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Clinicians form initial impressions about a childs diagnosis based on behavioral features, but research has not yet identified specific behaviors to guide initial diagnostic impressions. Participants were toddlers (N = 55, mean age 22.9 months) from a multi-site early detection study, referred for concern for ASD due to screening or parent/provider concern. Within 5 min of meeting a child, clinicians noted ASD or non-ASD impression, confidence in impression, and behaviors that informed their impression. These clinicians also determined final diagnoses for each child. When a childs final diagnosis was ASD (n = 35), senior clinicians formed an initial impression of ASD in 22 cases (63%) but missed 13 cases (37%). When final diagnosis was non-ASD (n = 20), senior clinicians made an initial impression of non-ASD in all cases (100%). Results were similar among junior clinicians. Senior and junior clinicians used the same behaviors to form accurate impressions of ASD and non-ASD: social reciprocity, nonverbal communication, and eye contact. Senior clinicians additionally used focus of attention when forming accurate impressions of ASD and non-ASD; junior clinicians used this behavior only when forming accurate non-ASD impressions. Clinicians initial impressions of ASD are very likely to be consistent with final diagnoses, but initial impressions of non-ASD need follow-up. Toddlers who show all four atypical behaviors (social reciprocity, nonverbal communication, eye contact, and focus of attention) might receive expedited ASD diagnoses. However, presence of apparently typical behaviors should not rule out ASD; for some children a longer evaluation is necessary to allow for more opportunities to observe subtle social behavior.

Prior studies suggest that habituation of sensory responses is reduced in autism and that diminished habituation could be related to atypical autistic sensory experiences, for example, by causing brain responses to aversive stimuli to remain strong over time instead of being suppressed. While many prior studies exploring habituation in autism have repeatedly presented identical stimuli, other studies suggest group differences can still be observed in habituation to intermittent stimuli. The present study explored habituation of electrophysiological responses to auditory complex tones of varying intensities (50-80 dB SPL), presented passively in an interleaved manner, in a well-characterized sample of 127 autistic (MDQ  = 65.41, SD = 20.54) and 79 typically developing (MDQ  = 106.02, SD = 11.50) children between 2 and 5 years old. Habituation was quantified as changes in the amplitudes of single-trial responses to tones of each intensity over the course of the experiment. Habituation of the auditory N2 response was substantially reduced in autistic participants as compared to typically developing controls, although diagnostic groups did not clearly differ in habituation of the P1 response. Interestingly, the P1 habituated less to loud 80 dB sounds than softer sounds, whereas the N2 habituated less to soft 50 dB sounds than louder sounds. No associations were found between electrophysiological habituation and cognitive ability or participants' caregiver-reported sound tolerance (Sensory Profile Hyperacusis Index). The results present study results extend prior research suggesting habituation of certain sensory responses is reduced in autism; however, they also suggest that habituation differences observed using this study's paradigm might not be a primary driver of autistic participants' real-world sound intolerance.

Evidence suggests autistic individuals at elevated familial likelihood of autism spectrum disorder (by virtue of having an autistic sibling) have stronger cognitive abilities on average than autistic individuals with no family history of the condition, who have a low familial likelihood of autism. Investigating phenotypic differences between community-referred infants and toddlers with autism symptoms at elevated or low familial likelihood of autism may provide important insight into heterogeneity in the emerging autism phenotype. This study compared behavioral, cognitive, and language abilities of community-referred infants and toddlers with confirmed autism symptoms at elevated (EL) or low familial likelihood of autism (LL). Participants were 121 children aged 12 to 36 months who participated in two larger randomized trials of parent-mediated interventions for children with autism symptoms. Behavioral phenotypes were compared across three groups: children with at least one autistic sibling (EL-Sibs, n = 30), those with at least one older, non-autistic sibling and no family history of autism (LL-Sibs, n = 40), and first-born children with no family history of autism (LL-FB, n = 51). EL-Sibs had less severe autism symptoms and stronger cognitive abilities than children in LL groups. While the rate of receptive language delay was similar across groups, the rate of expressive language delay was markedly lower among EL-Sibs. After controlling for age and nonverbal cognitive ability, EL-Sibs were significantly less likely to present with expressive language delay than LL-Sibs. Familial likelihood of autism may play an important role in shaping the emerging autism phenotype in infancy and toddlerhood.

