Somer L. Bishop

Insights into Autism Spectrum Disorder Genomic Architecture and Biology from 71 Risk Loci

Analysis of de novo CNVs (dnCNVs) from the full Simons Simplex Collection (SSC) (N = 2,591 families) replicates prior findings of strong association with autism spectrum disorders (ASDs) and confirms six risk loci (1q21.1, 3q29, 7q11.23, 16p11.2, 15q11.2-13, and 22q11.2). The addition of published CNV data from the Autism Genome Project (AGP) and exome sequencing data from the SSC and the Autism Sequencing Consortium (ASC) shows that genes within small de novo deletions, but not within large dnCNVs, significantly overlap the high-effect risk genes identified by sequencing. Alternatively, large dnCNVs are found likely to contain multiple modest-effect risk genes. Overall, we find strong evidence that de novo mutations are associated with ASD apart from the risk for intellectual disability. Extending the transmission and de novo association test (TADA) to include small de novo deletions reveals 71 ASD risk loci, including 6 CNV regions (noted above) and 65 risk genes (FDR ≤ 0.1).

A Multisite Study of the Clinical Diagnosis of Different Autism Spectrum Disorders

CONTEXT Best-estimate clinical diagnoses of specific autism spectrum disorders (autistic disorder, pervasive developmental disorder-not otherwise specified, and Asperger syndrome) have been used as the diagnostic gold standard, even when information from standardized instruments is available. OBJECTIVE To determine whether the relationships between behavioral phenotypes and clinical diagnoses of different autism spectrum disorders vary across 12 university-based sites. DESIGN Multisite observational study collecting clinical phenotype data (diagnostic, developmental, and demographic) for genetic research. Classification trees were used to identify characteristics that predicted diagnosis across and within sites. SETTING Participants were recruited through 12 university-based autism service providers into a genetic study of autism. PARTICIPANTS A total of 2102 probands (1814 male probands) between 4 and 18 years of age (mean [SD] age, 8.93 [3.5] years) who met autism spectrum criteria on the Autism Diagnostic Interview-Revised and the Autism Diagnostic Observation Schedule and who had a clinical diagnosis of an autism spectrum disorder. MAIN OUTCOME MEASURE Best-estimate clinical diagnoses predicted by standardized scores from diagnostic, cognitive, and behavioral measures. RESULTS Although distributions of scores on standardized measures were similar across sites, significant site differences emerged in best-estimate clinical diagnoses of specific autism spectrum disorders. Relationships between clinical diagnoses and standardized scores, particularly verbal IQ, language level, and core diagnostic features, varied across sites in weighting of information and cutoffs. CONCLUSIONS Clinical distinctions among categorical diagnostic subtypes of autism spectrum disorders were not reliable even across sites with well-documented fidelity using standardized diagnostic instruments. Results support the move from existing subgroupings of autism spectrum disorders to dimensional descriptions of core features of social affect and fixated, repetitive behaviors, together with characteristics such as language level and cognitive function.

Application of DSM-5 Criteria for Autism Spectrum Disorder to Three Samples of Children With DSM-IV Diagnoses of Pervasive Developmental Disorders

OBJECTIVE Substantial revisions to the DSM-IV criteria for autism spectrum disorders (ASDs) have been proposed in efforts to increase diagnostic sensitivity and specificity. This study evaluated the proposed DSM-5 criteria for the single diagnostic category of autism spectrum disorder in children with DSM-IV diagnoses of pervasive developmental disorders (PDDs) and non-PDD diagnoses. METHOD Three data sets included 4,453 children with DSM-IV clinical PDD diagnoses and 690 with non-PDD diagnoses (e.g., language disorder). Items from a parent report measure of ASD symptoms (Autism Diagnostic Interview-Revised) and clinical observation instrument (Autism Diagnostic Observation Schedule) were matched to DSM-5 criteria and used to evaluate the sensitivity and specificity of the proposed DSM-5 criteria and current DSM-IV criteria when compared with clinical diagnoses. RESULTS Based on just parent data, the proposed DSM-5 criteria identified 91% of children with clinical DSM-IV PDD diagnoses. Sensitivity remained high in specific subgroups, including girls and children under 4. The specificity of DSM-5 ASD was 0.53 overall, while the specificity of DSM-IV ranged from 0.24, for clinically diagnosed PDD not otherwise specified (PDD-NOS), to 0.53, for autistic disorder. When data were required from both parent and clinical observation, the specificity of the DSM-5 criteria increased to 0.63. CONCLUSIONS These results suggest that most children with DSM-IV PDD diagnoses would remain eligible for an ASD diagnosis under the proposed DSM-5 criteria. Compared with the DSM-IV criteria for Aspergers disorder and PDD-NOS, the DSM-5 ASD criteria have greater specificity, particularly when abnormalities are evident from both parents and clinical observation.

Association Between Restricted and Repetitive Behaviors and Nonverbal IQ in Children with Autism Spectrum Disorders

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.

