was less activated in toddlers with

S36 ZWAIGENBAUM et al
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SUPPLEMENT ARTICLE

ASD relative to typically developing mental trajectory that is predictive of markers, as well as meta-analysis across
peers while listening to a simple bed- all diagnoses of ASD. Given the het- studies.
time story. Notably, these toddlers with erogeneity of ASD expression, it is
ASD were referred from the community unlikely that a single behavior will be ACKNOWLEDGMENTS
rather than being identied from found universally across all children The conference chairs and working
a high-risk sibling sample.94 Another or will serve as the dening marker groups acknowledge the precon-
functional MRI study, also with ASD for a later emerging ASD. Future re- ference contributions of Katarzyna
toddlers from the general population, search may improve ASD risk pre- Chawarska, PhD, who was unable to at-
found reduced correlation between the diction by examining combinations of tend the conference. We also acknowl-
right and left hemispheres in brain symptomatic abnormalities (both in edge the efforts of Katherine F. Murray,
regions key for language and social a cross-sectional manner and over BSN, RN, Massachusetts General Hos-
processing.95 Moreover, the levels of time) that constitute cumulative risk pital for Children, in coordinating the
abnormal interhemispheric correla- indices.96 Moreover, such a risk- forum and subsequent conference
tion could be used to distinguish tod- proling approach could incorporate report process, and Sifor Ng in the
dlers with ASD from control subjects at both behavioral and biological mark- conference report process.
an individual level, with a sensitivity of ers24 and thus offer the possibility of The meeting and consensus report
72% and a specicity of 84%. These more reliable identication of infants were sponsored by the Autism Forum.
reports encourage the search for at very high risk who could benet An important goal of the forum is to
neurologic biomarkers or others that from early intervention and/or pre- identify early indicators of ASDs that
may reect underlying pathologic pro- ventive approaches to mitigate symp- may lead to effective health care ser-
cesses in ASD and possibly precede tom development. It is also essential vices. Autism Forum programs are de-
and/or predict behavioral changes. that future studies report individual- veloped under the guidance of its
level data and adopt more consistent parent organization, the Northwest
Cumulative risk indices measures of relevant constructs to Autism Foundation. For this project,
Researchers have not found a single allow for accurate estimates of sen- the Autism Research Institute pro-
behavioral sign or a single develop- sitivity and specicity of precise risk vided nancial support.

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(Continued from rst page)


Drs Zwaigenbaum and Bauman initiated a literature review, co-chaired the meeting that generated the consensus recommendations outlined in this article, and
drafted 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, and
Natowicz were members of the working group that reviewed selected publications, contributed to initial recommendations that were reviewed at the consensus
meeting, and critically reviewed the manuscript; Drs Choueiri, Fein, Kasari, Pierce, Buie, Carter, Davis, Granpeesheh, Mailloux, Newschaffer, Robins, Smith Roley, and
Wetherby contributed to the consensus meeting that formed the basis for the manuscript and critically reviewed the manuscript; and all authors approved the nal
manuscript 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, Canada
T5G 0B7. E-mail: lonniez@ualberta.ca
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 Modied Checklist for Autism in Toddlers in electronic products. Dr Stone is the
author 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 honorarium
as 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 conicts of interest to disclose.

S40 ZWAIGENBAUM et al
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Early Identification of Autism Spectrum Disorder: Recommendations for
Practice and Research
Lonnie Zwaigenbaum, Margaret L. Bauman, Wendy L. Stone, Nurit Yirmiya, Annette
Estes, Robin L. Hansen, James C. McPartland, Marvin R. Natowicz, Roula Choueiri,
Deborah Fein, Connie Kasari, Karen Pierce, Timothy Buie, Alice Carter, Patricia A.
Davis, Doreen Granpeesheh, Zoe Mailloux, Craig Newschaffer, Diana Robins,
Susanne Smith Roley, Sheldon Wagner and Amy Wetherby
Pediatrics 2015;136;S10
DOI: 10.1542/peds.2014-3667C
Updated Information & including high resolution figures, can be found at:
Services /content/136/Supplement_1/S10.full.html
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PEDIATRICS is the official journal of the American Academy of Pediatrics. A monthly


publication, it has been published continuously since 1948. PEDIATRICS is owned, published,
and trademarked by the American Academy of Pediatrics, 141 Northwest Point Boulevard, Elk
Grove Village, Illinois, 60007. Copyright 2015 by the American Academy of Pediatrics. All
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Early Identification of Autism Spectrum Disorder: Recommendations for
Practice and Research
Lonnie Zwaigenbaum, Margaret L. Bauman, Wendy L. Stone, Nurit Yirmiya, Annette
Estes, Robin L. Hansen, James C. McPartland, Marvin R. Natowicz, Roula Choueiri,
Deborah Fein, Connie Kasari, Karen Pierce, Timothy Buie, Alice Carter, Patricia A.
Davis, Doreen Granpeesheh, Zoe Mailloux, Craig Newschaffer, Diana Robins,
Susanne Smith Roley, Sheldon Wagner and Amy Wetherby
Pediatrics 2015;136;S10
DOI: 10.1542/peds.2014-3667C

The online version of this article, along with updated information and services, is
located on the World Wide Web at:
/content/136/Supplement_1/S10.full.html

PEDIATRICS is the official journal of the American Academy of Pediatrics. A monthly


publication, it has been published continuously since 1948. PEDIATRICS is owned,
published, and trademarked by the American Academy of Pediatrics, 141 Northwest Point
Boulevard, Elk Grove Village, Illinois, 60007. Copyright 2015 by the American Academy
of Pediatrics. All rights reserved. Print ISSN: 0031-4005. Online ISSN: 1098-4275.

Downloaded from by guest on April 3, 2017