This study evaluated the association between prenatal depression and offspring autism-related traits. The sample comprised 33 prenatal/pediatric cohorts participating in the Environmental influences on Child Health Outcomes program who contributed information on prenatal depression and autism-related traits. Autism-related traits were assessed continuously and at the diagnostic cut-off using the Social Responsiveness Scale for children up to 12 years of age. Main analyses included 3994 parent-child pairs with prenatal depression diagnoses data; secondary analyses included 1730 parent-child pairs with depression severity data. After confounder adjustment, we observed an increase in autism-related traits among children of individuals with prenatal depression compared to those without (adjusted β = 1.31 95% CI: 0.65, 1.98). Analyses stratified by child sex documented a similar significant association among boys (aβ = 1.34 95%CI: 0.36, 2.32) and girls (aβ = 1.26 95% CI: 0.37, 2.15). Prenatal depression was also associated with increased odds of moderate to severe autism-related traits (adjusted odds ratio: 1.64, 95%CI: 1.09, 2.46), the screening threshold considered high risk of autism spectrum disorder (ASD) diagnosis. Findings highlight the importance of prenatal depression screening and preventive interventions for children of pregnant individuals with depression to support healthy development. Future research is needed to clarify whether these findings reflect overlap in genetic risk for depression and ASD-related traits or another mechanism.

Males are diagnosed with autism much more frequently than females, and most research study samples reflect this male predominance. The result is that autistic females are understudied. There is a critical need to increase our understanding of autistic females, both biologically and clinically. The only way to do this is to recruit sex-balanced cohorts in studies so that similarities and differences between males and females can be evaluated in all autism research studies. The purpose of this commentary is to (1) provide historical context about how females came to be under-represented in all research, not just in the field of autism and (2) learn from other areas of health and medicine about the potentially dire consequences of not studying both sexes, and (3) draw attention to the need to recruit sex-balanced cohorts in autism research, particularly in neuroimaging studies.

Preschool autistic children with significant global developmental delays and very limited language skills are at high risk for remaining minimally verbal at entry into primary school. This study compared two early intervention models for improving social communication and spoken language outcomes in 164 children who received intervention in their community preschool program for 6 months, with a six-month follow-up. The primary outcome measure was a standardized language assessment, and secondary measures focused on social communication. Results indicated children on average made 6 months gain in language development in the active 6 months of intervention with no difference between intervention models. Children who initiated joint attention more frequently, or who had higher receptive language at baseline made more progress if assigned to receive JASPER, a naturalistic developmental behavioral intervention. Children who received Discrete Trial Training made greater spoken language progress from exit to follow-up. These findings suggest that progress can be made in autistic children who have very little spoken language and who receive targeted early interventions. Individual trajectories vary and depend in part on initial abilities in social communication and receptive language. Future research might consider methods to systematically personalize approaches to fit child characteristics and family preference. LAY SUMMARY: This study compared two different early intervention approaches for teaching spoken language to minimally verbal, globally delayed autistic preschoolers. Children were given an hour of therapy daily for 6 months and then reassessed 6 months later. The majority of the 164 participants were from historically excluded populations (low income and minority), and therapy was delivered in school community settings by expert clinicians. Results indicated that the participants made significant progress regardless of intervention approach: 6 months gain in standardized language scores over 6 months, but slower progress during the period after therapy ended. Children who initiated joint attention more frequently, or who had higher language understanding at baseline made more progress if assigned to receive JASPER, a naturalistic developmental behavioral intervention. Children who received Discrete Trial Training made greater language progress during 6-month period after therapy ended. These findings suggest that progress can be made in children with ASD who have very little spoken language and who receive targeted early interventions.

Reducing the age of first autism diagnosis facilitates access to critical early intervention services. A current "waitlist crisis" for autism diagnostic evaluation thus demands that we consider novel use of available clinical resources. Previous work has found that expert autism clinicians can identify autism in young children with high specificity after only a brief observation; rapid identification by non-experts remains untested. In the current study, 252 children ages 12-53 months presented for a comprehensive autism diagnostic evaluation. We found that junior clinicians in training to become autism specialists (n = 29) accurately determined whether or not a young child would be diagnosed with autism in the first five minutes of the clinic visit in 75% of cases. Specificity of brief observations was high (0.92), suggesting that brief observations may be an effective tool for triaging young children toward autism-specific interventions. In contrast, the lower negative predictive value (0.71) of brief observations, suggest that they should not be used to rule out autism. When trainees expressed more confidence in their initial impression, their impression was more likely to match the final diagnosis. These findings add to a body of literature showing that clinical observations of suspected autism should be taken seriously, but lack of clinician concern should not be used to rule out autism or overrule other indicators of likely autism, such as parent concern or a positive screening result.

Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder with substantial clinical heterogeneity, especially in language and communication ability. There is a need for validated language outcome measures that show sensitivity to true change for this population. We used Natural Language Processing to analyze expressive language transcripts of 64 highly-verbal children and young adults (age: 6-23 years, mean 12.8 years; 78.1% male) with ASD to examine the validity across language sampling context and test-retest reliability of six previously validated Automated Language Measures (ALMs), including Mean Length of Utterance in Morphemes, Number of Distinct Word Roots, C-units per minute, unintelligible proportion, um rate, and repetition proportion. Three expressive language samples were collected at baseline and again 4 weeks later. These samples comprised interview tasks from the Autism Diagnostic Observation Schedule (ADOS-2) Modules 3 and 4, a conversation task, and a narration task. The influence of language sampling context on each ALM was estimated using either generalized linear mixed-effects models or generalized linear models, adjusted for age, sex, and IQ. The 4 weeks test-retest reliability was evaluated using Lin's Concordance Correlation Coefficient (CCC). The three different sampling contexts were associated with significantly (P

The fuzzy nature of categories of psychopathology, such as autism, leads to significant research challenges. Alternatively, focusing research on the study of a common set of important and well-defined psychological constructs across psychiatric conditions may make the fundamental etiological processes of psychopathology easier to discern and treat (Cuthbert, 2022). The development of the research domain criteria (RDoC) framework is designed to guide this new research approach (Insel et al., 2010). However, progress in research may be expected to continually refine and reorganize the understanding of the specifics of these mental processes (Cuthbert & Insel, 2013). Moreover, knowledge gleaned from the study of both normative and atypical development can be mutually informative in the evolution of our understanding of these fundamental processes. A case in point is the study of social attention. This Autism 101 commentary provides an educational summary of research over the last few decades indicates that social attention is major construct in the study of human social-cognitive development, autism and other forms of psychopathology. The commentary also describes how this research can inform the Social Process dimension of the RDoC framework.

Children born preterm are at increased risk for autism spectrum disorder (ASD). There is limited knowledge about whether ASD phenotypes in children born preterm differ from children born at term. The objective of this study was to compare ASD core symptoms and associated characteristics among extremely preterm (EP) and term-born children with ASD. EP participants (n = 59) from the Extremely Low Gestational Age Newborn Study who met diagnostic criteria for ASD at approximately 10 years of age were matched with term-born participants from the Simons Simplex Collection on age, sex, spoken language level, and nonverbal IQ. Core ASD symptomatology was evaluated with the Autism Diagnostic Interview-Revised (ADI-R) and the Autism Diagnostic Observation Schedule (ADOS). Developmental milestones, anthropometrics, seizure disorder, and psychiatric symptoms were also investigated. The EP group had lower parent-reported symptom scores on ADI-R verbal communication, specifically stereotyped language, and restricted, repetitive behaviors. There were no between-group differences on ADI-R nonverbal communication and ADI-R reciprocal social interaction or with direct observation on the ADOS-2. The EP group was more likely to have delayed speech milestones and lower physical growth parameters. Results from female-only analyses were similar to those from whole-group analyses. In sum, behavioral presentation was similar between EP and IQ- and sex-matched term-born children assessed at age 10 years, with the exception of less severe retrospectively reported stereotyped behaviors, lower physical growth parameters, and increased delays in language milestones among EP-born children with ASD.

