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author:("houtman, Ted")
1.  A Parent-mediated Intervention to Increase Responsive Parental Behaviors and Child Communication in Children with ASD: A Randomized Clinical Trial 
Longitudinal research has demonstrated that responsive parental behaviors reliably predict subsequent language gains in children with autism spectrum disorder (ASD). To investigate the underlying causal mechanisms, we conducted a randomized clinical trial of an experimental intervention (Focused Playtime Intervention, FPI) that aims to enhance responsive parental communication (N = 70). Results showed a significant treatment effect of FPI on responsive parental behaviors. Findings also revealed a conditional effect of FPI on children’s expressive language outcomes at 12-month follow up, suggesting that children with baseline language skills below 12 months (N = 24) are most likely to benefit from FPI. Parents of children with more advanced language skills may require intervention strategies that go beyond FPI’s focus on responsive communication.
doi:10.1007/s10803-012-1584-y
PMCID: PMC3511916  PMID: 22825926
autism; randomized clinical trial; parent child communication; language; intervention
2.  Beyond Autism: A Baby Siblings Research Consortium Study of High-Risk Children at Three Years of Age 
Objective
First-degree relatives of persons with an autism spectrum disorder (ASD) are at increased risk for ASD-related characteristics. As little is known about the early expression of these characteristics, this study characterizes the non-ASD outcomes of 3-year-old high-risk (HR) siblings of children with ASD.
Method
Two groups of children without ASD participated: 507 HR siblings and 324 low-risk (LR) control subjects (no known relatives with ASD). Children were enrolled at a mean age of 8 months, and outcomes were assessed at 3 years. Outcome measures were Autism Diagnostic Observation Schedule (ADOS) calibrated severity scores, and Mullen Verbal and Non-Verbal Developmental Quotients (DQ).
Results
At 3 years, HR siblings without an ASD outcome exhibited higher mean ADOS severity scores and lower verbal and non-verbal DQs than LR controls. HR siblings were over-represented (21% HR versus 7% LR) in latent classes characterized by elevated ADOS severity and/or low to low-average DQs. The remaining HR siblings without ASD outcomes (79%) belonged to classes in which they were not differentially represented with respect to LR siblings.
Conclusions
Having removed a previously identified 18.7% of HR siblings with ASD outcomes from all analyses, HR siblings nevertheless exhibited higher mean levels of ASD severity and lower levels of developmental functioning than LR children. However, the latent class membership of four-fifths of the HR siblings was not significantly different from that of LR control subjects. One-fifth of HR siblings belonged to classes characterized by higher ASD severity and/or lower levels of developmental functioning. This empirically derived characterization of an early-emerging pattern of difficulties in a minority of 3-year-old HR siblings suggests the importance of developmental surveillance and early intervention for these children.
doi:10.1016/j.jaac.2012.12.011
PMCID: PMC3625370  PMID: 23452686
ASD; high-risk siblings; outcome; broad autism phenotype
3.  Imitation from 12 to 24 months in autism and typical development: A longitudinal Rasch analysis 
Developmental psychology  2011;47(6):1565-1578.
The development of imitation during the second year of life plays an important role in domains of socio-cognitive development such as language and social learning. Deficits in imitation ability in persons with autism spectrum disorder (ASD) have also been repeatedly documented from toddlerhood into adulthood, raising the possibility that early disruptions in imitation contribute to the onset of ASD and the deficits in language and social interaction that define the disorder. This study prospectively examined the development of imitation between 12 and 24 months of age in 154 infants at familial risk for ASD and 78 typically developing infants who were all later assessed at 36 months for ASD or other developmental delays. The study established a developmental measure of imitation ability, and examined group differences over time, using an analytic Rasch measurement model. Results revealed a unidimensional latent construct of imitation and verified a reliable sequence of imitation skills that was invariant over time for all outcome groups. Results also showed that all groups displayed similar significant linear increases in imitation ability between 12 and 24 months and that these increases were related to individual growth in both expressive language and ratings of social engagement, but not fine motor development. The group of children who developed ASD by age 3 years exhibited delayed imitation development compared to the low-risk typical outcome group across all time-points, but were indistinguishable from other high-risk infants who showed other cognitive delays not related to ASD.
doi:10.1037/a0025418
PMCID: PMC3712626  PMID: 21910524
imitation; autism; Rasch analysis; early identification; HGLM
4.  Infants’ Pre-Empathic Behaviors are Associated with Language Skills 
Infant behavior & development  2012;35(3):561-569.
