Caregiver greeting to infants under 6 months already reflects emerging differences in those later diagnosed with autism.

As infants develop, caregivers adjust their behaviour to scaffold their infant's emerging skills, such that changes in infants' social abilities are expected to elicit changes in caregiver behaviour. We examined whether changes in the probability of infant-directed caregiving behaviour-specifically, greeting, a ubiquitous signal used by caregivers to initiate reciprocal interactions-differ between infant-caregiver dyads with an infant later diagnosed with autism and dyads with a neurotypically developing infant during infants' first 6 months. Using longitudinal data from 163 dyads, we found that caregivers in autism dyads (n = 40) used greeting less and at later infant ages than caregivers with a neurotypically developing infant (neurotypical dyads, n = 83). Caregivers in dyads with infants at elevated familial genetic likelihood for autism who did not receive an autism diagnosis (EL-non-autism dyads, n = 40) showed no differences in greeting compared with neurotypical dyads. Socioeconomic status partially mediated the difference between autism and neurotypical dyads. These findings show that autism and socioeconomic status were associated with the mutually adapted dynamics of dyadic interaction beginning in the first postnatal weeks. Importantly, differences in caregiver greeting observed in autism dyads are not interpreted as suboptimal behaviour from caregivers but rather indicate how early emerging social differences related to autism, years before overt features are present, may alter social learning opportunities elicited by the infant.

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.

Development and Replication of Objective Measurements of Social Visual Engagement to Aid in Early Diagnosis and Assessment of Autism.

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.

Research interests of family physicians applying for research training.

BACKGROUND: There is an ongoing need for research to support the practice of high quality family medicine. The Family Medicine Discovers Rapid Cycle Scientific Discovery and Innovation (FMD RapSDI) program is designed to build capacity for family medicine scientific discovery and innovation in the United States. Our objective was to describe the applicants and research questions submitted to the RapSDI program in 2019 and 2020. METHODS: Descriptive analysis for applicant characteristics and rapid qualitative analysis using principles of grounded theory and content analysis to examine the research questions and associated themes. We examined differences by year of application submission and the applicant's career stage. RESULTS: Sixty-five family physicians submitted 70 applications to the RapSDI program; 45 in 2019 and 25 in 2020. 41% of applicants were in practice for five years or less (n = 27), 18% (n = 12) were in in practice 6-10 years, and 40% (n = 26) were ≥ 11 years in practice. With significant diversity in questions, the most common themes were studies of new innovations (n = 20, 28%), interventions to reduce cost (n = 20, 28%), improving screening or diagnosis (n = 19, 27%), ways to address mental or behavioral health (n = 18, 26%), and improving care for vulnerable populations (n = 18, 26%). CONCLUSION: Applicants proposed a range of research questions and described why family medicine is optimally suited to address the questions. Applicants had a desire to develop knowledge to help other family physicians, their patients, and their communities. Findings from this study can help inform other family medicine research capacity building initiatives.

Functional maturation in visual pathways predicts attention to the eyes in infant rhesus macaques: Effects of social status.

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 song potentiates infants' selective attention to adults' mouths over the first year of life.

The mechanisms by which infant-directed (ID) speech and song support language development in infancy are poorly understood, with most prior investigations focused on the auditory components of these signals. However, the visual components of ID communication are also of fundamental importance for language learning: over the first year of life, infants' visual attention to caregivers' faces during ID speech switches from a focus on the eyes to a focus on the mouth, which provides synchronous visual cues that support speech and language development. Caregivers' facial displays during ID song are highly effective for sustaining infants' attention. Here we investigate if ID song specifically enhances infants' attention to caregivers' mouths. 299 typically developing infants watched clips of female actors engaging them with ID song and speech longitudinally at six time points from 3 to 12 months of age while eye-tracking data was collected. Infants' mouth-looking significantly increased over the first year of life with a significantly greater increase during ID song versus speech. This difference was early-emerging (evident in the first 6 months of age) and sustained over the first year. Follow-up analyses indicated specific properties inherent to ID song (e.g., slower tempo, reduced rhythmic variability) in part contribute to infants' increased mouth-looking, with effects increasing with age. The exaggerated and expressive facial features that naturally accompany ID song may make it a particularly effective context for modulating infants' visual attention and supporting speech and language development in both typically developing infants and those with or at risk for communication challenges. A video abstract of this article can be viewed at https://youtu.be/SZ8xQW8h93A. RESEARCH HIGHLIGHTS: Infants' visual attention to adults' mouths during infant-directed speech has been found to support speech and language development. Infant-directed (ID) song promotes mouth-looking by infants to a greater extent than does ID speech across the first year of life. Features characteristic of ID song such as slower tempo, increased rhythmicity, increased audiovisual synchrony, and increased positive affect, all increase infants' attention to the mouth. The effects of song on infants' attention to the mouth are more prominent during the second half of the first year of life.

Music of infant-directed singing entrains infants' social visual behavior.

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.

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.

Influenza Management During the COVID-19 Pandemic: A Review of Recent Innovations in Antiviral Therapy and Relevance to Primary Care Practice.

Seasonal influenza requires appropriate management to protect public health and resources. Decreasing the burden of influenza will depend primarily on increasing vaccination rates as well as prompt initiation of antiviral therapy within 48 hours of symptom onset, especially in the context of the current coronavirus disease 2019 pandemic. A careful approach is required to prevent health services from being overwhelmed by a surge in demand that could exceed capacity. This review highlights the societal burden of influenza and discusses the prevention, diagnosis, and treatment of influenza as a complicating addition to the challenges of the coronavirus disease 2019 pandemic. The importance of vaccination for seasonal influenza and the role of antiviral therapy in the treatment and prophylaxis of seasonal influenza, including the most up-to-date recommendations from the Centers for Disease Control and Prevention for influenza management, will also be reviewed.

