Abstract Detecting early signs of autism is essential for timely diagnosis and initiation of effective inter-

ventions. Several research groups have initiated pro-

spective studies of high-risk populations including

infant siblings, to systematically collect data on early

signs within a longitudinal design. Despite the potential

advantages of prospective studies of young children at

high-risk for autism, there are also significant meth-

odological, ethical and practical challenges. This paper

outlines several of these challenges, including those

related to sampling (e.g., defining appropriate com-

parison groups), measurement and clinical implications

(e.g., addressing the needs of infants suspected of

having early signs). We suggest possible design and

implementation strategies to address these various

challenges, based on current research efforts in

the field and previous studies involving high-risk

populations.

Keywords Early identification Æ Screening Æ Longitudinal studies Æ Prospective studies Æ Infant Æ Autism Æ Child development Æ Siblings

Please note that the opinion and assertions contained herein are the private opinions of the authors and are not to be con- strued as official or as representing the views of the National Institute of Child Health and Human Development, the National Institute of Mental Health, or the National Institutes of Health.

L. Zwaigenbaum (&) Department of Paediatrics, McMaster Children’s Hospital at McMaster University, PO Box 2000, Hamilton, Ontario L8N 3Z5, Canada e-mail: [email protected]

A. Thurm Division of Pediatric Translational Research and Treatment Development, National Institute of Mental Health, Bethesda, MD, USA

W. Stone Departments of Pediatrics and Psychology & Human Development, Vanderbilt University, Nashville, TN, USA

G. Baranek Division of Occupational Science, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

S. Bryson Departments of Pediatrics and Psychology, Dalhousie University, Halifax, NS, USA

J. Iverson Department of Psychology, University of Pittsburgh, Pittsburgh, PA, USA

A. Kau Center for Developmental Biology and Perinatal Medicine, National Institute of Child Health and Human Development, Bethesda, MD, USA

A. Klin Yale Child Study Centre, Yale University, New Haven, CT, USA

C. Lord Department of Psychology, University of Michigan, Ann Arbor, MI, USA

R. Landa Department of Psychiatry and Behavioral Sciences, Kennedy Krieger Institute, Baltimore, MD, USA

J Autism Dev Disord (2007) 37:466–480

DOI 10.1007/s10803-006-0179-x

123

O R I G I N A L P A P E R

Studying the Emergence of Autism Spectrum Disorders in High-risk Infants: Methodological and Practical Issues

Lonnie Zwaigenbaum Æ Audrey Thurm Æ Wendy Stone Æ Grace Baranek Æ Susan Bryson Æ Jana Iverson Æ Alice Kau Æ Ami Klin Æ Cathy Lord Æ Rebecca Landa Æ Sally Rogers Æ Marian Sigman

Published online: 4 August 2006 � Springer Science+Business Media, Inc. 2006

Introduction

Overview

Several reviews over the past decade have highlighted

the importance of early recognition and specialized

intervention for improving outcomes for children with

autism spectrum disorders (ASD) (Dawson & Oster-

ling, 1997; Rogers, 1996; Smith, Groen, & Wynn, 2000).

Although recent service registry (Croen, Grether,

Hoogstrate, & Selvin, 2002) and population-based data

(Yeargin-Alsopp, et al., 2003) suggest that more chil-

dren are being diagnosed prior to age 4 years than in

the past, a formal diagnosis may still lag years behind

the time when parents initially identify concerns

(Coonrod & Stone, 2004; Howlin & Moore, 1997;

Siegel, Pliner, Eschler, & Elliott, 1988). As a result,

interest has increased in identifying and raising

awareness regarding the characteristics of ASD present

at young ages (Bryson, Zwaigenbaum & Roberts, 2004;

Landa, 2003). In addition to improving outcomes,

earlier diagnosis allows parents the opportunity to

receive counseling regarding current estimates of

recurrence risk in autism, which they may take into

account in future family planning. Research to date

supports the conclusions that one can: (1) reliably

diagnose as young as 24 months (Lord, 1995; Stone

et al., 1999); and (2) observe the behavioral markers of

autism well before 24 months (e.g., Dahlgren & Gill-

berg, 1989; Ohta, Nagai, Hara, & Sasaki, 1987; Rogers

& DiLalla, 1990).

