Quantitative autism symptom patterns recapitulate differential mechanisms of genetic transmission in single and multiple incidence families

Abstract Background Previous studies have demonstrated aggregation of autistic traits in undiagnosed family members of children with autism spectrum disorder (ASD), which has significant implications for ASD risk in their offspring. This study capitalizes upon a large, quantitatively characterized clinical-epidemiologic family sample to establish the extent to which family transmission pattern and sex modulate ASD trait aggregation. Methods Data were analyzed from 5515 siblings (2657 non-ASD and 2858 ASD) included in the Interactive Autism Network. Autism symptom levels were measured using the Social Responsiveness Scale (SRS) and by computing Diagnostic and Statistical Manual of Mental Disorders—Fifth Edition (DSM-5) symptom scores based on items from the SRS and Social Communication Questionnaire. Generalized estimating equation models evaluated the influence of family incidence types (single versus multiple incidence families; male-only ASD-affected families versus families with female ASD-affected children), diagnostic group (non-ASD children with and without a history of language delay with autistic speech and ASD-affected children), and sibling sex on ASD symptom levels. Results Non-ASD children manifested elevated ASD symptom burden when they were members of multiple incidence families—this effect was accentuated for male children in female ASD-containing families—or when they had a history of language delay with autistic qualities of speech. In this sample, ASD-affected children from multiple incidence families had lower symptom levels than their counterparts in single incidence families. Recurrence risk for ASD was higher for children from female ASD-containing families than for children from male-only families. Conclusions Sex and patterns of family transmission modulate the risk of autism symptom burden in undiagnosed siblings of ASD-affected children. Identification of these symptoms/traits and their molecular genetic causes may have significant implications for genetic counseling and for understanding inherited liabilities that confer risk for ASD in successive generations. Autism symptom elevations were more dramatic in non-ASD children from multiple incidence families and those with a history of language delay and autistic qualities of speech, identifying sub-groups at substantially greater transmission risk. Higher symptom burden and greater recurrence in children from female ASD-containing families indicate that familial aggregation patterns are further qualified by sex-specific thresholds, supportive of the notion that females require a higher burden of deleterious liability to cross into categorical ASD diagnosis

Profiles of circumscribed interests in autistic youth

Circumscribed interests (CI) encompass a range of different interests and related behaviors that can be characterized by either a high intensity but otherwise usual topic [referred to as restricted interests (RI)] or by a focus on topics that are not salient outside of autism [referred to as unusual interests (UI)]. Previous research has suggested that there is pronounced variability across individuals in terms of the endorsement of different interests, however, this variability has not been quantified using formal subtyping approaches. Therefore, using Latent Profile Analysis in a sample of 1,892 autistic youth (Mage = 10.82, SDage = 4.14; 420 females), this study aimed to identify subgroups based on the RU and UI profiles. Three profiles of autistic individuals were identified. They were characterized as Low CI, Predominantly RI, and Predominantly UI. Importantly, profiles differed on several key demographic and clinical variables, including age, sex composition, IQ, language level, social and communication abilities, anxiety, and obsessive-compulsive behaviors. Although replication across other samples is needed, the profiles identified in this study are potentially promising for future research given their distinct profiles of RI and UI and unique patterns of associations with key cognitive and clinical variables. Therefore, this study represents an important initial step towards more individualized assessment and support for diverse presentations of CI in autistic youth

Subdomains of restricted and repetitive behaviors within autism: Exploratory structural equation modeling using the diagnostic interview for social and communication disorders