Infants’ responses to other people’s distress reflect efforts to make sense of affective information about another person and apply it to oneself. This study sought to determine whether 12-month olds’ responses to another person’s display of negative affect reflect characteristics that support social learning and predict social functioning and language skills at 36 months. Measures of infants’ responsiveness include congruent changes in affect and looking time to the person in distress. Attention to the examiner displaying positive affect, analyzed as a control condition, was not related to social functioning or language skills at 36 months. Neither attention nor affective response to the examiner’s distress at 12 months was related to social functioning at 36 months. However, longer time spent looking at the examiner feigning distress predicted higher language scores. Moreover, infants who demonstrated a congruent affective response to distress had higher receptive language scores at 36 months than children who did not respond affectively. Importantly, these relations were not mediated by maternal education, household income, or 12-month verbal skills. These findings are consistent with the notion that adaptation to changes in a social partner’s affective state supports an infants’ ability to glean useful information from interactions with more experienced social partners. Infants’ sensitivity to affective signals may thus be related to the ability to interpret other people’s behavior and to achieve interpersonal understanding through language.
doi:10.1016/j.infbeh.2012.05.007
PMCID: PMC3428260  PMID: 22728336
Empathy; Infancy; Social Interaction; Language Development; Social Development
5.  Selective Visual Attention at Twelve Months: Signs of Autism in Early Social Interactions 
We examined social attention and attention shifting during (a) a play interaction between 12-month olds and an examiner and (b) after the examiner pretended to hurt herself. We coded the target and duration of infants’ visual fixations and frequency of attention shifts. Siblings of children with autism and controls with no family history of autism were tested at 12 months and screened for ASD at 36 months. Groups did not differ on proportion of attention to social stimuli or attention shifting during the play condition. All groups demonstrated more social attention and attention shifting during the distress condition. Infants later diagnosed with ASD tended to continue looking at a toy during the distress condition despite the salience of social information.
doi:10.1007/s10803-011-1262-5
PMCID: PMC3298631  PMID: 21519953
Autism; Broader autism phenotype; Visual attention; Attention shifting; Early identification
6.  Recurrence Risk for Autism Spectrum Disorders: A Baby Siblings Research Consortium Study 
Pediatrics  2011;128(3):e488-e495.
OBJECTIVE:
The recurrence risk of autism spectrum disorders (ASD) is estimated to be between 3% and 10%, but previous research was limited by small sample sizes and biases related to ascertainment, reporting, and stoppage factors. This study used prospective methods to obtain an updated estimate of sibling recurrence risk for ASD.
METHODS:
A prospective longitudinal study of infants at risk for ASD was conducted by a multisite international network, the Baby Siblings Research Consortium. Infants (n = 664) with an older biological sibling with ASD were followed from early in life to 36 months, when they were classified as having or not having ASD. An ASD classification required surpassing the cutoff of the Autism Diagnostic Observation Schedule and receiving a clinical diagnosis from an expert clinician.
RESULTS:
A total of 18.7% of the infants developed ASD. Infant gender and the presence of >1 older affected sibling were significant predictors of ASD outcome, and there was an almost threefold increase in risk for male subjects and an additional twofold increase in risk if there was >1 older affected sibling. The age of the infant at study enrollment, the gender and functioning level of the infant's older sibling, and other demographic factors did not predict ASD outcome.
CONCLUSIONS:
The sibling recurrence rate of ASD is higher than suggested by previous estimates. The size of the current sample and prospective nature of data collection minimized many limitations of previous studies of sibling recurrence. Clinical implications, including genetic counseling, are discussed.
doi:10.1542/peds.2010-2825
PMCID: PMC3164092  PMID: 21844053
autism; recurrence; sibling risk
7.  Response to Distress in Infants at Risk for Autism: A Prospective Longitudinal Study 
Background
Infants and preschoolers with ASD show impairment in their responses to other people's distress relative to children with other developmental delays and typically developing children. This deficit is expected to disrupt social interactions, social learning, and the formation of close relationships. Response to distress has not been evaluated previously in infants with ASD earlier than 18 months of age.
Methods
Participants were 103 infant siblings of children with autism and 55 low-risk controls. All children were screened for ASD at 36 months and 14 were diagnosed with ASD. Infants' responsiveness to distress was evaluated at 12, 18, 24, and 36 months. An examiner pretended to hit her finger with a toy mallet and infants' responses were video-recorded. Attention to the examiner and congruent changes in affect were coded on four-point Likert scales.
Results
Cross-sectional and longitudinal analyses confirm that the ASD group paid less attention and demonstrated less change in affect in response to the examiner's distress relative to the high-risk and low-risk participants who were not subsequently diagnosed with ASD. Group differences remained when verbal skills and general social responsiveness were included in the analytic models.
