Celine Saulnier

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.

Sensory and attention abnormalities in autistic spectrum disorders

Individuals with autistic spectrum disorders (ASDs) often experience, describe and exhibit unusual patterns of sensation and attention. These anomalies have been hypothesized to result from overarousal and consequent overfocused attention. Parents of individuals with ASD rated items in three domains, ‘sensory overreactivity’, ‘sensory underreactivity’ and ‘sensory seeking behaviors’, of an expanded version of the Sensory Profile, a 103-item rating scale developed for the present study. Parents also rated symptom severity, overselective attention and exceptional memory, and completed the Vineland Adaptive Behavior Scales. Of 222 rated subjects, 144 had complete data. Cluster analysis showed the predicted overfocused pattern of sensation and attention, comprising overreactivity, perseverative behavior and interests, overfocused attention and exceptional memory in 43 percent of this sample. This pattern was striking in 10 percent. The neurological basis of overreactivity and overfocusing is discussed in relation to the overarousal hypothesis. Attention is drawn to its considerable prevalence in the ASD population.

Neural signatures of autism

Functional magnetic resonance imaging of brain responses to biological motion in children with autism spectrum disorder (ASD), unaffected siblings (US) of children with ASD, and typically developing (TD) children has revealed three types of neural signatures: (i) state activity, related to the state of having ASD that characterizes the nature of disruption in brain circuitry; (ii) trait activity, reflecting shared areas of dysfunction in US and children with ASD, thereby providing a promising neuroendophenotype to facilitate efforts to bridge genomic complexity and disorder heterogeneity; and (iii) compensatory activity, unique to US, suggesting a neural system–level mechanism by which US might compensate for an increased genetic risk for developing ASD. The distinct brain responses to biological motion exhibited by TD children and US are striking given the identical behavioral profile of these two groups. These findings offer far-reaching implications for our understanding of the neural systems underlying autism.

The Role of Adaptive Behavior in Autism Spectrum Disorders: Implications for Functional Outcome

The relationship between adaptive functioning and autism symptomatology was examined in 1,089 verbal youths with ASD examining results on Vineland-II, IQ, and measures of ASD severity. Strong positive relationships were found between Vineland subscales and IQ. Vineland Composite was negatively associated with age. IQ accounted a significant amount of the variance in overall adaptive skills (55%) beyond age and ASD severity. Individuals with ASD demonstrated significant adaptive deficits and negligible associations were found between the level of autism symptomatology and adaptive behavior. The results indicate that IQ is a strong predictor of adaptive behavior, the gap between IQ and adaptive impairments decreases in lower functioning individuals with ASD, and older individuals have a greater gap between IQ and adaptive skills.

Non-ASD outcomes at 36 months in siblings at familial risk for autism spectrum disorder (ASD): A baby siblings research consortium (BSRC) study

We characterized developmental outcomes of a large sample of siblings at familial high‐risk of autism spectrum disorder (ASD), who themselves did not have ASD (n = 859), and low‐risk controls with no family history of ASD (n = 473). We report outcomes at age 3 years using the Mullen Scales of Early Learning, the Autism Diagnostic Observation Schedule (ADOS), the Autism Diagnostic Interview—Revised (ADI‐R) and adaptive functioning on the Vineland Adaptive Behavior Scales. Around 11% of high‐risk siblings had mild‐to‐moderate levels of developmental delay, a rate higher than the low‐risk controls. The groups did not differ in the proportion of toddlers with mild‐to‐moderate language delay. Thirty percent of high‐risk siblings had elevated scores on the ADOS, double the rate seen in the low‐risk controls. High‐risk siblings also had higher parent reported levels of ASD symptoms on the ADI‐R and lower adaptive functioning on the Vineland. Males were more likely to show higher levels of ASD symptoms and lower levels of developmental ability and adaptive behavior than females across most measures but not mild‐to‐moderate language delay. Lower maternal education was associated with lower developmental and adaptive behavior outcomes. These findings are evidence for early emerging characteristics related to the “broader autism phenotype” (BAP) previously described in older family members of individuals with ASD. There is a need for ongoing clinical monitoring of high‐risk siblings who do not have an ASD by age 3 years, as well as continued follow‐up into school age to determine their developmental and behavioral outcomes. Autism Res 2017, 10: 169–178.

