[show abstract][hide abstract] ABSTRACT: Autism is among the most clearly genetically determined of all cognitive-developmental disorders, with males affected more often than females. We have analyzed autism risk in multiplex families from the Autism Genetic Resource Exchange (AGRE) and find strong evidence for dominant transmission to male offspring. By incorporating generally accepted rates of autism and sibling recurrence, we find good fit for a simple genetic model in which most families fall into two types: a small minority for whom the risk of autism in male offspring is near 50%, and the vast majority for whom male offspring have a low risk. We propose an explanation that links these two types of families: sporadic autism in the low-risk families is mainly caused by spontaneous mutation with high penetrance in males and relatively poor penetrance in females; and high-risk families are from those offspring, most often females, who carry a new causative mutation but are unaffected and in turn transmit the mutation in dominant fashion to their offspring.
Proceedings of the National Academy of Sciences 08/2007; 104(31):12831-6. · 9.74 Impact Factor
[show abstract][hide abstract] ABSTRACT: Characterizing early communicative development in children with Autism Spectrum Disorders (ASD) is valuable for understanding profiles of ability in this population. The current investigation was modeled on Charman, Drew, Baird & Baird (2003b). Analyses explored parent report of early vocabulary, non-verbal communication, functional object use and play skills on the MacArthur-Bates Communicative Development Inventory (CDI) in 93 children with ASD, 31 children with developmental delay (DD) and 29 typically developing children. Results were generally consistent with those of Charman and colleagues (2003b), suggesting that skills improve with increasing non-verbal mental age and chronological age but that most children with ASD are delayed in receptive and expressive vocabulary and non-verbal communication, functional object use and play skills. Vocabulary profiles in the ASD sample were similar to those in the comparison samples, as was the developmental pattern of gesture and vocabulary mastery. However, when compared to published norms, children with ASD may show less of a discrepancy between their receptive and expressive vocabulary.
Journal of Child Language 08/2007; 34(3):623-54. · 1.41 Impact Factor
[show abstract][hide abstract] ABSTRACT: Autism spectrum disorders (ASD) are characterized by early impairments in language and related social communication skills. This investigation explored whether scores on the MacArthur-Bates Communicative Development Inventory (CDI) at ages 2 and 3 years predict outcome at age 9 years in children with ASD and developmental delay (DD).
Sixty-two children referred for possible autism at age 2 years, and 19 children with DD, were followed to age 9 years. Vocabulary, prespeech, and gestures scores on CDIs administered at ages 2 and 3 years were used to predict follow-up IQ, language, adaptive skills, and scores on diagnostic measures.
CDI scores at ages 2 and 3 did not predict outcome for the DD group. For the ASD sample, CDI receptive and expressive language and late gestures at ages 2 and 3 years predicted a number of follow-up variables, although scores at age 3 years were generally more predictive than scores at age 2 years.
The CDI yielded scores that were predictive of outcome, suggesting that this parent report measure may be a quick and informative assessment of early verbal and nonverbal skills in children with ASD.
Journal of Speech Language and Hearing Research 07/2007; 50(3):667-81. · 1.97 Impact Factor
[show abstract][hide abstract] ABSTRACT: The oxytocin receptor gene (OXTR) has been studied in autism because of the role of oxytocin (OT) in social cognition. Linkage has also been demonstrated to the region of OXTR in a large sample. Two single nucleotide polymorphisms (SNPs) and a haplotype constructed from them in OXTR have been associated with autism in the Chinese Han population. We tested whether these associations replicated in a Caucasian sample with strictly defined autistic disorder. We genotyped the two previously associated SNPs (rs2254298, rs53576) in 57 Caucasian autism trios. Probands met clinical, ADI-R, and ADOS criteria for autistic disorder. Significant association was detected at rs2254298 (p=0.03) but not rs53576. For rs2254298, overtransmission of the G allele to probands with autistic disorder was found which contrasts with the overtransmission of A previously reported in the Chinese Han sample. In both samples, G was more frequent than A. However, in our Caucasian autism trios and the CEU Caucasian HapMap samples the frequency of A was less than that reported in the Chinese Han and Chinese in Bejing HapMap samples. The haplotype test of association did not reveal excess transmission from parents to affected offspring. These findings provide support for association of OXTR with autism in a Caucasian population. Overtransmission of different alleles in different populations may be due to a different pattern of linkage disequilibrium between the marker rs2254298 and an as yet undetermined susceptibility variant in OXTR.