People with autism spectrum disorder (ASD) and non-spectrum developmental delays frequently exhibit maladaptive behaviors throughout the lifespan, which can have pervasive effects on quality of life. Maladaptive behaviors have been shown to change over time as a function of various individual-level factors (e.g., cognitive ability), yet research is primarily limited to parent-reported measures. To expand upon this work, the present study aimed to examine trajectories of teacher- and parent-reported maladaptive behaviors (i.e., hyperactivity, irritability, social withdrawal) and to test whether individual-level predictors (e.g., autism features, verbal intelligence quotient) and school-related predictors (e.g., teacher type, student-adult ratio, personal aide, school type) impact these trajectories among 165 individuals with ASD or non-spectrum delays from ages 9 to 18. Multilevel models revealed that, according to both teacher and parent report, participants showed the greatest improvement in hyperactivity, less but still notable improvement in irritability, and stable levels of social withdrawal over time. Higher verbal ability and fewer ASD features, in addition to mainstream school placement, emerged as important individual- and school-related differences associated with fewer maladaptive behaviors over time. The multi-informant perspective and longitudinal design provide novel insight into the manifestations of these maladaptive behaviors across different contexts and across time. Findings highlight the consistency of teacher- and parent-reported trajectories over time and further emphasize the importance of targeting maladaptive behaviors using a multisystem intervention approach in both school and home contexts.

Parental age is a known risk factor for autism spectrum disorder (ASD), however, studies to identify the biologic changes underpinning this association are limited. In recent years, "epigenetic clock" algorithms have been developed to estimate biologic age and to evaluate how the epigenetic aging impacts health and disease. In this study, we examined the relationship between parental epigenetic aging and their child's prospective risk of ASD and autism related quantitative traits in the Early Autism Risk Longitudinal Investigation study. Estimates of epigenetic age were computed using three robust clock algorithms and DNA methylation measures from the Infinium HumanMethylation450k platform for maternal blood and paternal blood specimens collected during pregnancy. Epigenetic age acceleration was defined as the residual of regressing chronological age on epigenetic age while accounting for cell type proportions. Multinomial logistic regression and linear regression models were completed adjusting for potential confounders for both maternal epigenetic age acceleration (n = 163) and paternal epigenetic age acceleration (n = 80). We found accelerated epigenetic aging in mothers estimated by Hannum's clock was significantly associated with lower cognitive ability and function in offspring at 12 months, as measured by Mullen Scales of Early Learning scores (β = -1.66, 95% CI: -3.28, -0.04 for a one-unit increase). We also observed a marginal association between accelerated maternal epigenetic aging by Horvath's clock and increased odds of ASD in offspring at 36 months of age (aOR = 1.12, 95% CI: 0.99, 1.26). By contrast, fathers accelerated aging was marginally associated with decreased ASD risk in their offspring (aOR = 0.83, 95% CI: 0.68, 1.01). Our findings suggest epigenetic aging could play a role in parental age risks on child brain development.

Respiratory sinus arrhythmia (RSA), an index of parasympathetic nervous system activity, has been linked with sleep quality among children with neurotypical development. The current study extended examination of these processes to children with autism spectrum disorder (ASD), a group at considerable risk for sleep problems. Participants included 54 children with ASD (aged 6-10 years, 43% Hispanic). RSA data were collected via a wired MindWare system during a 3-min baseline and a 3-min challenge task. Parents reported on their childrens sleep problems and sleep duration using the Childrens Sleep Habits Questionnaire, Abbreviated. Although no significant correlations emerged between RSA indices and parent-reported child sleep, baseline RSA and RSA reactivity interacted in the prediction of sleep problems. For children with higher RSA reactivity, higher baseline RSA was associated with fewer sleep problems, but for children with lower RSA reactivity, baseline RSA was not predictive. No main effects or interactions of RSA predicted sleep duration. Findings suggest resilience against sleep problems for children with ASD presenting with higher baseline RSA and higher RSA reactivity. Implications of these results center upon directly targeting psychophysiology (i.e., parasympathetic nervous system regulation) as a possible mechanism to improve sleep in children with ASD, and developing personalized interventions based on physiological markers of risk and resilience.

Autistic individuals are at an increased risk for both sleep disturbances and depression. While studies in the general population and in autistic adults have drawn general links between sleep disturbances and mental health, few studies have examined the extent to which specific sleep problems may be implicated in the extremely high rates of depression among autistic adults. This study aimed to describe the patterns of sleep disturbances in autistic young adults, and their associations with depressive symptoms while controlling for relevant demographic factors. A sample of 304 legally independent adults (age 18-35 years old) with a childhood diagnosis of autism spectrum disorder self-reported on their average sleep behaviors during the past week and depressive symptoms on the Beck Depressive Inventory-II. A significant proportion (86.01%) of autistic young adults experienced at least one of the primary sleep disturbances of interest, including short total sleep time (39.59%), poor sleep efficiency (60.07%), and delayed sleep phase (36.18%). Additionally, lower sleep efficiency and delayed sleep phase were both associated with higher depressive symptoms. The associations between sleep and depressive symptoms identified in our study suggest that sleep treatments may hold potential for ameliorating depressive symptoms in autistic adults who also experience sleep problems. Further research using daily sleep diaries and objective measures of sleep behaviors, as well as longitudinal studies, are needed to understand how changes in sleep may relate to changes in depressive symptoms in autistic adults.