Most of the work aimed at identifying early signs of

ASD has been retrospective, focusing on early behav-

ioral evidence of the disorder in children who have

already received a diagnosis. The most common

methods used to gather information about earlier

behaviors have been retrospective reports from parents

and analysis of early home videotapes. Although

research using these approaches has supported clinical

efforts aimed at earlier detection, many questions

regarding early signs, their timing, and their underlying

developmental mechanisms remain. Prospective

research into the early development of ASD in

high-risk infants is an exciting new frontier, and can

potentially answering these questions more systemati-

cally, while avoiding some of the biases associated with

retrospective designs. In this paper, we outline the

theoretical advantages and general feasibility of pro-

spective studies of young children at high-risk for

ASD, and acknowledge and discuss the significant

methodological, ethical and practical challenges that

accompany these studies. Issues discussed include the

design of high-risk studies, selection of comparison

groups, measurement of developmental delay and

deviance, generalizability, and clinical interpretation of

findings.

Identifying Early Signs of Autism using

Retrospective Designs

Retrospective parental reports offer a unique window

into early behaviors of children with ASD, as parents

have the advantage of observing their children’s

behavior over time and across a variety of settings.

Investigators report a wide range of symptoms that are

more common in children with autism under the age of

24 months than similar-aged children with develop-

mental delays or mental retardation (DD). Early

symptoms associated with autism cross several devel-

opmental domains, including social behavior (Dahlgren

& Gillberg, 1989; De Giacomo & Fombonne, 1998;

Hoshino et al., 1982; Ohta et al., 1987; Young, Brewer,

& Pattison, 2003), communication (Dahlgren &

Gillberg, 1989; De Giacomo & Fombonne, 1998; Ohta

et al., 1987; Young et al., 2003), affective expression

(Dahlgren & Gillberg, 1989; De Giacomo &

Fombonne, 1998; Hoshino et al., 1982), and sensory

hypo- and hypersensitivities (Dahlgren & Gillberg,

1989; De Giacomo & Fombonne, 1998; Hoshino et al.,

1982). These findings have been very important in

guiding further research aimed at identifying early signs

of ASD. However, a number of factors limit parents’

ability to provide accurate descriptions of early

behaviors. First, a parent’s incidental observations

regarding the subtle social and communicative differ-

ences that characterize young children with autism may

be limited compared to systematic assessment by

trained clinicians (Stone, Hoffman, Lewis, & Ousley,

1994). Moreover, their tendency to use compensatory

strategies to elicit their child’s best behaviors (with or

without their awareness) may affect their behavioral

descriptions (Baranek, 1999). Retrospective parental

R. Landa Department of Psychiatry and Behavioral Sciences, Johns Hopkins School of Medicine, Baltimore, MD, USA

S. Rogers Department of Psychiatry and Behavioral Sciences, University of California at Davis, Sacramento, CA, USA

M. Sigman Departments of Psychology and Psychiatry, University of California, Los Angeles, CA, USA

J Autism Dev Disord (2007) 37:466–480 467

123

reports may be also be prone to errors and distortions of

recall, especially when one asks parents to remember

behaviors that occurred many years ago. In particular,

having already received a diagnosis of autism for their

child, parents may bias their reports toward behaviors

that are consistent with the diagnosis. A recent retro-

spective study overcame some of these problems by

gathering information about behaviors under

24 months from parents of preschoolers before they had

received a diagnosis (Wimpory, Hobson, Williams, &

Nash, 2000). However, limitations of this methodology

remain, as retrospective reports are not generally

informative on the issue of whether differences in early

social and communicative development are best char-

acterized by delayed emergence, reduced frequency, or

truly abnormal or deviant quality of fundamental skills

such as joint attention.

A second strategy for obtaining retrospective

information about characteristics of autism present

before 24 months is the analysis of early videotapes of

children made by their parents. This approach has

significant strengths relative to retrospective parental

reports: it allows the observation of behaviors as they

occur in familiar and natural settings, and enables

objective rating of behavior by unbiased observers.

However, this methodology is not without its limita-

tions, the foremost being that parents record these

tapes to preserve family memories, rather than to

document their child’s behavior across a variety of

settings. As a result, tapes from different families will

naturally vary as a function of the quality of the

recording, the activities and settings that were

recorded, and the length of time the child is visible.