Non-ASD outcomes at 36 months in siblings at familial risk for autism spectrum disorder (ASD)

We characterized developmental outcomes of a large sample of siblings at familial high‐risk of autism spectrum disorder (ASD), who themselves did not have ASD (n = 859), and low‐risk controls with no family history of ASD (n = 473). We report outcomes at age 3 years using the Mullen Scales of Early Learning, the Autism Diagnostic Observation Schedule (ADOS), the Autism Diagnostic Interview—Revised (ADI‐R) and adaptive functioning on the Vineland Adaptive Behavior Scales. Around 11% of high‐risk siblings had mild‐to‐moderate levels of developmental delay, a rate higher than the low‐risk controls. The groups did not differ in the proportion of toddlers with mild‐to‐moderate language delay. Thirty percent of high‐risk siblings had elevated scores on the ADOS, double the rate seen in the low‐risk controls. High‐risk siblings also had higher parent reported levels of ASD symptoms on the ADI‐R and lower adaptive functioning on the Vineland. Males were more likely to show higher levels of ASD symptoms and lower levels of developmental ability and adaptive behavior than females across most measures but not mild‐to‐moderate language delay. Lower maternal education was associated with lower developmental and adaptive behavior outcomes. These findings are evidence for early emerging characteristics related to the “broader autism phenotype” (BAP) previously described in older family members of individuals with ASD. There is a need for ongoing clinical monitoring of high‐risk siblings who do not have an ASD by age 3 years, as well as continued follow‐up into school age to determine their developmental and behavioral outcomes. Autism Res 2017, 10: 169–178.

Assessment of Autism Across the Lifespan: A Way Forward

The prevalence of autism spectrum disorders (ASDs) is currently estimated at 1 in 68 individuals in the US (Centers for Disease Control and Prevention (Morb Mortal Wkly Rep 63:1–21, 2014)), and recommendations for screening and best practices for diagnostic evaluations have been formulated in scientific, clinical, and institutional venues, if not successfully implemented. As such, this article reviews the best practices in the field for toddler, school-age and adolescent/adult assessments, describes at-risk symptomatology in toddlers, reviews common co-morbidities to be aware of at each time point, discusses cultural issues with regard to diagnoses, and brings forth new research, particularly with regard to earlier screening and diagnosis.

Predicting social and communicative ability in school-age children with autism spectrum disorder: A pilot study of the Social Attribution Task, Multiple Choice

The Social Attribution Task, Multiple Choice is introduced as a measure of implicit social cognitive ability in children, addressing a key challenge in quantification of social cognitive function in autism spectrum disorder, whereby individuals can often be successful in explicit social scenarios, despite marked social adaptive deficits. The 19-question Social Attribution Task, Multiple Choice, which presents ambiguous stimuli meant to elicit social attribution, was administered to children with autism spectrum disorder (N = 23) and to age-matched and verbal IQ–matched typically developing children (N = 57). The Social Attribution Task, Multiple Choice performance differed between autism spectrum disorder and typically developing groups, with typically developing children performing significantly better than children with autism spectrum disorder. The Social Attribution Task, Multiple Choice scores were positively correlated with age (r = 0.474) while being independent from verbal IQ (r = 0.236). The Social Attribution Task, Multiple Choice was strongly correlated with Vineland Adaptive Behavior Scales Communication (r = 0.464) and Socialization (r = 0.482) scores, but not with Daily Living Skills scores (r = 0.116), suggesting that the implicit social cognitive ability underlying performance on the Social Attribution Task, Multiple Choice is associated with real-life social adaptive function.