In the present study, we provide a preliminary evaluation of the validity and reliability of using weighting procedures to measure communication in play samples for preschool-aged boys with autism or fragile X syndrome (FXS). Because weighting procedure communication scores (WPCSs) reflect growth in both communicative frequency and complexity, establishing the psychometrics of the component scores, in addition to the overall metric, affords investigators the opportunity to describe growth within and across skills. Results, for both groups, provide support regarding the psychometric appropriateness (i.e., convergent validity, divergent validity, and internal consistency) for all WPCSs. That said, a trend was observed for reliability scores to be slightly lower or more variable in boys with autism than in boys with FXS. Finally, although significant associations were observed in the associations between WPCSs across play contexts, contexts effects were observed for all three WPCSs. Together, results from this study provide promising preliminary data indicating the utility of using WPCSs in children with neurodevelopmental disabilities. Lay Summary: Language supports long-term positive outcomes; it is important to identify accurate and flexible ways of measuring language in children over time. We considered the effectiveness of using a procedure that considers changes in the number of communication acts and the types of acts produced during a play session by preschool-aged boys with autism or fragile X syndrome. These procedures were found to be valid and reliable.

Prior work has suggested associations between prenatal exposure to several classes of pesticides and child autism spectrum disorder (ASD). We examined a previously developed pesticide residue burden score (PRBS) and intake of high pesticide residue foods in association with ASD-related traits. Participants were drawn from the Early Autism Risk Longitudinal Investigation (EARLI) (n = 256), a cohort following mothers who previously had a child with ASD through a subsequent pregnancy and that child's development. ASD-related traits were captured according to total Social Responsiveness Scale (SRS) scores at age 3 (mean raw total SRS score = 35.8). Dietary intake was assessed through a food frequency questionnaire collected during pregnancy. We also incorporated organic intake and fatty foods in modified versions of the PRBS. Associations between high-residue fruit and vegetable intake, the overall PRBS and modified versions of it, and SRS scores were assessed using multivariable linear regression. Overall, we did not observe associations between pesticide residues in foods and ASD-related outcomes, and modified versions of the PRBS yielded similar findings. However, reductions in ASD-related traits were observed with higher overall fruit and vegetable intake (adjusted estimates for Q4 vs. Q1: β -12.76, 95%CI -27.8, 2.3). Thus, findings from this high familial probability cohort did not suggest relationships between pesticide residues in the diet according to the PRBS and ASD-related traits. Beneficial effects of fruit and vegetable intake may influence these relationships. Future work should consider fruit and vegetable intake in association with ASD-related outcomes. LAY SUMMARY: Diet is the main source of exposure to most pesticides in use today. In this study, we examined the relationship between pesticide exposure from residues in the diet during pregnancy and child autism-related traits. We found that these pesticide residues from the diet were not related to child autism-related outcomes at age three. However, higher prenatal fruit and vegetable intake was associated with reductions in child autism-related traits.