Moreover, if children do not behave as expected (or

desired), parents may re-record taped segments until

they obtain the desired response. Efforts to standardize

tapes across families can be extremely difficult and

time intensive (Baranek, 1999). Moreover, most

studies employing home videotapes have used children

with typical development (TD) rather than those with

DD as comparison groups, which limits the extent of

our knowledge about autism-specific deficits. Behav-

iors found to differentiate children with ASD from

children with TD under 24 months by at least two

studies are: responding to name (Baranek, 1999;

Osterling & Dawson, 1994; Osterling, Dawson, &

Munson, 2002), looking at others (Adrien et al., 1993;

Maestro et al., 2002; Osterling & Dawson, 1994;

Osterling et al., 2002), smiling at others (Adrien et al.,

1993; Maestro et al., 2002), and motor stereotypies

(Adrien et al., 1993; Baranek, 1999). Only two studies

published to date compared behaviors of children with

ASD with those of children with DD younger than

24 months; these found that children with ASD were

less likely to respond to their name (Baranek, 1999;

Osterling et al., 2002) and to look at others (Osterling

et al., 2002). Notably, analysis of home videos also

highlights that there is may be a subgroup of ‘‘late

onset’’ children whose early behavioral symptoms are

less apparent (Osterling et al., 2002; Werner, Dawson,

Osterling, & Dinno, 2000).

Potential Advantages of Prospective Studies

Retrospective parental reports and analyses of home

videos can help guide the development of early iden-

tification and screening procedures (as argued by Fil-

ipek et al., 1999), but these procedures must ultimately

be validated empirically in prospective studies, with

sufficient follow-up of both screen positive and screen

negative children to allow estimates of sensitivity and

specificity. In fact, prospective studies of high-risk

infants (which, until recently, have been rare in autism)

may also identify novel behavioral (and biological)

markers that show the way forward in developing more

effective early identification and screening measures.

Prospective studies are not subject to recall biases, they

can be designed to examine specific constructs of

interest, and they can provide comparable data col-

lection points and methods across children. Perhaps,

most importantly, these studies allow collection of data

longitudinally across different ages, which can foster

our understanding of developmental trajectories and

the impact of early delays in one domain (e.g., social

orienting) on the subsequent development of another

(e.g., language).

High-risk samples have informed studies of other

neurodevelopmental and neuropsychiatric conditions,

including language/reading disorders (Carroll &

Snowling, 2004), attention deficit hyperactivity disor-

der (Faraone, Biederman, Mennin, Gershon, & Tsu-

ang, 1996), bipolar affective disorder (Chang, Steiner,

& Ketter, 2000; Geller, Tillman, Craney, & Bolhofner,

2004), and schizophrenia (Schubert & McNeil, 2004).

Prospective studies of siblings and offspring of affected

probands have generated significant insights regarding

premorbid development and predictors of illness in

these high-risk groups. For example, children with

schizophrenic parents have attention and verbal

memory deficits, gross motor delays, and dysfunction

of smooth-pursuit eye movements (Erlenmeyer-Kim-

ling, 2000; Schubert & McNeil, 2004), and children with

a parent or sibling with dyslexia have greater difficulty

with phonological processing than age-matched low-

risk controls, despite normal early language develop-

ment (Carroll & Snowling, 2004). Notably, these

468 J Autism Dev Disord (2007) 37:466–480

123

studies generally focus on group differences between

high- and low-risk children rather than the association

between early markers and outcome status, because of

insufficient power and/or follow-up. In contrast,

autism can be diagnosed in early childhood, so out-

comes can be determined after a relatively short

follow-up period. Hence, one can study autism pro-

spectively much more easily (i.e., with fewer resources

and with less risk of sample loss) than an adult-onset

disorder such as schizophrenia.

Prospective Studies in Autism: Siblings and other

High-Risk Groups

Several populations at increased risk of ASD that can

be identified in early childhood: children with early

signs of autism or developmental delays (DD) identi-

fied through population screening, children at

increased risk of autism due to specific medical diag-

noses or genetic anomalies, and the main focus of this

paper, infants with an older sibling with ASD.

