Eye-Tracking-Based Measurement of Social Visual Engagement Compared With Expert Clinical Diagnosis of Autism.

Importance: In the US, children with signs of autism often experience more than 1 year of delay before diagnosis and often experience longer delays if they are from racially, ethnically, or economically disadvantaged backgrounds. Most diagnoses are also received without use of standardized diagnostic instruments. To aid in early autism diagnosis, eye-tracking measurement of social visual engagement has shown potential as a performance-based biomarker. Objective: To evaluate the performance of eye-tracking measurement of social visual engagement (index test) relative to expert clinical diagnosis in young children referred to specialty autism clinics. Design, Setting, and Participants: In this study of 16- to 30-month-old children enrolled at 6 US specialty centers from April 2018 through May 2019, staff blind to clinical diagnoses used automated devices to measure eye-tracking-based social visual engagement. Expert clinical diagnoses were made using best practice standardized protocols by specialists blind to index test results. This study was completed in a 1-day protocol for each participant. Main Outcomes and Measures: Primary outcome measures were test sensitivity and specificity relative to expert clinical diagnosis. Secondary outcome measures were test correlations with expert clinical assessments of social disability, verbal ability, and nonverbal cognitive ability. Results: Eye-tracking measurement of social visual engagement was successful in 475 (95.2%) of the 499 enrolled children (mean [SD] age, 24.1 [4.4] months; 38 [8.0%] were Asian; 37 [7.8%], Black; 352 [74.1%], White; 44 [9.3%], other; and 68 [14.3%], Hispanic). By expert clinical diagnosis, 221 children (46.5%) had autism and 254 (53.5%) did not. In all children, measurement of social visual engagement had sensitivity of 71.0% (95% CI, 64.7% to 76.6%) and specificity of 80.7% (95% CI, 75.4% to 85.1%). In the subgroup of 335 children whose autism diagnosis was certain, sensitivity was 78.0% (95% CI, 70.7% to 83.9%) and specificity was 85.4% (95% CI, 79.5% to 89.8%). Eye-tracking test results correlated with expert clinical assessments of individual levels of social disability (r = -0.75 [95% CI, -0.79 to -0.71]), verbal ability (r = 0.65 [95% CI, 0.59 to 0.70]), and nonverbal cognitive ability (r = 0.65 [95% CI, 0.59 to 0.70]). Conclusions and Relevance: In 16- to 30-month-old children referred to specialty clinics, eye-tracking-based measurement of social visual engagement was predictive of autism diagnoses by clinical experts. Further evaluation of this test's role in early diagnosis and assessment of autism in routine specialty clinic practice is warranted. Trial Registration: ClinicalTrials.gov Identifier: NCT03469986.

Expert Clinician Certainty in Diagnosing Autism Spectrum Disorder in 16-30-Month-Olds: A Multi-site Trial Secondary Analysis.

Differential diagnosis of young children with suspected autism spectrum disorder (ASD) is challenging, and clinician uncertainty about a child's diagnosis may contribute to misdiagnosis and subsequent delays in access to early treatment. The current study was designed to replicate and expand a recent report in this Journal (McDonnell et al. in J Autism Dev Disord 49:1391-1401, https://doi.org/10.1080/15374416.2020.1823850 , 2019), in which only 60% of diagnoses were made with complete certainty by clinicians evaluating 478 toddlers and preschool children referred for possible ASD to specialized clinics. In this study, secondary analyses were performed on diagnostic, demographic and clinical data for 496 16-30-month-old children who were consecutive referrals to a 6-site clinical trial executed by specialized centers with experienced clinicians following best-practice procedures for the diagnosis of ASD. Overall, 70.2% of diagnoses were made with complete certainty. The most important factor associated with clinician uncertainty was mid-level autism-related symptomatology. Mid-level verbal age equivalents were also associated with clinician uncertainty, but measures of symptomatology were stronger predictors. None of the socio-demographic variables, including sex of the child, was significantly associated with clinician certainty. Close to one third of early diagnoses of ASD are made with a degree of uncertainty. The delineation of specific ranges on the ADOS-2 most likely to result in clinician uncertainty identified in this study may provide an opportunity to reduce random subjectivity in diagnostic decision-making via calibration of young-child diagnostic thresholds based on later-age longitudinal diagnostic outcome data, and via standardization of decision-making in regard to clinical scenarios frequently encountered by clinicians.

Mechanisms of Diminished Attention to Eyes in Autism.