Angelman syndrome (AS) is a genetic neurodevelopmental disorder characterized by developmental delay, lack of speech, seizures, intellectual disability, hypotonia, and motor coordination deficits. Motor abilities are an important outcome measure in AS as they comprise a broad repertoire of metrics including ataxia, hypotonia, delayed ambulation, crouched gait, and poor posture, and motor dysfunction affects nearly every individual with AS. Guided by collaborative work with AS clinicians studying gait, the goal of this study was to perform an in-depth gait analysis using the automated treadmill assay, DigiGait. Our hypothesis is that gait presents a strong opportunity for a reliable, quantitative, and translational metric that can serve to evaluate novel pharmacological, dietary, and genetic therapies. In this study, we used an automated gait analysis system, in addition to standard motor behavioral assays, to evaluate components of motor, exploration, coordination, balance, and gait impairments across the lifespan in an AS mouse model. Our study demonstrated marked global motoric deficits in AS mice, corroborating previous reports. Uniquely, this is the first report of nuanced aberrations in quantitative spatial and temporal components of gait in AS mice compared to sex- and age-matched wildtype littermates followed longitudinally using metrics that are analogous in AS individuals. Our findings contribute evidence toward the use of nuanced motor outcomes (i.e., gait) as valuable and translationally powerful metrics for therapeutic development for AS, as well as other genetic neurodevelopmental syndromes. LAY SUMMARY: Movement disorders affect nearly every individual with Angelman Syndrome (AS). The most common motor problems include spasticity, ataxia of gait (observed in the majority of ambulatory individuals), tremor, and muscle weakness. This report focused on quantifying various spatial and temporal aspects of gait as a reliable, translatable outcome measure in a preclinical AS model longitudinally across development. By increasing the number of translational, reliable, functional outcome measures in our wheelhouse, we will create more opportunities for identifying and advancing successful medical interventions.

Given inconsistent evidence on preconception or prenatal tobacco use and offspring autism spectrum disorder (ASD), this study assessed associations of maternal smoking with ASD and ASD-related traits. Among 72 cohorts in the Environmental Influences on Child Health Outcomes consortium, 11 had ASD diagnosis and prenatal tobaccosmoking (n = 8648). and 7 had Social Responsiveness Scale (SRS) scores of ASD traits (n = 2399). Cohorts had diagnoses alone (6), traits alone (2), or both (5). Diagnoses drew from parent/caregiver report, review of records, or standardized instruments. Regression models estimated smoking-related odds ratios (ORs) for diagnoses and standardized mean differences for SRS scores. Cohort-specific ORs were meta-analyzed. Overall, maternal smoking was unassociated with child ASD (adjusted OR, 1.08; 95% confidence interval [CI], 0.72-1.61). However, heterogeneity across studies was strong: preterm cohorts showed reduced ASD risk for exposed children. After excluding preterm cohorts (biased by restrictions on causal intermediate and exposure opportunity) and small cohorts (very few ASD cases in either smoking category), the adjusted OR for ASD from maternal smoking was 1.44 (95% CI, 1.02-2.03). Children of smoking (versus non-smoking) mothers had more ASD traits (SRS T-score + 2.37 points, 95% CI, 0.73-4.01 points), with results homogeneous across cohorts. Maternal preconception/prenatal smoking was consistently associated with quantitative ASD traits and modestly associated with ASD diagnosis among sufficiently powered United States cohorts of non-preterm children. Limitations resulting from self-reported smoking and unmeasured confounders preclude definitive conclusions. Nevertheless, counseling on potential and known risks to the child from maternal smoking is warranted for pregnant women and pregnancy planners. LAY SUMMARY: Evidence on the association between maternal prenatal smoking and the child's risk for autism spectrum disorder has been conflicting, with some studies reporting harmful effects, and others finding reduced risks. Our analysis of children in the ECHO consortium found that maternal prenatal tobacco smoking is consistently associated with an increase in autism-related symptoms in the general population and modestly associated with elevated risk for a diagnosis of autism spectrum disorder when looking at a combined analysis from multiple studies that each included both pre- and full-term births. However, this study is not proof of a causal connection. Future studies to clarify the role of smoking in autism-like behaviors or autism diagnoses should collect more reliable data on smoking and measure other exposures or lifestyle factors that might have confounded our results.

Traditional longitudinal modeling approaches require normally distributed data and do not account for sample heterogeneity. Parenting stress, in particular, can be difficult to model across time without transforming the data as it is usually high for caregivers of children with ASD. This study used novel linear quantile mixed models (LQMMs) to model non-normal parent stress scores across two caregiver-mediated interventions involving toddlers with ASD. The sample included 86 caregiver-child dyads who were randomized to either a parent-only psychoeducational intervention or hands-on parent training in a naturalistic developmental intervention. Child and parent-related domains of the Parenting Stress Index (PSI) were the primary outcomes in this study. The PSI was collected at entry, 10-week exit, 3-month follow-up, and 6-month follow-up periods. Separate LQMMs were used to model five specific quantiles ( τ=0.1,0.25,0.5,0.75,and0.9) of the two PSI domains across the complete intervention timeline. These five quantiles effectively modeled the entire conditional distribution of parenting stress scores. The LQMMs indicated that child-related parenting stress decreased across all quantiles within both interventions, with no difference in the rate of parenting stress change between the intervention groups. For parent-related parenting stress, the effect of intervention depended on the group's stress level; some parents increased their perceived stress within the hands-on intervention at the 3-month follow-up. Overall, this study demonstrated that the use of LQMMs yielded additional information, beyond traditional longitudinal models, regarding the relationship between parenting stress within two caregiver-mediated intervention protocols. This study also discussed the methodological contributions and potential future applications of LQMMs. LAY SUMMARY: This study used a newer longitudinal modeling technique to examine how parenting stress changed across two caregiver-mediated interventions for toddlers with ASD. Results showed that certain parents in the JASPER condition might require additional support as they exit the study and enter into their first follow-up period. It was also determined that this new modeling technique could be a valuable tool to analyze highly variable data often present in ASD intervention studies.