Visual Traces of Language Acquisition in Toddlers with Autism Spectrum Disorder During the Second Year of Life.

Infants show shifting patterns of visual engagement to faces over the first years of life. To explore the adaptive implications of this engagement, we collected eye-tracking measures on cross-sectional samples of 10-25-month-old typically developing toddlers (TD;N = 28) and those with autism spectrum disorder (ASD;N = 54). Concurrent language assessments were conducted and relationships between visual engagement and expressive and receptive language were analyzed between groups, and within ASD subgroups. TD and ASD toddlers exhibited greater mouth- than eye-looking, with TD exhibiting higher levels of mouth-looking than ASD. Mouth-looking was positively associated with expressive language in TD toddlers, and in ASD toddlers who had acquired first words. Mouth-looking was unrelated to expressive language in ASD toddlers who had not yet acquired first words.

Affording autism an early brain development re-definition.

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 Centers for Disease Control and Prevention (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.

Early developmental changes in visual social engagement in infant rhesus monkeys.

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.

Blink Rate Patterns Provide a Reliable Measure of Individual Engagement with Scene Content.

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.

Research Review: Outcomes of 24- to 36-month-old children with autism spectrum disorder vary by ascertainment strategy: a systematic review and meta-analysis.

BACKGROUND: Despite widespread recommendations for early surveillance of risk for autism spectrum disorder (ASD), no research to date has shown that early surveillance leads to better clinical outcomes. Preliminary research has suggested that children with ASD ascertained via prospective follow-up have better outcomes than those ascertained via community referral. Because prospective studies include early surveillance, by comparing outcomes of children with ASD across ascertainment strategies, we may gain insight into the effects of early surveillance relative to its absence. METHODS: A systematic review was conducted to identify studies reporting outcomes of 24- to 36-month-olds with ASD ascertained via prospective follow-up, community referral, or universal screening. A meta-analysis using a random effects model was used to calculate overall effect size estimates for developmental level and symptom severity across ascertainment cohorts. RESULTS: Eleven prospective, ten community referral, and eight universal screening studies were identified, reporting on 1,658 toddlers with ASD. We found no differences in outcomes between community referral and universal screening studies. Relative to both, prospective studies reported significantly higher developmental levels and lower symptom severities. CONCLUSIONS: Outcomes of young children with ASD ascertained via prospective follow-up are better than those of children with ASD recruited via community referral or universal screening. Although we discuss why sampling bias is not likely the driving force behind these findings, we cannot rule out the possibility that sampling bias contributes to the observed differences; future studies should probe the effects of sociodemographic variables on clinical outcomes as a function of ascertainment strategy. This limitation notwithstanding, our results raise the possibility that prospective follow-up may confer a 'surveillance effect' that contributes to improved developmental and diagnostic outcomes in children with ASD. Future research should test this hypothesis and determine the specific mechanism by which surveillance may improve outcomes.

Behavioral predictors of autism recurrence are genetically independent and influence social reciprocity: evidence that polygenic ASD risk is mediated by separable elements of developmental liability.

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.

Topology of the Structural Social Brain Network in Typical Adults.

Although a large body of research has identified discrete neuroanatomical regions involved in social cognition and behavior (the "social brain"), the existing findings are based largely on studies of specific brain structures defined within the context of particular tasks or for specific types of social behavior. The objective of the current work was to view these regions as nodes of a larger collective network and to quantitatively characterize both the topology of that network and the relative criticality of its many nodes. Large-scale data mining was performed to generate seed regions of the social brain. High-quality diffusion MRI data of typical adults were used to map anatomical networks of the social brain. Network topology and nodal centrality were analyzed using graph theory. The structural social brain network demonstrates a high degree of global functional integration with strong local segregation. Bilateral dorsomedial prefrontal cortices and amygdala play the most central roles in the network. Strong probabilistic evidence supports modular divisions of the social brain into subnetworks bearing good resemblance to functionally classified clusters. The present network-driven approach quantifies the structural topology of the social brain as a whole. This work can serve as a critical benchmark against which to compare (1) developmental change in social brain topology over time (from infancy through adolescence and beyond) and (2) atypical network topologies that may be a sign or symptom of disorder (as in conditions such as autism, Williams syndrome, schizophrenia, and others).

Neonatal Transitions in Social Behavior and Their Implications for Autism.

Within the context of early infant-caregiver interaction, we review a series of pivotal transitions that occur within the first 6 months of typical infancy, with emphasis on behavior and brain mechanisms involved in preferential orientation towards, and interaction with, other people. Our goal in reviewing these transitions is to better understand how they may lay a necessary and/or sufficient groundwork for subsequent phases of development, and also to understand how the breakdown thereof, when development is atypical and those transitions become derailed, may instead yield disability. We review these developmental processes in light of recent studies documenting disruptions to early-emerging brain and behavior mechanisms in infants later diagnosed with autism spectrum disorder, shedding light on the brain-behavior pathogenesis of autism.

A Longitudinal Investigation of Preferential Attention to Biological Motion in 2- to 24-Month-Old Infants.

Preferential attention to biological motion is an early-emerging mechanism of adaptive action that plays a critical role in social development. The present study provides a comprehensive longitudinal mapping of developmental change in preferential attention to biological motion in 116 infants at 7 longitudinal time points. Tested repeatedly from 2 until 24 months of age, results reveal that preferential attention to biological motion changes considerably during the first months of life. Previously reported preferences in both neonates and older infants are absent in the second month but do reemerge by month 3 and become increasingly pronounced during the subsequent two years. These results highlight the second month of life as a potentially critical transition period in social visual engagement.