Neuropsychiatric Phenotypes in 3q29 Deletion Syndrome

Background The 1.6 Mb 3q29 deletion is associated with a 40-fold increased risk for schizophrenia. However, additional behavioral phenotypes, including autism spectrum disorder (ASD), are not well characterized. Methods We ascertained individuals with 3q29 deletion syndrome (3q29Del, “cases”, n=94, 58.5% male) and typically developing controls (n=64, 51.6% male) through the 3q29 registry (https://3q29deletion.patientcrossroads.org). Self-report of neuropsychiatric illness was evaluated for 94 cases. Subsets of records were evaluated with the Social Responsiveness Scale (SRS), Social Communication Questionnaire (SCQ), Autism Spectrum Screening Questionnaire (ASSQ), and Achenbach Behavior Checklists. Results 3q29Del cases report increased prevalence of autism diagnosis versus the general population (29.8% vs. 1.47%, p Conclusions Our sample of 3q29Del is significantly enriched for ASD diagnosis, especially among females, and features of autism may be present even when an ASD diagnosis is not reported. Further, the presentation of ASD in this population is novel, with substantially less impaired social motivation compared to idiopathic ASD. Our study implies that ASD evaluation should be the standard of care for individuals with 3q29Del. From a research perspective, the novel ASD subtype present in 3q29Del is an ideal entry point for expanding understanding of ASD.Background The 1.6 Mb 3q29 deletion is associated with neurodevelopmental and psychiatric phenotypes, including increased risk for autism spectrum disorder (ASD) and a 20-40-fold increased risk for schizophrenia. However, the phenotypic spectrum of the deletion, particularly with respect to ASD, remains poorly described. Methods We ascertained individuals with 3q29 deletion syndrome (3q29Del, “cases”, n=93, 58.1% male) through the 3q29 registry (https://3q29deletion.patientcrossroads.org); typically developing controls (n=64, 51.6% male) were ascertained for comparison. Self-report of neuropsychiatric illness was evaluated for 93 cases. Subsets of participants were evaluated with the Social Responsiveness Scale (SRS, n=48 cases, 56 controls), Social Communication Questionnaire (SCQ, n=33 cases, 46 controls), Autism Spectrum Screening Questionnaire (ASSQ, n=24 cases, 35 controls), and Achenbach Behavior Checklists (n=48 cases, 57 controls). Results 3q29Del cases report a higher prevalence of autism diagnoses versus the general population (30.1% vs. 1.47%, p<2.2E-16). Notably, 3q29 deletion confers a greater influence on risk for ASD in females (OR=49.4, p=1.09E-05) than in males (OR=24.6, p=6.06E-09); this is aligned with the reduced male:female bias from 4:1 in the general population to 1.8:1 in our study sample. Although 70% of cases do not report a diagnosis of ASD, there is evidence of significant social disability (3q29Del SRS T-score=71.8, control SRS T-score=45.9, p=2.16E-13). Cases also report increased frequency of generalized anxiety disorder compared to controls (26.9% vs. 6.2%, p=0.001), which is mirrored by elevated mean scores on the Achenbach DSM-oriented sub-scales (p<0.001). Finally, cases show a novel constellation of ASD features on the SRS as compared to idiopathic ASD, with substantially elevated Restricted Interests and Repetitive Behaviors, but only mild impairment in Social Motivation. Conclusions Our sample of 3q29Del is significantly enriched for ASD diagnosis, especially among females, and features of autism may be present even when an ASD diagnosis is not reported. Further, the presentation of ASD in this population is novel, with substantially less impaired social motivation compared to idiopathic ASD. Our study implies that ASD evaluation should be the standard of care for individuals with 3q29Del. From a research perspective, the novel ASD subtype present in 3q29Del is an ideal entry point for expanding understanding of ASD.

Walking Ability is Associated with Social Communication Skills in Infants at High Risk for Autism Spectrum Disorder

Achievement of early motor milestones in infancy affords new opportunities for social interaction and communication. Research has shown that both motor and social deficits are observed in infants who later develop autism spectrum disorder (ASD). The current study examined associations between motor and social-communication skills in 12-month-old infant siblings of children with ASD who are at heightened risk for developmental delays (N=86) and low-risk, typically developing infants (N=113). Infants were classified into one of three groups based on their walking ability: walkers (walks independently), standers (stands independently), or pre-walkers (does not yet stand or walk independently). Social-communication and cognitive skills were assessed with two standardized assessments (Communication and Symbolic Behaviors Scales [CSBS] and Mullen Scales of Early Learning) and compared across the three walking groups. Results demonstrated that high-risk walkers showed superior social-communication skills, but commensurate cognitive skills, compared to high-risk pre-walkers. In contrast, social-communication and cognitive skills were largely comparable for low-risk infants, regardless of walking status. Findings suggest that for high-risk infants, who are already vulnerable to developmental delays and ASD, independent walking may facilitate the emergence of social-communication abilities. Pivotal motor milestones may serve as useful indicators of social-communication delays and targets for intervention.