Conclusions
Diagnostic groups differ on distress response from 12 to 36 months of age. Distress-response measures are predictive of later ASD diagnosis above and beyond verbal impairments. Distress response is a worthwhile target for early intervention programs.
doi:10.1111/j.1469-7610.2010.02270.x
PMCID: PMC2920353  PMID: 20546081
autism; early identification; siblings; empathy; infancy
8.  Early Childhood Predictors of the Social Competence of Adults with Autism 
Longitudinal research into adult outcomes in autism remains limited. Unlike previous longitudinal examinations of adult outcome in autism, the twenty participants in this study were evaluated across multiple assessments between early childhood (M = 3.9 years) and adulthood (M = 26.6 years). In early childhood, responsiveness to joint attention (RJA), language, and intelligence were assessed. In adulthood, the parents of participants responded to interviews assessing the adaptive functioning, autistic symptomology and global functioning of their children. RJA and early childhood language predicted a composite measure of adult social functioning and independence. Early childhood language skills and intelligence predicted adult adaptive behaviors. RJA predicted adult non-verbal communication, social skills and symptoms. Adaptive behaviors changed with development, but symptoms of autism did not. Additional factors associated with adult outcomes are discussed.
doi:10.1007/s10803-011-1222-0
PMCID: PMC3265725  PMID: 22187106
Autism; Longitudinal; Outcome; Adulthood; Social functioning
9.  Common genetic variants on 5p14.1 associate with autism spectrum disorders 
Nature  2009;459(7246):528-533.
Autism spectrum disorders (ASDs) represent a group of childhood neurodevelopmental and neuropsychiatric disorders characterized by deficits in verbal communication, impairment of social interaction, and restricted and repetitive patterns of interests and behaviour. To identify common genetic risk factors underlying ASDs, here we present the results of genome-wide association studies on a cohort of 780 families (3,101 subjects) with affected children, and a second cohort of 1,204 affected subjects and 6,491 control subjects, all of whom were of European ancestry. Six single nucleotide polymorphisms between cadherin 10 (CDH10) and cadherin 9 (CDH9)—two genes encoding neuronal cell-adhesion molecules—revealed strong association signals, with the most significant SNP being rs4307059 (P = 3.4 × 10−8, odds ratio = 1.19). These signals were replicated in two independent cohorts, with combined P values ranging from 7.4 × 10−8 to 2.1 × 10−10. Our results implicate neuronal cell-adhesion molecules in the pathogenesis of ASDs, and represent, to our knowledge, the first demonstration of genome-wide significant association of common variants with susceptibility to ASDs.
doi:10.1038/nature07999
PMCID: PMC2943511  PMID: 19404256
10.  A Prospective Study of the Emergence of Early Behavioral Signs of Autism 
Objective
To examine prospectively the emergence of behavioral signs of autism in the first years of life in infants at low and high risk for autism.
Method
A prospective longitudinal design was used to compare 25 infants later diagnosed with an autism spectrum disorder (ASD) with 25 gender-matched low-risk children later determined to have typical development. Participants were evaluated at 6, 12, 18, 24, and 36 months of age. Frequencies of gaze to faces, social smiles, and directed vocalizations were coded from video and rated by examiners.
Results
The frequency of gaze to faces, shared smiles, and vocalizations to others were highly comparable between groups at 6 months of age, but significantly declining trajectories over time were apparent in the group later diagnosed with ASD. Group differences were significant by 12 months of age on most variables. Although repeated evaluation documented loss of skills in most infants with ASD, most parents did not report a regression in their child’s development.
Conclusions
These results suggest that behavioral signs of autism are not present at birth, as once suggested by Kanner, but emerge over time through a process of diminishment of key social communication behaviors. More children may present with a regressive course than previously thought, but parent report methods do not capture this phenomenon well. Implications for onset classification systems and clinical screening are also discussed.
PMCID: PMC2923050  PMID: 20410715
Autism; Onset; Infancy; Regression
11.  How Early Do Parent Concerns Predict Later Autism Diagnosis? 
Objective
To study the relationship between parent concerns about development in the first year and a half of life and later autism diagnostic outcomes.
Method
Parent concerns about development were collected for infants at high and low risk for autism, using a prospective, longitudinal design. Parents were asked about developmental concerns at study intake and when their infant was 6, 12, and 18 months. Infants were then followed up until 36 months, when diagnostic status was determined.
Results
By the time their child was 12 months, parents who have an older child with autism reported significantly more concerns in autism spectrum disorders-related areas than parents of children with typical outcomes. These concerns were significantly related to independent measures of developmental status and autism symptoms and helped predict which infants would later be diagnosed with autism or autism spectrum disorders. At 6 months, however, the concerns of parents who have an older child with autism do not predict outcome well.
Conclusion
Explicitly probing for parent concerns about development is useful for identifying children in need of closer monitoring and surveillance, as recommended by the American Academy of Pediatrics.
