The autism symptom interview, school-age: A brief telephone interview to identify autism spectrum disorders in 5-to-12-year-old children.

This study reports on the initial validation of the Autism Symptom Interview (ASI), School-Age, a brief (15-20 min) phone interview derived from questions from the Autism Diagnostic Interview-Revised (ADI-R). The ASI, School-Age was administered by interviewers with minimal training to parents of children ages 5 to 12 who had all been previously identified with (or referred for assessment of) ASD or another neurodevelopmental disorder. Children then underwent a comprehensive assessment to determine a best-estimate clinical diagnosis of ASD (n = 159) or non-ASD (e.g. language disorder, intellectual disability, ADHD; n = 130). Clinicians who conducted the assessments were blind to ASI results. ROC analyses compared ASI scores to clinical diagnosis. Due to the small number of participants with non-ASD diagnoses who were classified as nonverbal (i.e. not yet using phrases on a daily basis), it was not possible to assess sensitivity and specificity of the nonverbal algorithm in this sample. The verbal algorithm yielded a sensitivity of 0.87 (95% CI = 0.81-0.92) and a specificity of 0.62 (95% CI = 0.53-0.70). When used in conjunction with the Autism Diagnostic Observation Schedule (ADOS), sensitivity and specificity were 0.82 (95% CI = 0.74-0.88) and 0.92 (95% CI = 0.86-0.96), respectively. Internal consistency and test-retest reliability were both excellent. Particularly for verbal school age children, the ASI may serve as a useful tool to more quickly ascertain or classify children with ASD for research or clinical triaging purposes. Additional data collection is underway to determine the utility of the ASI in children who are younger and/or nonverbal. Autism Res 2017, 10: 78-88. © 2016 International Society for Autism Research, Wiley Periodicals, Inc.

Multidimensional Influences on Autism Symptom Measures: Implications for Use in Etiological Research.

OBJECTIVE: Growing awareness that symptoms of autism spectrum disorder (ASD) transcend multiple diagnostic categories, and major advances in the identification of genetic syndromes associated with ASD, have led to widespread use of ASD symptom measures in etiologic studies of neurodevelopmental disorders. Insufficient consideration of potentially confounding factors such as cognitive ability or behavior problems can have important negative consequences in interpretation of findings, including erroneous estimation of associations between ASD and etiologic factors. METHOD: Participants were 388 children 2 to 13 years old with diagnoses of ASD or another neurodevelopmental disorder without ASD. Receiver operating characteristics methods were used to assess the influence of IQ and emotional and behavioral problems on the discriminative ability of 3 widely used ASD symptom measures: the Social Responsiveness Scale (SRS), the Autism Diagnostic Interview-Revised (ADI-R), and the Autism Diagnostic Observation Schedule (ADOS). RESULTS: IQ influenced the discriminative thresholds of the SRS and ADI-R, and emotional and behavioral problems affected the discriminative thresholds of the SRS, ADI-R, and ADOS. This resulted in low specificity of ASD cutoffs on the SRS and ADI-R for children with intellectual disability without ASD (27-42%) and low specificity across all 3 instruments for children without ASD with increased emotional and behavioral problems (36-59%). Adjustment for these characteristics resulted in improved discriminative ability for all of the ASD measures. CONCLUSION: The findings indicate that scores on ASD symptom measures reflect far more than ASD symptoms. Valid interpretation of scores on these measures requires steps to account for the influences of IQ and emotional and behavioral problems.

Replication of Standardized ADOS Domain Scores in the Simons Simplex Collection.

Raw totals from diagnostic and screening measures for autism spectrum disorder (ASD) are frequently used as dimensional measures of autism symptom severity without appropriate correction for confounding factors, such as developmental level or non-ASD-specific behavior problems. Although these associated features are important to consider when diagnosing ASD and developing intervention plans, both researchers and clinicians sometimes need metrics of ASD severity that are not influenced by these factors. The Autism Diagnostic Observation Schedule (ADOS) domain calibrated severity scores (CSS) were created to provide separate estimates of social affect (SA-CSS) and restricted, repetitive behaviors (RRB-CSS) that are relatively independent of child characteristics (Hus et al., 2014). Using a sample of 2,509 probands with ASD from the Simons Simplex Collection (SSC), this study provides the first replication of the ADOS domain CSS in an independent sample. Consistent with the original standardization study, when applied to existing SSC data, the ADOS domain CSS were less influenced by age and cognitive ability compared to raw domain totals. Domain CSS were also relatively independent of behavior problems. Use of the ADOS domain CSS to assess relationships between ASD symptoms and genetic risk factors will increase confidence that associations reflect domain-specific relationships. Scores also offer less developmentally-influenced estimates of ASD severity for future phenotypic explorations in the SSC. This independent replication provides support for the application of the ADOS domain CSS in other samples, though further replication in population-based samples will be an important next step.

De novo insertions and deletions of predominantly paternal origin are associated with autism spectrum disorder.

Whole-exome sequencing (WES) studies have demonstrated the contribution of de novo loss-of-function single-nucleotide variants (SNVs) to autism spectrum disorder (ASD). However, challenges in the reliable detection of de novo insertions and deletions (indels) have limited inclusion of these variants in prior analyses. By applying a robust indel detection method to WES data from 787 ASD families (2,963 individuals), we demonstrate that de novo frameshift indels contribute to ASD risk (OR = 1.6; 95% CI = 1.0-2.7; p = 0.03), are more common in female probands (p = 0.02), are enriched among genes encoding FMRP targets (p = 6 × 10(-9)), and arise predominantly on the paternal chromosome (p < 0.001). On the basis of mutation rates in probands versus unaffected siblings, we conclude that de novo frameshift indels contribute to risk in approximately 3% of individuals with ASD. Finally, by observing clustering of mutations in unrelated probands, we uncover two ASD-associated genes: KMT2E (MLL5), a chromatin regulator, and RIMS1, a regulator of synaptic vesicle release.