Importance Autism spectrum disorder is a common and early-emerging neurodevelopmental condition. While 80% of parents report having had concerns for their child’s development before age 2 years, many children are not diagnosed until ages 4 to 5 years or later. Objective To develop an objective performance-based tool to aid in early diagnosis and assessment of autism in children younger than 3 years. Design, Setting, and Participants In 2 prospective, consecutively enrolled, broad-spectrum, double-blind studies, we developed an objective eye-tracking–based index test for children aged 16 to 30 months, compared its performance with best-practice reference standard diagnosis of autism (discovery study), and then replicated findings in an independent sample (replication study). Discovery and replication studies were conducted in specialty centers for autism diagnosis and treatment. Reference standard diagnoses were made using best-practice standardized protocols by specialists blind to eye-tracking results. Eye-tracking tests were administered by staff blind to clinical results. Children were enrolled from April 27, 2013, until September 26, 2017. Data were analyzed from March 28, 2018, to January 3, 2019. Main Outcomes and Measures Prespecified primary end points were the sensitivity and specificity of the eye-tracking–based index test compared with the reference standard. Prespecified secondary end points measured convergent validity between eye-tracking–based indices and reference standard assessments of social disability, verbal ability, and nonverbal ability. Results Data were collected from 1089 children: 719 children (mean [SD] age, 22.4 [3.6] months) in the discovery study, and 370 children (mean [SD] age, 25.4 [6.0] months) in the replication study. In discovery, 224 (31.2%) were female and 495 (68.8%) male; in replication, 120 (32.4%) were female and 250 (67.6%) male. Based on reference standard expert clinical diagnosis, there were 386 participants (53.7%) with nonautism diagnoses and 333 (46.3%) with autism diagnoses in discovery, and 184 participants (49.7%) with nonautism diagnoses and 186 (50.3%) with autism diagnoses in replication. In the discovery study, the area under the receiver operating characteristic curve was 0.90 (95% CI, 0.88-0.92), sensitivity was 81.9% (95% CI, 77.3%-85.7%), and specificity was 89.9% (95% CI, 86.4%-92.5%). In the replication study, the area under the receiver operating characteristic curve was 0.89 (95% CI, 0.86-0.93), sensitivity was 80.6% (95% CI, 74.1%-85.7%), and specificity was 82.3% (95% CI, 76.1%-87.2%). Eye-tracking test results correlated with expert clinical assessments of children’s individual levels of ability, explaining 68.6% (95% CI, 58.3%-78.6%), 63.4% (95% CI, 47.9%-79.2%), and 49.0% (95% CI, 33.8%-65.4%) of variance in reference standard assessments of social disability, verbal ability, and nonverbal cognitive ability, respectively. Conclusions and Relevance In two diagnostic studies of children younger than 3 years, objective eye-tracking–based measurements of social visual engagement quantified diagnostic status as well as individual levels of social disability, verbal ability, and nonverbal ability in autism. These findings suggest that objective measurements of social visual engagement can be used to aid in autism diagnosis and assessment.

Context: Within the first week of life, typical human newborns give preferential attention to the eyes of others. Similar findings in other species suggest that attention to the eyes is a highly conserved phylogenetic mechanism of social development. For children with autism, however, diminished and aberrant eye contact is a lifelong hallmark of disability. Objective: To quantify preferential attention to the eyes of others at what is presently the earliest point of diagnosis in autism. Design: We presented the children with 10 videos. Each video showed an actress looking directly into the camera, playing the role of caregiver, and engaging the viewer (playing pat-a-cake, peek-a-boo, etc). Children's visual fixation patterns were measured by eye tracking. Participants: Fifteen 2-year-old children with autism were compared with 36 typically developing children and with 15 developmentally delayed but nonautistic children. Main Outcome Measure: Preferential attention was measured as percentage of visual fixation time to 4 regions of interest: eyes, mouth, body, and object. Level of social disability was assessed by the Autism Diagnostic Observation Schedule. Results: Looking at the eyes of others was significantly decreased in 2-year-old children with autism (P<.001), while looking at mouths was increased (P<.01) in comparison with both control groups. The 2 control groups were not distinguishable on the basis of fixation patterns. In addition, fixation on eyes by the children with autism correlated with their level of social disability; less fixation on eyes predicted greater social disability (r=-0.669, P<.01). Conclusions: Looking at the eyes of others is important in early social development and in social adaptation throughout one's life span. Our results indicate that in 2-year-old children with autism, this behavior is already derailed, suggesting critical consequences for development but also offering a potential biomarker for quantifying syndrome manifestation at this early age.