Predictors of Perceived Negative Impact in Mothers of Children With Autism Spectrum Disorder

Mothers of 110 children with autism spectrum disorders (ASD) were interviewed with the Child and Adolescent Impact Assessment when their children were approximately 9 years old. Regression analyses revealed that African American mothers reported lower levels of perceived negative impact of having a child with ASD than did Caucasian mothers. Higher repetitive behavior scores on the Autism Diagnostic Interview-Revised, lower adaptive behavior scores on the Vineland Adaptive Behavior Scales, and less perceived social support were also significant predictors of higher perceived negative impact. Identifying predictors of perceived negative impact is an important first step in designing interventions to support families and target parents who may be at risk for experiencing higher levels of stress.

Daily Experiences Among Mothers of Adolescents and Adults with Autism Spectrum Disorder

In the present study, 96 co-residing mothers of adolescents and adults with an autism spectrum disorder (ASD) participated in an 8-day diary study and reported on their daily experiences. In comparison with a nationally representative sample of mothers of children without disabilities, mothers of adolescent and adult children with ASD spent significantly more time providing childcare and doing chores, and less time in leisure activities. Fatigue, arguments, avoided arguments, and stressful events were also more common among mothers of individuals with ASD. However, mothers of individuals with ASD reported similar levels of positive interactions and volunteerism as the comparison group. Daily experiences were subsequently related to well-being in both groups. These findings highlight the need for family support services.

Behavioral and Cognitive Characteristics of Females and Males With Autism in the Simons Simplex Collection

OBJECTIVE To examine differences in behavioral symptoms and cognitive functioning between males and females with autism spectrum disorder (ASD). METHOD We analyzed data from 2,418 probands with autism (304 females and 2,114 males) included in the Simons Simplex Collection. Sex differences were evaluated across measures of autism symptoms, cognitive and motor functioning, adaptive behavior, and associated behavior problems. Measurement bias was examined using latent variable models of symptoms. Unadjusted and propensity-adjusted analyses were computed to ensure that sex differences were not due to unbalanced sampling. Moderator and mediator analyses evaluated whether sex differences were modified by clinical characteristics or were driven by cognitive ability. RESULTS Females with ASD had greater social communication impairment, lower levels of restricted interests, lower cognitive ability, weaker adaptive skills, and greater externalizing problems relative to males. Symptom differences could not be accounted for by measurement differences, indicating that diagnostic instruments captured autism similarly in males and females. IQ reductions mediated greater social impairment and reduced adaptive behavior in females with ASD, but did not mediate reductions in restricted interests or increases in irritability. CONCLUSIONS A specific female ASD phenotype is emerging that cannot be accounted for by differential symptom measurement. The present data suggest that the relatively low proportion of high-functioning females may reflect the effect of protective biological factors or may be due to under-identification. Additional carefully accrued samples are needed to confirm the present pattern and to evaluate whether observed sex ratios in high-functioning cases are reduced if female-specific indicators of restricted interests are included.

Sex and gender differences in autism spectrum disorder: summarizing evidence gaps and identifying emerging areas of priority

One of the most consistent findings in autism spectrum disorder (ASD) research is a higher rate of ASD diagnosis in males than females. Despite this, remarkably little research has focused on the reasons for this disparity. Better understanding of this sex difference could lead to major advancements in the prevention or treatment of ASD in both males and females. In October of 2014, Autism Speaks and the Autism Science Foundation co-organized a meeting that brought together almost 60 clinicians, researchers, parents, and self-identified autistic individuals. Discussion at the meeting is summarized here with recommendations on directions of future research endeavors.

Convergent validity of the Mullen Scales of Early Learning and the differential ability scales in children with autism spectrum disorders.

Despite widespread use of the Mullen Scales of Early Learning (MSEL; E. M. Mullen, 1995 ) as a cognitive test for children with autism spectrum disorders and other developmental disabilities, the instrument has not been independently validated for use in these populations. Convergent validity of the MSEL and the Differential Ability Scales (DAS; C. D. Elliott, 1990 , 2007 ) was examined in 53 children with autism spectrum disorder and 19 children with nonspectrum diagnoses. Results showed good convergent validity with respect to nonverbal IQ (NVIQ), verbal IQ (VIQ), and NVIQ-VIQ profiles. These findings provide preliminary support for the practice of using MSEL age-equivalents to generate NVIQ and VIQ scores. Establishing convergent validity of cognitive tests is needed before IQs derived from different tests can be conceptualized as a uniform construct.

Measuring Anxiety as a Treatment Endpoint in Youth with Autism Spectrum Disorder

Despite the high rate of anxiety in individuals with autism spectrum disorder (ASD), measuring anxiety in ASD is fraught with uncertainty. This is due, in part, to incomplete consensus on the manifestations of anxiety in this population. Autism Speaks assembled a panel of experts to conduct a systematic review of available measures for anxiety in youth with ASD. To complete the review, the panel held monthly conference calls and two face-to-face meetings over a fourteen-month period. Thirty eight published studies were reviewed and ten assessment measures were examined: four were deemed appropriate for use in clinical trials, although with conditions; three were judged to be potentially appropriate, while three were considered not useful for clinical trials assessing anxiety. Despite recent advances, additional relevant, reliable and valid outcome measures are needed to evaluate treatments for anxiety in ASD.