The current study aimed to explore the factor structure of a broad range of restricted and repetitive behaviors (RRB) within the autism spectrum. Exploratory structural equation modeling was conducted using individual item-level data from the Diagnostic Interview for Social and Communication Disorders (DISCO). DISCO is a comprehensive semi-structured interview used by clinicians to elicit information from caregivers about the individual's profile of development and behavior. Data from a sample of 226 individuals with a clinical diagnosis of autism spectrum disorder (ASD) (189 males; M age = 11.82 years, SD age = 7.87) were analyzed. The six-factor structure provided the most optimal and interpretable fit (comparative fit index = 0.944, Tucker–Lewis index = 0.923, root mean square error of approximation = 0.018). Derived factors were interpreted as repetitive motor behaviors (RMB), unusual sensory and object focused interests (USOI), sensory sensitivity (SS), insistence on sameness (IS), circumscribed interests (CI) and stereotyped language (SL). Age was significantly negatively associated with RMB, USOI and SL but not with SS, IS or CI factor scores. None of the factors were associated with sex. ASD individuals with intellectual disability (ID) had the highest RMB, USOI, SS and SL scores while those without ID had the highest IS and CI scores. Our findings provide preliminary evidence for the utility of the DISCO as a comprehensive measure of several distinct RRB domains in both research and clinical contexts. Importantly, the current investigation highlights crucial areas for measurement development

The Autism Symptom Dimensions Questionnaire: Development and psychometric evaluation of a new, open-source measure of autism symptomatology

Aim: To describe the development and initial psychometric evaluation of a new, freely available measure, the Autism Symptom Dimensions Questionnaire (ASDQ). Method: After development and revision of an initial 33-item version, informants completed a revised 39-item version of the ASDQ on 1467 children and adolescents (aged 2-17 years), including 104 with autism spectrum disorder (ASD). Results: The initial 33-item version of the ASDQ had good reliability and construct validity. However, only four specific symptom factors were identified, potentially due to an insufficient number of items. Factor analyses of the expanded instrument identified a general ASD factor and nine specific symptom factors with good measurement invariance across demographic groups. Scales showed good-to-excellent overall and conditional reliability. Exploratory analyses of predictive validity for ASD versus neurotypical and other developmental disability diagnoses indicated good accuracy for population and at-risk contexts. Interpretation: The ASDQ is a free and psychometrically sound informant report instrument with good reliability of measurement across a continuous range of scores and preliminary evidence of predictive validity. The measure may be a useful alternative to existing autism symptom measures but further studies with comparison of clinical diagnoses using criterion-standard instruments are needed

Increased frontal cortical folding in autism: A preliminary MRI study

Abstract The gyrification index (GI), the ratio of total to outer cortical contour, was applied to measure the cerebral folding patterns in autism. GI was examined on a frontal coronal slice obtained from MRI scans of 30 nonmentally retarded individuals with autism and 32 matched healthy controls. In the autistic group, left frontal GI was higher in children and adolescents but not in adults. Cortical folding was decreased bilaterally with age in the total autistic sample but not in controls. These preliminary findings suggest that the gyrification patterns in autism may be abnormal, which could be related to the various cortical anomalies observed in this disorder

Plasma anandamide concentrations are lower in children with autism spectrum disorder

Background: Autism spectrum disorder (ASD) is a neurodevelopmentaldisorder characterized by restricted, stereotyped behaviors and impairments in social communication. Although the underlying biological mechanisms of ASD remain poorly understood, recent preclinical research has implicated the endogenous cannabinoid (or endocannabinoid), anandamide, as a significant neuromodulator in rodent models of ASD. Despite this promising preclinical evidence, no clinical studies to date have tested whether endocannabinoids are dysregulated in individuals with ASD. Here, we addressed this critical gap in knowledge by optimizing liquid chromatography-tandem mass spectrometry methodology to quantitatively analyze anandamide concentrations in banked blood samples collected from a cohort of children withand without ASD (N= 112). Findings: Anandamide concentrations significantly differentiated ASD cases (N= 59) from controls (N= 53), such that children with lower anandamide concentrations were more likely to have ASD (p= 0.041). In keeping with this notion, anandamide concentrations were also significantly lower in ASD compared to control children (p= 0.034). Conclusions: These findings are the first empirical human data to translate preclinical rodent findings to confirm a link between plasma anandamide concentrations in children with ASD. Although preliminary, these data suggest that impaired anandamide signaling may be involved in the pathophysiology of ASD

Daily living skills scale: Development and preliminary validation of a new, open-source assessment of daily living skills