[show abstract][hide abstract] ABSTRACT: Autism Diagnostic Observation Schedule (ADOS) Modules 1-3 item and domain total distributions were reviewed for 1,630 assessments of children aged 14 months to 16 years with an autism spectrum disorder (ASD) or with heterogeneous non-spectrum disorders. Children were divided by language level and age to yield more homogeneous cells. Items were chosen that best differentiated between diagnoses and were arranged into domains on the basis of multi-factor item-response analysis. Reflecting recent research, the revised algorithm now consists of two new domains, Social Affect and Restricted, Repetitive Behaviors (RRB), combined to one score to which thresholds are applied, resulting in generally improved predictive value.
Journal of Autism and Developmental Disorders 05/2007; 37(4):613-27. · 3.34 Impact Factor
[show abstract][hide abstract] ABSTRACT: Autistic disorder (AD) and Williams syndrome (WS) are neurodevelopmental disorders characterized by contrasting abnormal social behavior (the former, socially avoidant; the latter, outwardly social); nonetheless, there are individuals with WS who display some behaviors that are characteristic of AD. We quantified the extent to which autism spectrum disorder (ASD) behaviors were present in children with WS.
Twenty children with WS (27-58 months) and 26 age- and IQ-equivalent children with AD were administered the Autism Diagnostic Observation Schedule (ADOS). ADOS behaviors were compared between groups.
Two children with WS met DSM-IV criteria for AD, one of whom was also classified as having AD by the ADOS algorithm. Discriminant analysis of ADOS behaviors indicated that gesture, showing, and quality of social overtures best discriminated the groups.
Although some children with WS demonstrated some ASD behaviors, and a minority of children with WS had coexisting AD, the symptom profile in WS was different from AD. Despite some deficits in communication behaviors, showing, and initiating joint attention, children with WS made social overtures and efforts to engage others, whereas children with AD tended not to do so.
Journal of the American Academy of Child & Adolescent Psychiatry 04/2007; 46(3):323-31. · 6.97 Impact Factor
[show abstract][hide abstract] ABSTRACT: The relationship between adaptive functioning (ability) and autism symptomatology (disability) remains unclear, especially for higher functioning individuals with autism spectrum disorder (ASD). This study investigates ability and disability using the Vineland and Autism Diagnostic Observation Schedule (ADOS), respectively, in two clinical samples of children with ASD. Participants included 187 males with VIQ > 70. Vineland scores were substantially below VIQ, highlighting the magnitude of adaptive impairments despite cognitive potential. A weak relationship was found between ability and disability. Negative relationships were found between age and Vineland scores and no relationships were found between age and ADOS scores. Positive relationships were found between IQ and Vineland Communication. Results stress the need for longitudinal studies on ability and disability in ASD and emphasize the importance of adaptive skills intervention.
Journal of Autism and Developmental Disorders 04/2007; 37(4):748-59. · 3.34 Impact Factor
[show abstract][hide abstract] ABSTRACT: Autism spectrum disorders (ASDs) are common, heritable neurodevelopmental conditions. The genetic architecture of ASDs is complex, requiring large samples to overcome heterogeneity. Here we broaden coverage and sample size relative to other studies of ASDs by using Affymetrix 10K SNP arrays and 1,181 [corrected] families with at least two affected individuals, performing the largest linkage scan to date while also analyzing copy number variation in these families. Linkage and copy number variation analyses implicate chromosome 11p12-p13 and neurexins, respectively, among other candidate loci. Neurexins team with previously implicated neuroligins for glutamatergic synaptogenesis, highlighting glutamate-related genes as promising candidates for contributing to ASDs.