At least two research groups have studied early

signs of autism in high-risk samples identified by

population screening. Charman et al., (1997) and

Swettenham et al., (1998), reported on a high-risk group

of children who failed the Checklist for Autism in

Toddlers (CHAT; Baron-Cohen, Allen, & Gillberg,

1992), a screening measure administered at 18 months

of age. Detailed assessment of social, communication

and play skills was completed at 20 months, and

diagnostic outcomes were assessed at age of three and a

half. Children subsequently diagnosed with autism were

compared to those subsequently diagnosed with devel-

opmental delay based to their 20-month skills. At this

early age, the children with autism spent less time

looking at adults during free play (Swettenham et al.,

1998), were less likely to look at the face of an adult

feigning distress (Charman et al., 1997), showed less

gaze switching between people and objects (Charman

et al., 1997; Swettenham et al., 1998), and showed less

imitation (Charman et al., 1997). Wetherby et al., (2004)

followed a group of children who had failed communi-

cation screening using the Communication and Sym-

bolic Behavior Scales Developmental Profile (CSBS

DP, Wetherby & Prizant, 2002). They obtained video-

tapes of the CSBS Behavior Sample at a mean age of

18–21 months for children who received later diagnoses

of autism, DD, or who were typically developing.

Specific features that differentiated children with

autism from the other two groups include social-

communication behaviors (e.g., reduced eye gaze,

coordination of gaze with other nonverbal behaviors,

directing attention, responding to name, and unusual

prosody) and repetitive body and object use. Notably,

the content of the initial screen (i.e., children are se-

lected based on a particular profile of early signs), may

introduce sampling biases, and the fact that data are

only collected from the point of first screening onward

limits the age range over which autism can be studied.

There are also children at increased risk for autism

due to medical risk factors, such as Fragile X syndrome

(Rogers, Wehner & Hagerman et al., 2001), specific

chromosome abnormalities (Xu, Zwaigenbaum, Szat-

mari & Scherer, 2004), tuberous sclerosis (Bolton &

Griffiths, 1997), and prenatal exposure to valproic acid

(Williams et al., 2001) or thalidomide (Stromland et al.,

2002). However, these specific risk factors are all rel-

atively rare and would be difficult to study in large

numbers, and may be associated with unique clinical

features that may not generalize to other children with

autism.

There is growing interest in studying infant siblings

of children with ASD, who are arguably the most

clearly defined high-risk group available. Notably,

Baron-Cohen et al., (2002) originally developed the

CHAT screening algorithm based on items that, at

18 months, were atypical in four siblings subsequently

diagnosed with autism. More recent reports by Pilow-

sky and colleagues (Pilowski, Yirmiya, Shalev, &

Gross-Tsur, 2003; Pilowski, Yirmiya, Doppelt, Gross-

Tsur, & Shalev, 2004) support the feasibility of study-

ing early development in siblings and Zwaigenbaum

et al., (2005) reported several behavioral markers

which, at 12 months, predict a subsequent diagnosis of

autism in a sibling sample. In addition, Landa & Gar-

rett-Mayer (2006) report developmental levels and

trajectories in that differentiate infant siblings later

diagnosed with autism spectrum disorder, beginning at

6 months of age. Autism is associated with the highest

relative risk in siblings, compared to general popula-

tion of all the neuropsychiatric disorders (Szatmari,

Jones, Zwaigenbaum & MacLean, 1998). Previous

studies found rates of autism in siblings of children

with autism range from 3% to 5%, which is at least

20 times higher than rates of autism in the general

population (Bailey, Phillips & Rutter, 1996; Simonoff,

1998; Szatmari et al., 1998). In fact, estimates of

recurrence risk (that is, the risk to later-born children)

may be as high as 8.6% when one child in the family

has autism, and 35% when two siblings have autism

(Ritvo et al., 1989). Notably, these risk estimates may

be somewhat conservative, as they come mainly from

studies conducted over 20 years ago, using more

restrictive diagnostic criteria (DSM-III).