OBJECTIVE: Two hypotheses, gaze aversion and gaze indifference, are commonly cited to explain a diagnostic hallmark of autism: reduced attention to others' eyes. The two posit different areas of atypical brain function, different pathogenic models of disability, and different possible treatments. Evidence for and against each hypothesis is mixed but has thus far focused on older children and adults. The authors evaluated both mechanistic hypotheses in two sets of experiments at the time of initial diagnosis. METHOD: Eye-tracking data were collected in 86 2-year-olds: 26 with autism, tested at initial diagnosis; 38 matched typically developing children; and 22 matched developmentally delayed children. In two experiments, the authors measured response to direct and implicit cueing to look at the eyes. RESULTS: When directly cued to look at the eyes, 2-year-olds with autism did not look away faster than did typically developing children; their latency varied neither categorically nor dimensionally by degree of eye cueing. Moreover, direct cueing had a stronger sustained effect on their amount of eye-looking than on that of typically developing children. When presented with implicit social cues for eye-looking, 2-year-olds with autism neither shifted their gaze away nor more subtly averted their gaze to peripheral locations. CONCLUSIONS: The results falsify the gaze aversion hypothesis; instead, at the time of initial diagnosis, diminished eye-looking in autism is consistent with passive insensitivity to the social signals in others' eyes.

Parsing heterogeneity in autism spectrum disorders: visual scanning of dynamic social scenes in school-aged children.

OBJECTIVE: To examine patterns of variability in social visual engagement and their relationship to standardized measures of social disability in a heterogeneous sample of school-aged children with autism spectrum disorders (ASD). METHOD: Eye-tracking measures of visual fixation during free-viewing of dynamic social scenes were obtained for 109 children with ASD (mean age, 10.2 ± 3.2 years), 37 of whom were matched with 26 typically-developing (TD) children (mean age, 9.5 ± 2.2 years) on gender, age, and IQ. The smaller subset allowed between-group comparisons, whereas the larger group was used for within-group examinations of ASD heterogeneity. RESULTS: Between-group comparisons revealed significantly attenuated orientation to socially salient aspects of the scenes, with the largest effect size (Cohen's d = 1.5) obtained for reduced fixation on faces. Within-group analyses revealed a robust association between higher fixation on the inanimate environment and greater social disability. However, the associations between fixation on the eyes and mouth and social adaptation varied greatly, even reversing, when comparing different cognitive profile subgroups. CONCLUSIONS: Although patterns of social visual engagement with naturalistic social stimuli are profoundly altered in children with ASD, the social adaptivity of these behaviors varies for different groups of children. This variation likely represents different patterns of adaptation and maladaptation that should be traced longitudinally to the first years of life, before complex interactions between early predispositions and compensatory learning take place. We propose that variability in these early mechanisms of socialization may serve as proximal behavioral manifestations of genetic vulnerabilities.

Cognitive and social functions and growth factors in a mouse model of Rett syndrome.

Rett syndrome (RTT) is an autism-spectrum disorder caused by mutations in the X-linked gene encoding methyl-CpG-binding protein 2 (MeCP2). Abnormalities in social behavior, stereotyped movements, and restricted interests are common features in both RTT and classic autism. While mouse models of both RTT and autism exist, social behaviors have not been explored extensively in mouse models of RTT. Here, we report cognitive and social abnormalities in Mecp2(1lox) null mice, an animal model of RTT. The null mice show severe deficits in short- and long-term object recognition memories, reminiscent of the severe cognitive deficits seen in RTT girls. Social behavior, however, is abnormal in that the null mice spend more time in contact with stranger mice than do wildtype controls. These findings are consistent with reports of increased reciprocal social interaction in RTT girls relative to classic autism. We also report here that the levels of the neurotrophins brain-derived neurotrophic factor (BDNF), insulin-like growth factor-1 (IGF-1), and nerve growth factor (NGF) are decreased in the hippocampus of the null mice, and discuss how this may provide an underlying mechanism for both the cognitive deficits and the increased motivation for social contact observed in the Mecp2(1lox) null mice. These studies support a differential etiology between RTT and autism, particularly with respect to sociability deficits.

Environmental enrichment alters locomotor behaviour and ventricular volume in Mecp2 1lox mice.

Rett syndrome (RTT) is an autistic spectrum developmental disorder associated with mutations in the X-linked Mecp2 gene, and severe behavioural and neuropathological deficits. In a mouse model of RTT (Mecp2(1lox)), we examined whether environmental enrichment (EE) alters behavioural performance and regional brain volume. At weaning, Mecp2(1lox) and control mice were assigned to enriched or standard housing. From postnatal day 29 to 43, mice were subjected to behavioural tasks measuring motor and cognitive performance. At postnatal day 44, volumes of whole brain, cerebellum, ventricles, and motor cortex were measured using magnetic resonance imaging. EE provided subtle improvements to locomotor activity and contextual fear conditioning in Mecp2(1lox) mice. Additionally, EE reduced ventricular volumes, which correlated with improved locomotor activity, suggesting that neuroanatomical changes contribute to improved behaviour. Our results suggest that post-weaning EE may provide a non-invasive palliative treatment for RTT.