STAART Network Centers: University of California, Los Angeles (UCLA)

Infants at Risk of Autism: A Longitudinal Study
Principle Investigator: Sigman; site: UCLA

A long-term goal of our research is to understand the earliest features of autism, leading to the design of early diagnostic measures and potential targets for early treatment. Autism is rarely diagnosed before the third year of life, yet retrospective video studies of infants later diagnosed with autism indicate that symptoms are often present by the first birthday. Earlier identification and treatment require greater knowledge of the developmental trajectory of children at risk for autism. A main goal of this study is to define this trajectory, via a longitudinal study across the age span from 6 to 42 months. This application is linked to a project submitted as part of a STAART Center by UCLA. Across the two sites (UC Davis & UCLA), the study will contrast the early development of children at risk for autism, infant siblings of children with autism (n = 180), with two other groups of infants at less risk, those with older siblings with developmental delays (n = 90), and those with older typically developing siblings (n = 90). Due to the strong genetic influence in autism and based on previous studies, we expect that 3 to 6% of the infant siblings of children with autism will develop autism in the first three years of life. An additional 15 to 35% of them will develop the broader autism phenotype, consisting of features that are milder but qualitatively similar to autism. Past research on the broader phenotype has focused on older children and adults; symptoms in early childhood have not been studied. New data from an ongoing multinational pilot study of infant siblings (Principal Investigator: Marian Sigman,) demonstrate significant group differences in verbal and nonverbal communication. Given these and other data, the second main goal of this study is to define the developing broader autism phenotype across infancy and early childhood.

Specific aims:

1. To compare the developmental course from 6 to 42 months of age of the three groups of infants, examining both social and communicative characteristics known to be associated with autism and the precursors of these characteristics
2. To identify siblings who develop either the full syndrome of autism, or the broader autism phenotype, in the preschool period
3. To examine relations between measures of facial, emotional, and linguistic perception and social and communicative interaction at 6 and 18 months with later development of autism or the broader phenotype.

Speech and Language Loci in Autism
Principal Investigator: Geschwind; site: UCLA

Genetic factors contribute significantly to autism susceptibility, but the heterogeneity of autism and autism spectrum disorders poses a challenge for genetic studies. Research from several groups suggests that studying cognitive or behavioral components of autism, or endophenotypes may aid in identification of more homogeneous subgroups and hasten the identification of genetic loci underlying this condition. We hypothesize that speech and language related endophenotypes may underlie several of the suggestive or probable autism linkage peaks. To uncover the extent to which speech and language related endophenotypes contribute to autism susceptibility loci, data and subjects from two ongoing projects, including Project I in this center proposal, will be used to identify and narrow language-related QTLs to a region small enough to permit a large scale gene by gene search. Our ongoing work in the AGRE resource has identified several autism peaks at the level of possible or probable linkage. In addition, we have identified one major and several minor linkage peaks related to speech and language delay in autistic siblings in this large autism cohort (AGRE). Parents and unaffected siblings in this sample have already been genotyped and, thus, have the potential to add power to the analysis without the requirement for additional genotyping. Therefore, we propose to evaluate parents and non-autistic sibs for a history of speech delay using an efficient questionnaire methodology in at least 330 AGRE families, bringing the number of sib pairs available for analysis to 690. QTL methodologies will be used to identify loci in the entire sample, as well as a subgroup of families stratified according to a parental history of developmental language-related problems. Independent confirmation of the speech and language related loci identified in AGRE will be assessed using the prospectively collected cohort of 180 infant-sib/autistic child pairs studied for language and social communication development in Project I. This provides the advantage of testing the language-related loci in an independent sample that is prospectively studied for receptive and expressive language and speech assessment, rather than depending entirely on retrospectively collected historical data. In addition, the availability of data on both receptive and expressive language will allow preliminary refinement of the language phenotype underlying these loci. Multivariate analysis will be used to explore the relationships among social communication, language, and outcomes of the children in Project I, and to explore the extent to which identified genetic loci have pleiotropic effects. Candidate genes within narrow linkage regions will be tested for association using SNP genotyping and family based association methods.