[show abstract][hide abstract] ABSTRACT: To address methodological challenges in research on psychosocial interventions for autism spectrum disorder (ASD), a model was developed for systematically validating and disseminating interventions in a sequence of steps. First, initial efficacy studies are conducted to establish interventions as promising. Next, promising interventions are assembled into a manual, which undergoes pilot-testing. Then, randomized clinical trials test efficacy under controlled conditions. Finally, effectiveness studies evaluate outcomes in community settings. Guidelines for research designs at each step are presented. Based on the model, current priorities in ASD research include (a) preparation for efficacy and effectiveness trials by developing manuals for interventions that have shown promise and (b) initial efficacy studies on interventions for core features of ASD such as social reciprocity.
Journal of Autism and Developmental Disorders 03/2007; 37(2):354-66. · 3.34 Impact Factor
[show abstract][hide abstract] ABSTRACT: Many chromosomal regions for susceptibility to autism spectrum disorders (ASDs) have been identified, but few have reached genomewide significance. In response, researchers have attempted to increase the power of their analyses by stratifying samples to increase phenotypic homogeneity. Although homogeneity has typically been defined by a single variable, resultant groups often differ in other dimensions that may be directly pertinent. Group differences in age, gender, IQ, and measures of autism severity are examined as related to Autism Diagnostic Interview-Revised (ADI-R) domains previously used for subsetting or Quantitative Trait Analysis (QTL).
Participants were research participants and clinic referrals for assessment of possible autism. Assessments included the ADI-R, Autism Diagnostic Observation Schedule, Vineland Adaptive Behavior Scales, and a developmental or cognitive test. Data were collected for 983 individuals, ages 4 to 52 years, with diagnoses of autism and ASDs.
Findings suggest that, of several potential grouping variables, only restricted and repetitive behaviors associated with Insistence on Sameness were independent of age, IQ, and autism severity.
Results emphasize the potential unintended effects of stratification and the importance of understanding such interrelationships between phenotypic characteristics when defining subgroups or performing QTL.
[show abstract][hide abstract] ABSTRACT: Restricted and repetitive behaviors (RRBs) on the Autism Diagnostic Interview- Revised (ADI-R: Lord, Rutter, & Le Couteur (1994) were examined in 165 children with Autism Spectrum Disorders (ASD), 49 children with non-spectrum developmental disorders (DD), and 65 children with typical development (TD) at approximately 2 years of age. A factor analysis found evidence for a repetitive sensorimotor (RSM) factor and an insistence on sameness (IS) factor. Behaviors that loaded on the RSM factor were prevalent in children with ASD and significantly more common and severe than in children with DD or TD. On average, children with ASD had more RSM behaviors. Behaviors that loaded on the IS factor were relatively uncommon and did not differ in prevalence or severity across groups.
Journal of Autism and Developmental Disorders 02/2007; 37(1):73-85. · 3.34 Impact Factor
[show abstract][hide abstract] ABSTRACT: Social neuroscience is a new, interdisciplinary field devoted to understanding how biological systems im- plement social processes and behavior. Social neuroscience capitalizes on biological concepts and methods to inform and refine theories of social behavior, and it uses social and behavioral constructs and data to inform and refine the- ories of neural organizationandfunction.We focus here on the progress and potential of social neuroscience in the area of mental health. Research in social neuroscience has grown dramatically in recent years.Among the most active areas of research we found are brain-imaging studies in normal children and adults; animal models of social be- havior; studies of stroke patients; imaging studies of psy- chiatric patients; and research on social determinants of peripheral neural, neuroendocrine, and immunological processes. We also found that these areas of research are proceeding along largely independent trajectories. Our goals in this article are to review the development of this field, examine some currently promising approaches, identify obstacles and opportunities for future advances and integration, and consider howthis research can inform work on the diagnosis and treatment of mental disorders.