Adults with autism spectrum disorder (ASD) experience high rates of both unemployment and depression. Though job loss predicts increased risk of depression in the general population, studies have yet to directly examine this relationship among individuals with ASD. With the backdrop of rising unemployment due to COVID-19, we used a longitudinal design to examine whether employment changes predicted increasing depressive symptoms among young adults with ASD. Online surveys were collected from young adults with ASD at two times: just before widespread social distancing measures were adopted in the United States, and again 10 weeks later. Both time points included measurement of depressive symptoms (Beck Depression Inventory-2). At Time 2, COVID-related employment changes and the perceived impact of those changes on well-being were collected. Of the young adults who were employed at Time 1 (n = 144), over one-third (37.5%) reported employment changes during the first 2 months of COVID-19. Most of this change was job loss or reductions in hours or pay ("job loss/reduction"). Controlling for Time 1 depressive symptoms, young adults who experienced job loss/reduction had significantly higher depressive symptoms at Time 2 than those without an employment change. Individuals' perceived impact of employment change also predicted depressive symptoms. These findings suggest that losing a job or experiencing reductions in hours or pay leads to worsening depressive symptoms among adults with ASD. Better supporting autistic adults in the workplace may not only decrease the likelihood of job loss, but also combat the exceedingly high rates of depression in this group. LAY SUMMARY: Though unemployment has been linked to mental health problems in the general population, this relationship is seldom considered among adults with autism. In this study, we found that adults on the autism spectrum who lost their jobs or experienced reductions in pay or hours during the first 2 months of COVID-19 had worsening depression compared to adults who did not have job changes. Our findings suggest that increasing access to employment may help alleviate poor mental health among autistic adults.

Young adults with autism spectrum disorder (ASD) experience limited social connectedness, difficulty living independently, and other poor outcomes at high rates. Vocational activities, including employment and postsecondary education, are associated with increased positive outcomes and subjective well-being in typical adults. This study identified vocational activity trajectory groups in adults with ASD, examined change in these trajectories from ages 18 to 28, and compared levels of parent- and self-report subjective well-being across trajectory groups. One hundred fifty-one adults with ASD were drawn from an ongoing longitudinal study. Data on psychosocial outcomes and vocational activities were compiled from parent-report demographic forms. Vocational activities were scored using the vocational index (VDI). There was no significant effect of age on the slope of vocational trajectories (p = 0.787). Participants in the Independent Activities group had significantly higher parent-report happiness factor scores than participants in the No Activities group (F [3, 107] = 3.56, p = 0.017) and significantly higher self-report happiness factor scores than participants in the Volunteer Activities group (F [2, 35] = 6.46, p = 0.004). The Independent Activities group was also significantly more likely to have at least one social contact (X2 [3, 118] = 10.54, p = 0.014), however, there was no difference in trajectories groups in the likelihood of living independently (X2 [3, 120] = 1.71, p = 0.634). The results of this study indicate vocational activities in young adults with ASD are stable across time. In the current sample, participation in independent vocational activities was associated with increased levels of subjective well-being.