The risk to relatives of individuals with autism also

extends beyond the traditional boundaries of the

J Autism Dev Disord (2007) 37:466–480 469

123

autistic spectrum (Bailey, Palferman, Heavey, & Le

Couteur, 1998). Family members have higher rates of

certain psychiatric and developmental disorders, com-

pared to individuals with no family history of autism

(Landa, Folstein & Isaacs, 1991; Landa et al., 1992;

Pickles et al., 2000; Piven, Palmer, Jacobi, Childress, &

Arndt, 1997; Smalley, McCracken, & Tanguay, 1995;

Yirmiya & Shaked, 2005). As well, because of the early

age of diagnosis of the proband, one can ascertain sib-

lings in early infancy or even prenatally, making it

possible to study early neurodevelopmental mecha-

nisms, and to partially avoid (or at least to systemati-

cally measure) the impact of potentially confounding

environmental factors. Infant sibling research offers

unique opportunities to study the neural origins and

developmental cascade that leads to autism, potentially

providing new insights into its neurobiology, improved

methods of early detection, and earlier opportunities for

intervention.

In August 2003, the National Alliance for Autism

Research (NAAR) and the National Institute of Child

Health and Human Development (NICHD) co-spon-

sored a workshop for researchers engaged in the study

of populations of young children at high-risk for autism,

particularly siblings of children with autism. Despite the

theoretical advantages and exciting opportunities

associated with this research design, there are clearly

significant methodological, ethical and practical chal-

lenges facing researchers studying young children at

high-risk for autism. In the remainder of this paper we

outline several of these challenges, including those

related to sampling (e.g., recruitment of adequately

sized samples, determining inclusion/exclusion criteria

for high-risk infants and appropriate comparison

groups), measurement (e.g., selection of constructs and

measures) and clinical implications (e.g., clinical man-

agement of infants who appear to have early signs of

ASD). We suggest possible design and implementation

solutions for these various challenges, based on current

research efforts in the field and previous studies

involving high-risk populations. These issues have

implications not only for research with infant siblings,

but also for research in other aspects of early charac-

terization and diagnosis of autism.

Issues Related to Sampling

Sample Size

High-risk studies in other fields (e.g., schizophrenia,

dyslexia) have generally been designed to compare

siblings with controls on a group basis, without

knowing the ultimate outcomes of individual siblings

(Carroll & Snowling, 2004; Erlenmeyer-Kimling,

2000). Initial infant sibling studies of ASD by Pilowski

and colleagues (2003, 2004) also focus on group com-

parisons. However, if the main objective of a sibling

study is to identify early markers that are predictive of

a specific diagnosis, then individual outcomes become

important, and one must power the sample size with

reference to the expected number of participants who

will have the diagnosis of interest (i.e., not the total

number of infants enrolled).

The required sample size for these studies will

depend on the specific research question posed. A few

issues are considered for illustration. First, if one

defines the outcome of interest more broadly (e.g.,

language delay), there will be a larger number of sib-

lings with that outcome, potentially making it easier to

detect differences between ‘affected’ and ‘unaffected’

siblings. However, predictors of secondary outcomes

such as language delay may not generalize outside of an

autism sibling sample, limiting the clinical utility of such

findings. A second issue to consider is the strength of

the association between the predictor variables and

outcome under study (e.g., the sensitivity and specificity

of early markers for the subsequent diagnosis of aut-

ism), which will influence the power to detect a rela-

tionship. However, the investigator may sometimes

select predictor variables on a theoretical basis, so the

actual strength of the relation between predictor and

outcome variables may be difficult to estimate with

confidence. A third variable to consider is the number

of outcomes/variables being studied; for example,

contrasting siblings by more than two outcomes (e.g.,

ASD versus developmental delay versus typical devel-

opment), or examining the effects of stratification

variables (e.g., gender) within and across groups may be

of interest, but will require even larger samples sizes.

Due to limitations on numbers of infants born to

older siblings with autism within specified geographic

regions, studies may maximize their efforts to collect

data in a timely fashion by establishing collaborations

across multiple sites and utilizing a common set of

core assessment measures. Such collaborations accel-

erate the process of identifying early predictors of

outcome by increasing the collective sample size so

that investigators can address more refined questions

about outcomes and predictors. Although collabora-

tions between research groups require additional ef-

fort and resources to support the necessary steps of

ensuring consistency in methods and measures, as well

as inter-rater reliability for observations, these proce-

dures allow the examination of consistency of findings

across sites, ensure the fidelity of assessment

470 J Autism Dev Disord (2007) 37:466–480

123

measures, and facilitate future attempts to repl

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