Specific Aims:

1. Previous work has identified one major and several minor linkage peaks related to speech and language delay in autistic siblings in a large autism cohort (AGRE sample). Parents and unaffected siblings in this sample have already been genotyped and, thus, have the potential to add power to the analysis without the requirement for additional genotyping. In order to extend the language delay analysis to the first-degree relatives of autistic siblings, parents and non-autistic sibs will be evaluated for a history of speech delay using an efficient questionnaire methodology in 330 families.
2. Linkage analysis will be performed with the language delay data collected in aim 1 using t) quantitative trait locus mapping (QTL) methodology to include the unaffected siblings in whom quantitative data can be reliably collected and 2) data on parental history of developmental language-related difficulties will be used to stratify the sib-pair sample into families with and without a parental history of developmental language problems.
3. The infant sib cohort studied in Project I in this proposed center offers an unusual opportunity for prospective study of expressive and receptive language and its relationship to autism. Independent confirmation and refinement of the language related loci identified in Aims 1 and 2 will be assessed using the cohort of 180 sibpairs studied in Project I.

Citalopram Treatment in Children with Autism Spectrum Disorders and High Levels of Repetitive Behavior
Principal Investigator: McCracken; site: UCLA
Multi-site study - see description under Social and Affective Processes in Autism
Primary Site: Boston University School of Medicine

Peer Interventions in Autism
Principal Investigator: Kasari; site: UCLA

Children with autism suffer from poor or absent peer relationships across their life span and regardless of age and ability. Although a number of peer intervention models have been employed, these models have not been subjected to systematic comparison, nor have they been implemented in regular school programs for school-aged children. The proposed research examines the effects of intervention on the peer relationships and social networks of children with autism. The goal of the proposed project is to examine children with autism's social inclusion in the classroom as a result of two different targeted peer interventions, a combined intervention condition, or no treatment. In one treatment, the intervention focuses on specifically improving the social skills of the child with autism. In the other treatment, the intervention focuses on peer engagement skills of typical classmates with the target child with autism. The combined condition offers a more comprehensive intervention, working with both the child with autism and their typical peers. The no-treatment comparison group reflects the current state of practice in local school districts, in which there are typically no systematic peer related interventions, just exposure to typical models.

Specific Aims:

1. Examine the effects of 2 different peer interaction interventions, a combination condition, and no systematic intervention on the social inclusion (social network ratings) of children with autism.
2. To assess the quality of peer interactions in unstructured playground settings as a function of intervention or no-intervention groups.
3. To determine the individual characteristics of child, teacher and classroom that predict to better social inclusion outcome.
4. To determine the effects of interventions on ratings of loneliness and friendship quality for targeted children.

Parent-Assisted Friendship Training in Autism
Principal Investigator: Frankel; site: UCLA

Social deficits are life long problems for children with Autism (ASD), yet few effective treatments exist. Almost none of the interventions commonly used to improve children's peer relations have used parents to aid the generalization of skills taught or have focused on the development of best friends. Parent Assisted Children's Friendship Training (CFT) is a 12-week outpatient based treatment which teaching children with Friendship problems how popular and accepted children handle key situations. Parents are integrated into treatment through collateral sessions that teach them how to monitor their child's interaction with peers and develop their child's social network. The plan is to diagnose children meeting criteria for ASD. Subjects will be evaluated for the presence of specific behaviors interfering with peer acceptance (e.g.,loud talking, public nosepicking).Subjects having these behaviors will be given individual behavioral programs for 4 weeks during the beginning of treatment. All subjects will be assigned randomly to one of two groups of 50 subjects each: CFTor Wait list (WL). This project proposes to compare 50 elementary school-aged subjects with high-functioning autism spectrum disorder who received parent-assisted friendship training (CFT) with 50 subjects in a wait-list control condition. Outcome measures are parent, teacher, and child questionnaires and play observation ratings. CFT teaches children to behave like popular and accepted peers in key situations and teaches parent how to supervise their child in play situations and help their child choose suitable friends.

Specific aims of the project are to assess the short-term impact of CFT vs.WL upon:

1. teacher report and behavioral play observation of peer interaction,
2. parent report of best friendships and
3. child report of self-esteem, loneliness and friendship quality, and
4. to test variables which may predict treatment response. Likely candidate variables measure the child's deviant and adaptive behavior and social comprehension at baseline.

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