PMCID: PMC2919345  PMID: 19827218
12.  Behavioral Profiles of Affected and Unaffected Siblings of Children with Autism: Contribution of Measures of Mother–Infant Interaction and Nonverbal Communication 
We investigated whether deficits in social gaze and affect and in joint attention behaviors are evident within the first year of life among siblings of children with autism who go on to be diagnosed with autism or ASD (ASD) and siblings who are non-diagnosed (NoASD-sib) compared to low-risk controls. The ASD group did not differ from the other two groups at 6 months of age in the frequency of gaze, smiles, and vocalizations directed toward the caregiver, nor in their sensitivity to her withdrawal from interaction. However, by 12 months, infants in the ASD group exhibited lower rates of joint attention and requesting behaviors. In contrast, NoASD-sibs did not differ from comparison infants on any variables of interest at 6 and 12 months.
doi:10.1007/s10803-010-1051-6
PMCID: PMC3044086  PMID: 20568002
Autism; Broader autism phenotype; Early identification; Mother–infant interaction; Still face procedure; Nonverbal communication
13.  Play and Developmental Outcomes in Infant Siblings of Children with Autism 
We observed infant siblings of children with autism later diagnosed with ASD (ASD siblings; n = 17), infant siblings of children with autism with and without other delays (Other Delays and No Delays siblings; n = 12 and n = 19, respectively) and typically developing controls (TD controls; n = 19) during a free-play task at 18 months of age. Functional, symbolic, and repeated play actions were coded. ASD siblings showed fewer functional and more non-functional repeated play behaviors than TD controls. Other Delays and No Delays siblings showed more non-functional repeated play than TD controls. Group differences disappeared with the inclusion of verbal mental age. Play as an early indicator of autism and its relationship to the broader autism phenotype is discussed.
doi:10.1007/s10803-010-0941-y
PMCID: PMC2904459  PMID: 20112084
Autism spectrum disorders; Functional play; Symbolic play; Repetitive behaviors; Play; Infant siblings of children with autism
14.  Genome-Wide Analyses of Exonic Copy Number Variants in a Family-Based Study Point to Novel Autism Susceptibility Genes 
PLoS Genetics  2009;5(6):e1000536.
The genetics underlying the autism spectrum disorders (ASDs) is complex and remains poorly understood. Previous work has demonstrated an important role for structural variation in a subset of cases, but has lacked the resolution necessary to move beyond detection of large regions of potential interest to identification of individual genes. To pinpoint genes likely to contribute to ASD etiology, we performed high density genotyping in 912 multiplex families from the Autism Genetics Resource Exchange (AGRE) collection and contrasted results to those obtained for 1,488 healthy controls. Through prioritization of exonic deletions (eDels), exonic duplications (eDups), and whole gene duplication events (gDups), we identified more than 150 loci harboring rare variants in multiple unrelated probands, but no controls. Importantly, 27 of these were confirmed on examination of an independent replication cohort comprised of 859 cases and an additional 1,051 controls. Rare variants at known loci, including exonic deletions at NRXN1 and whole gene duplications encompassing UBE3A and several other genes in the 15q11–q13 region, were observed in the course of these analyses. Strong support was likewise observed for previously unreported genes such as BZRAP1, an adaptor molecule known to regulate synaptic transmission, with eDels or eDups observed in twelve unrelated cases but no controls (p = 2.3×10−5). Less is known about MDGA2, likewise observed to be case-specific (p = 1.3×10−4). But, it is notable that the encoded protein shows an unexpectedly high similarity to Contactin 4 (BLAST E-value = 3×10−39), which has also been linked to disease. That hundreds of distinct rare variants were each seen only once further highlights complexity in the ASDs and points to the continued need for larger cohorts.
Author Summary
Autism spectrum disorders (ASDs) are common neurodevelopmental syndromes with a strong genetic component. ASDs are characterized by disturbances in social behavior, impaired verbal and nonverbal communication, as well as repetitive behaviors and/or a restricted range of interests. To identify genes likely to contribute to ASD etiology, we performed high density genotyping in 912 multiplex families from the Autism Genetics Resource Exchange (AGRE) collection and contrasted results to those obtained for 1,488 healthy controls. To enrich for variants most likely to interfere with gene function, we restricted our analyses to deletions and gains encompassing exons. Of the many genomic regions highlighted, 27 were seen to harbor rare variants in cases and not controls, both in the first phase of our analysis, and also in an independent replication cohort comprised of 859 cases and 1,051 controls. More work in a larger number of individuals will be required to determine which of the rare alleles highlighted here are indeed related to the ASDs and how they act to shape risk.
doi:10.1371/journal.pgen.1000536
PMCID: PMC2695001  PMID: 19557195

Results 1-14 (14)