Background: Reciprocal social behavior (RSB) is a developmental prerequisite for social competency, and deficits in RSB constitute a core feature of autism spectrum disorder (ASD). Although clinical screeners categorically ascertain risk of ASD in early childhood, rapid methods for quantitative measurement of RSB in toddlers are not yet established. Such measurements are critical for tracking developmental trajectories and incremental responses to intervention. Methods: We developed and validated a 20-minute video-referenced rating scale, the video-referenced rating of reciprocal social behavior (vrRSB), for untrained caregivers to provide standardized ratings of quantitative variation in RSB. Parents of 252 toddler twins [Monozygotic (MZ)=31 pairs, Dizygotic (DZ)=95 pairs] ascertained through birth records, rated their twins’ RSB at two time points, on average 6 months apart, and completed two developmental measures, the Modified Checklist for Autism in Toddlers (M-CHAT) and the MacArthur Communicative Development Inventory Short Form (MCDI-s). Results: Scores on the vrRSB were fully continuously distributed, with excellent 6-month test-retest reliability ([intraclass correlation coefficient] ICC=0.704, p<0.000). MZ twins displayed markedly greater trait concordance than DZ twins, (MZ ICC=0.863, p<0.000, DZ ICC=0.231, p<0.012). VrRSB score distributions were highly distinct for children passing versus failing the M-CHAT (t=−8.588, df=31, p<.000), incrementally improved from 18-24 months, and were inversely correlated with receptive and expressive vocabulary on the MCDI-s. Conclusions: Like quantitative autistic trait ratings in school-aged children and adults, toddler scores on the vrRSB are continuously distributed and appear highly heritable. These ratings exhibited minimal measurement error, high inter-individual stability, and developmental progression in RSB as children matured from 18-24 months, supporting their potential utility for serially quantifying the severity of early autistic syndromes over time and in response to intervention. In addition, these findings inform the genetic-environmental structure of RSB in early typical development.

The preponderance of causal influence on total population attributable risk for autism is polygenic in nature, but it is not known how such liability engenders the development of the syndrome. In 348 epidemiologically ascertained toddler twins, we explored associations between autistic traits and three robust, highly heritable predictors of familial autism recurrence: variation in attention, motor coordination, and parental autistic trait burden. We observed that these predictors—despite collectively accounting for over one third of variance in clinical recurrence—are genetically independent in early childhood, and jointly account for a comparable share of inherited influence on early reciprocal social behavior in the general population. Thus, combinations of what are otherwise discrete, inherited behavioral liabilities—some not specific to autism—appear to jointly mediate common genetic risk for autism. Linking genetic variants and neural signatures to these independent traits prior to the onset of the development of autism will enhance understanding of mechanisms of causation in familial autistic syndromes. Moreover, ongoing biomarker discovery efforts will benefit from controlling for the effects of these common liabilities, which aggregate in individuals with autism but are also continuously distributed in “controls”. Finally, early inherited liabilities that participate in the early ontogeny of autistic syndromes represent parsimonious intervention targets for polygenic forms of the condition, and represent candidate trans-diagnostic endophenotypes of potential relevance to a diversity of neuropsychiatric syndromes.

Impairments in social interaction in Autism Spectrum Disorder (ASD) differ greatly across individuals and vary throughout an individual's lifetime. Yet, an important marker of ASD in infancy is deviations in social-visual engagement, such as the reliably detectable early deviations in attention to the eyes or to biological movement (Klin et al., 2015). Given the critical nature of these early developmental periods, understanding its neurobehavioral underpinnings by means of a nonhuman primate model will be instrumental to understanding the pathophysiology of ASD. Like humans, rhesus macaques 1) develop in rich and complex social behaviors, 2) progressively develop social skills throughout infancy, and 3) have high similarities with humans in brain anatomy and cognitive functions (Machado and Bachevalier, 2003). In this study, male infant rhesus macaques living with their mothers in complex social groups were eye-tracked longitudinally from birth to 6 months while viewing full-faced videos of unfamiliar rhesus monkeys differing in age and sex. The results indicated a critical period for the refinement of social skills around 4–8 weeks of age in rhesus macaques. Specifically, infant monkeys’ fixation to the eyes shows an inflection in developmental trajectory, increasing from birth to 8 weeks, decreasing slowly to a trough between 14–18 weeks, before increasing again. These results parallel the developmental trajectory of social visual engagement published in human infants (Jones & Klin, 2013) and suggest the presence of a switch in the critical networks supporting these early developing social skills that is highly conserved between rhesus macaque and human infant development.