[show abstract][hide abstract] ABSTRACT: Social neuroscience is a new, interdisciplinary field devoted to understanding how biological systems im-plement social processes and behavior. Social neuroscience capitalizes on biological concepts and methods to inform and refine theories of social behavior, and it uses social and behavioral constructs and data to inform and refine the-ories of neural organization and function. We focus here on the progress and potential of social neuroscience in the area of mental health. Research in social neuroscience has grown dramatically in recent years. Among the most active areas of research we found are brain-imaging studies in normal children and adults; animal models of social be-havior; studies of stroke patients; imaging studies of psy-chiatric patients; and research on social determinants of peripheral neural, neuroendocrine, and immunological processes. We also found that these areas of research are proceeding along largely independent trajectories. Our goals in this article are to review the development of this field, examine some currently promising approaches, identify obstacles and opportunities for future advances and integration, and consider how this research can inform work on the diagnosis and treatment of mental disorders.
[show abstract][hide abstract] ABSTRACT: The serotonin transporter gene (SLC6A4) is a strong autism candidate gene because of its association with anxiety, aggression and attention, and the effectiveness of selective serotonin reuptake inhibitors (SSRIs) in treating certain behavioral symptoms. In families with individuals with autism, several reports of biased transmission of both alleles (short, long) at the serotonin transporter gene promotor polymorphism (5-HTTLPR) locus of SLC6A4 now exist. The heterogeneity in these reports may be due to clinical heterogeneity. The authors hypothesized that 5-HTTLPR genotypes would be related to variation in specific symptoms in children with autism.
The authors explored whether variants of two functional polymorphisms of SLC6A4 (5-HTTLPR, intron 2 variable number tandem repeat [2 VNTR]) were related to behavioral characteristics measured by the Autism Diagnostic Interview-Revised and Autism Diagnostic Observation Schedule. Subjects (N=73, age 3-19 years old) met diagnostic criteria for autistic disorder based on both measures.
Evidence of genotype-phenotype interactions on the Autism Diagnostic Interview-Revised was found with the 5-HTTLPR short group of HTTLPR (S/L or S/S genotypes) being rated as more severe on the subdomain "failure to use nonverbal communication to regulate social interaction," and the long group (L/L genotype) being more severe on the subdomain "stereotyped and repetitive motor mannerisms" and on an aggression measure. In contrast, on the Autism Diagnostic Observation Schedule, the long group was associated with greater severity on directed facial expressions and unusual sensory interests. There were no significant relationships between the intron 2 VNTR genotypes and subdomains or domains of symptoms on the Autism Diagnostic Interview-Revised or the Autism Diagnostic Observation Schedule.
These findings provide initial support for genotype-specific phenotypes for 5-HTTLPR in autism based on ratings from the Autism Diagnostic Interview-Revised and Autism Diagnostic Observation Schedule.
American Journal of Psychiatry 01/2007; 163(12):2148-56. · 14.72 Impact Factor
[show abstract][hide abstract] ABSTRACT: Research focusing on early development in children with Autism Spectrum Disorders (ASD) has been of particular interest in recent years. A greater understanding of the accuracy of early diagnosis, as well as the developmental pathways that are observed in young children with ASD, is of both theoretical and practical importance. In accordance with these concerns, this review addresses questions about three topics: the reliability of early diagnosis, the validity of using narrow versus broad diagnostic categories, and trajectories of development in children with ASD. Findings from two prospective longitudinal studies are reviewed. The first investigation included children referred for ASD at age 2 who were followed for one year. The second study followed children referred for ASD at age 2 until age 9. Results suggested that early diagnoses can be made reliably, that there is no empirical evidence for using narrowly defined diagnostic categories within ASD and that trajectories of development showed considerable heterogeneity.
[show abstract][hide abstract] ABSTRACT: Standard case criteria are proposed for combined use of the Autism Diagnostic Interview-Revised and Autism Diagnostic Observation Schedule to diagnose autism and to define the broader category of autism spectrum disorders.
Single and combined Autism Diagnostic Interview-Revised and Autism Diagnostic Observation Schedule algorithms were compared to best estimate diagnoses in four samples: U.S. (n = 960) and Canadian (n = 232) participants 3 years and older, U.S. participants younger than 36 months (n = 270), and U.S. participants older than 36 months with profound mental retardation (n = 67).