Autistic individuals and individuals with a range of other neurodevelopmental conditions (NDD) often present with lower levels of daily living skills (DLS) when compared to their neurotypical peers. Importantly, lower levels of DLS have been linked to a range of negative outcomes, including lower rates of post-secondary education, lower employment rates, and higher daily support needs across autism and NDD. However, there are currently no open-source informant-reported instruments for capturing key aspects of DLS. This study describes the development, refinement, and initial psychometric evaluation of a new, relatively brief (53-item). Daily Living Skills Scale (DLSS) in a sample of 1,361 children aged 2–17 years, Confirmatory Factor Analysis demonstrated an excellent fit of unidimensional model to the data (CFI = 0.953, TLI = 0.951, RMSEA = 0.073 [95% CI: 0.071–0.074]). The single-factor CFA model showed evidence of measurement invariance of factor loadings, thresholds, and residual variance (strict invariance) across sex, age, race, and ethnicity. Model reliability and internal consistency were excellent (ω = 0.98; α = 0.97). Conditional reliability estimates indicated very good reliability (= 0.80) for the total DLS scale from very low (θ = −4.2) to high (θ = +2.4) scores. Conceptually derived self-care, homecare, and community participation subscales also showed strong reliability and internal consistency. With further replication, the EFS has excellent potential for wide adoption across research and clinical contexts

A Twin Study of Heritable and Shared Environmental Contributions to Autism

The present study examined genetic and shared environment contributions to quantitatively-measured autism symptoms and categorically-defined ASD. Participants included 568 twins from the Interactive Autism Network. Autism symptoms were obtained using the Social Communication Questionnaire and Social Responsiveness Scale. Categorically-defined ASD was based on clinical diagnoses. DeFries-Fulker and liability threshold models examined etiologic influences. Very high heritability was observed for extreme autism symptom levels (h2g=.92-1.20). Extreme levels of social and repetitive behavior symptoms were strongly influenced by common genetic factors. Heritability of categorically-defined ASD diagnosis was comparatively low (.21, 95% CI=0.15-0.28). High heritability of extreme autism symptom levels confirms previous observations of strong genetic influences on autism. Future studies will require large, carefully ascertained family pedigrees and quantitative symptom measurements

Demographic and clinical correlates of autism symptom domains and autism spectrum diagnosis

Demographic and clinical factors may influence assessment of autism symptoms. This study evaluated these correlates and also examined whether social communication and interaction and restricted/repetitive behavior provided unique prediction of autism spectrum disorder diagnosis. We analyzed data from 7352 siblings included in the Interactive Autism Network registry. Social communication and interaction and restricted/repetitive behavior symptoms were obtained using caregiver-reports on the Social Responsiveness Scale. Demographic and clinical correlates were covariates in regression models predicting social communication and interaction and restricted/repetitive behavior symptoms. Logistic regression and receiver operating characteristic curve analyses evaluated the incremental validity of social communication and interaction and restricted/repetitive behavior domains over and above global autism symptoms. Autism spectrum disorder diagnosis was the strongest correlate of caregiver-reported social communication and interaction and restricted/repetitive behavior symptoms. The presence of comorbid diagnoses also increased symptom levels. Social communication and interaction and restricted/repetitive behavior symptoms provided significant, but modest, incremental validity in predicting diagnosis beyond global autism symptoms. These findings suggest that autism spectrum disorder diagnosis is by far the largest determinant of quantitatively measured autism symptoms. Externalizing (attention deficit hyperactivity disorder) and internalizing (anxiety) behavior, low cognitive ability, and demographic factors may confound caregiver-report of autism symptoms, potentially necessitating a continuous norming approach to the revision of symptom measures. Social communication and interaction and restricted/repetitive behavior symptoms may provide incremental validity in the diagnosis of autism spectrum disorder

Validation of Proposed DSM-5 Criteria for Autism Spectrum Disorder

The primary aim of the present study was to evaluate the validity of proposed DSM-5 criteria for Autism Spectrum Disorder (ASD)