Eye-blinking has emerged as a promising means of measuring viewer engagement with visual content. This method capitalizes on the fact that although we remain largely unaware of our eye-blinking in everyday situations, eye-blinks are inhibited at precise moments in time so as to minimize the loss of visual information that occurs during a blink. Probabilistically, the more important the visual information is to the viewer, the more likely he or she will be to inhibit blinking. In the present study, viewer engagement was experimentally manipulated in order to: (1) replicate past studies suggesting that a group of viewers will blink less often when watching content that they perceive as more important or relevant; (2) test the reliability of the measure by investigating constraints on the timescale over which blink rate patterns can be used to accurately quantify viewer engagement; and (3) examine whether blink rate patterns can be used to quantify what an individual – as opposed to a group of viewers—perceives as engaging. Results demonstrate that blink rate patterns can be used to measure changes in individual and group engagement that unfold over relatively short (1 second) and long (60 second) timescales. However, for individuals with lower blink rates, blink rate patterns may provide less optimal measures when engagement shifts rapidly (at intervals of 1 second or less). Findings support the use of eye-blink measures in future studies investigating a person’s subjective perception of how engaging a stimulus is.

Differences in looking at the eyes of others are one of the earliest behavioral markers for social difficulties in neurodevelopmental disabilities, including autism. However, it is unknown how early visuo-social experiences relate to the maturation of infant brain networks that process visual social stimuli. We investigated functional connectivity (FC) within the ventral visual object pathway as a contributing neural system. Densely sampled, longitudinal eye-tracking and resting state fMRI (rs-fMRI) data were collected from infant rhesus macaques, an important model of human social development, from birth through 6 months of age. Mean trajectories were fit for both datasets and individual trajectories from subjects with both eye-tracking and rs-fMRI data were used to test for brain-behavior relationships. Exploratory findings showed infants with greater increases in FC between left V1 to V3 visual areas have an earlier increase in eye-looking before 2 months. This relationship was moderated by social status such that infants with low social status had a stronger association between left V1 to V3 connectivity and eye-looking than high status infants. Results indicated that maturation of the visual object pathway may provide an important neural substrate supporting adaptive transitions in social visual attention during infancy.

Infant-directed singing is a culturally universal musical phenomenon known to promote the bonding of infants and caregivers. Entrainment is a widely observed physical phenomenon by which diverse physical systems adjust rhythmic activity through interaction. Here we show that the simple act of infant-directed singing entrains infant social visual behavior on subsecond timescales, increasing infants’ looking to the eyes of a singing caregiver: as early as 2 months of age, and doubling in strength by 6 months, infants synchronize their eye-looking to the rhythm of infant-directed singing. Rhythmic entrainment also structures caregivers’ own cueing, enhancing their visual display of social-communicative content: caregivers increase wide-eyed positive affect, reduce neutral facial affect, reduce eye motion, and reduce blinking, all in time with the rhythm of their singing and aligned in time with moments when infants increase their eye-looking. In addition, if the rhythm of infant-directed singing is experimentally disrupted—reducing its predictability—then infants’ time-locked eye-looking is also disrupted. These results reveal generic processes of entrainment as a fundamental coupling mechanism by which the rhythm of infant-directed singing attunes infants to precisely timed social-communicative content and supports social learning and development.

The national priority to advance early detection and intervention for children with autism spectrum disorder (ASD) has not reduced the late age of ASD diagnosis in the US over several consecutive CDC surveillance cohorts, with traditionally under-served populations accessing diagnosis later still. In this review, we explore a potential perceptual barrier to this enterprise which views ASD in terms that are contradicted by current science, and which may have its origins in the current definition of the condition and in its historical associations. To address this perceptual barrier, we propose a re-definition of ASD in early brain development terms, with a view to revisit the world of opportunities afforded by current science to optimize children’s outcomes despite the risks that they are born with. This view is presented here to counter outdated notions that potentially devastating disability is determined the moment a child is born, and that these burdens are inevitable, with opportunities for improvement being constrained to only alleviation of symptoms or limited improvements in adaptive skills. The impetus for this piece is the concern that such views of complex neurodevelopmental conditions, such as ASD, can become self-fulfilling science and policy, in ways that are diametrically opposed to what we currently know, and are learning every day, of how genetic risk becomes, or not, instantiated as lifetime disabilities.

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.