Sensitivities and specificities of 80% and higher were obtained when strict criteria for an autism diagnosis using both instruments were applied in the U.S. samples, and 75% or greater in the Canadian sample. Single-instrument criteria resulted in significant loss of specificity. Specificity was poor in the sample with profound mental retardation. Lower sensitivity and specificity were also obtained when proposed criteria for broader spectrum disorders were applied.
The Autism Diagnostic Interview-Revised and Autism Diagnostic Observation Schedule make independent, additive contributions to the judgment of clinicians that result in a more consistent and rigorous application of diagnostic criteria.
Journal of the American Academy of Child & Adolescent Psychiatry 10/2006; 45(9):1094-103. · 6.97 Impact Factor
[show abstract][hide abstract] ABSTRACT: The present study explored the relationship between nonverbal IQ and restricted and repetitive behaviors (RRBs) in 830 children with Autism Spectrum Disorders. The role of chronological age as a moderator of this relationship was also investigated. For many behaviors, there was a significant interaction between nonverbal IQ and chronological age, such that nonverbal IQ (NVIQ) was more strongly related to the prevalence of RRBs in older children. For the majority of such behaviors (e.g. repetitive use of objects, hand and finger mannerisms), RRB prevalence was negatively associated with NVIQ. However, the prevalence of certain behaviors (e.g. circumscribed interests) showed positive relationships with NVIQ, which provides some support for the idea of different classes of RRBs. For the severity of different RRBs, there were several significant effects for age and NVIQ, but few interactions.
[show abstract][hide abstract] ABSTRACT: Autism represents an unusual pattern of development beginning in the infant and toddler years.
To examine the stability of autism spectrum diagnoses made at ages 2 through 9 years and identify features that predicted later diagnosis.
Prospective study of diagnostic classifications from standardized instruments including a parent interview (Autism Diagnostic Interview-Revised [ADI-R]), an observational scale (Pre-Linguistic Autism Diagnostic Observation Schedule/Autism Diagnostic Observation Schedule [ADOS]), and independent clinical diagnoses made at ages 2 and 9 years compared with a clinical research team's criterion standard diagnoses.
Three inception cohorts: consecutive referrals for autism assessment to (1) state-funded community autism centers, (2) a private university autism clinic, and (3) case controls with developmental delay from community clinics.
At 2 years of age, 192 autism referrals and 22 developmentally delayed case controls; 172 children seen at 9 years of age.
Consensus best-estimate diagnoses at 9 years of age.
Percentage agreement between best-estimate diagnoses at 2 and 9 years of age was 67, with a weighted kappa of 0.72. Diagnostic change was primarily accounted for by movement from pervasive developmental disorder not otherwise specified to autism. Each measure at age 2 years was strongly prognostic for autism at age 9 years, with odds ratios of 6.6 for parent interview, 6.8 for observation, and 12.8 for clinical judgment. Once verbal IQ (P = .001) was taken into account at age 2 years, the ADI-R repetitive domain (P = .02) and the ADOS social (P = .05) and repetitive domains (P = .005) significantly predicted autism at age 9 years.
Diagnostic stability at age 9 years was very high for autism at age 2 years and less strong for pervasive developmental disorder not otherwise specified. Judgment of experienced clinicians, trained on standard instruments, consistently added to information available from parent interview and standardized observation.
Archives of General Psychiatry 07/2006; 63(6):694-701. · 13.77 Impact Factor
[show abstract][hide abstract] ABSTRACT: A multi-site study of 351 children with Autism Spectrum Disorders (ASD) and 31 typically developing children used caregiver interviews to describe the children's early acquisition and loss of social-communication milestones. For the majority of children with ASD who had experienced a regression, pre-loss development was clearly atypical. Children who had lost skills also showed slightly poorer outcomes in verbal IQ and social reciprocity, a later mean age of onset of autistic symptoms, and more gastrointestinal symptoms than children with ASD and no regression. There was no evidence that onset of autistic symptoms or of regression was related to measles-mumps-rubella vaccination. The implications of these findings for the existence of a 'regressive phenotype' of ASD are discussed.
Journal of Autism and Developmental Disorders 05/2006; 36(3):299-316. · 3.34 Impact Factor