The COVID-19 pandemic has posed unique challenges for families and caregivers, as well as for autism-focused clinicians, who are faced with providing a thorough and accurate evaluation of children's specific needs and diagnoses in the absence of in-person assessment tools. The shift to telehealth assessments has challenged clinicians to reconsider approaches and assumptions that underlie the diagnostic assessment process, and to adopt new ways of individualizing standard assessments according to family and child needs. Mandates for physical distancing have uncovered deficiencies in diagnostic practices for suspected autism and have illuminated biases that have posed obstacles preventing children and families from receiving the services that they truly need. This Commentary outlines several considerations for improving diagnostic practices as we move forward from the current pandemic and continue to strive to build an adaptable, sustainable, equitable, and family-centered system of care. LAY SUMMARY: Physical distancing and the abrupt end to in-person services for many children on the autism spectrum has forced clinicians to examine the existing challenges with autism spectrum disorder (ASD) diagnostic assessment and consider things they want to keep and things that should be changed in the years ahead. New approaches such as telehealth both alleviated and exacerbated existing disparities, and brought into stark focus the importance of equitable and timely access to family-centered care. This commentary suggests ways of improving clinical practices related to ASD assessment to continue along this path.

Diagnosticians report that autism spectrum disorder (ASD) is immediately apparent in some, but not all, children ultimately diagnosed. Clinicians' initial diagnostic impressions have implications for ASD early detection, yet the literature raises questions about their accuracy. This study explores diagnostic impressions of ASD specialists made within the first 5 minutes of meeting a young child and investigates factors associated with the match between initial impressions and final diagnoses. Participants were children (n = 294, aged 12-53 months) referred for an ASD evaluation as part of multi-site ASD screening studies. After 5 minutes observing each child, clinicians with expertise diagnosing ASD recorded if they thought the child would meet criteria for ASD following a complete evaluation, and recorded their confidence in this impression. Clinicians' initial impressions matched the final diagnosis in 81% of cases. Ninety-two percent of cases initially thought to have ASD met criteria following a full evaluation; however, 24% of cases initially thought not to have ASD also met criteria, suggesting a high miss rate. Clinicians were generally confident in their initial impressions, reporting highest confidence for children initially thought correctly not to have ASD. ASD behavioral presentation, but not demographic characteristics or developmental level, were associated with matching initial impression and final diagnosis, and confidence. Brief observations indicating ASD should trigger referral to intervention services, but are likely to under-detect positive cases and should not be used to rule out ASD, highlighting the need to incorporate information beyond initial clinical impression. LAY SUMMARY: When children come in for an autism evaluation, clinicians often form early impressions-before doing any formal testing-about whether the child has autism. We studied how often these early impressions match the final diagnosis, and found that clinicians could not easily rule out autism (many children who initially appeared not to have autism were ultimately diagnosed), but were generally accurate ruling in autism (when a child appeared to have autism within 5 minutes, they were almost always so diagnosed).

People with autism spectrum disorder (ASD) exhibit a variety of medical morbidities at significantly higher rates than the general population. Using an established monkey model of naturally occurring low sociality, we investigated whether low-social monkeys show an increased burden of medical morbidities compared to their high-social counterparts. We systematically reviewed the medical records of N = 152 (n = 73 low-social; n = 79 high-social) rhesus macaques (Macaca mulatta) to assess the number of traumatic injury, gastrointestinal, and inflammatory events, as well as the presence of rare medical conditions. Subjects' nonsocial scores, determined by the frequency they were observed in a nonsocial state (i.e., alone), and macaque Social Responsiveness Scale-Revised (mSRS-R) scores were also used to test whether individual differences in social functioning were related to medical morbidity burden. Medical morbidity type significantly differed by group, such that low-social monkeys incurred higher rates of traumatic injury compared to high-social monkeys. Nonsocial scores and mSRS-R scores also significantly and positively predicted traumatic injury rates, indicating that monkeys with the greatest social impairment were most impacted on this health measure. These findings from low-social monkeys are consistent with well-documented evidence that people with ASD incur a greater number of traumatic injuries and receive more peer bullying than their neurotypical peers, and add to growing evidence for the face validity of this primate model. LAY SUMMARY: People with autism exhibit multiple medical problems at higher rates than the general population. We conducted a comprehensive medical record review of monkeys that naturally exhibit differences in sociality and found that low-social monkeys are more susceptible to traumatic injuries than high-social monkeys. These results are consistent with reports that people with autism also incur greater traumatic injury and peer bullying and add to growing evidence for the validity of this monkey model.

Atypical responses to fearful stimuli and the presence of various forms of anxiety are commonly seen in children with autism spectrum disorder (ASD). The fear potentiated startle paradigm (FPS), which has been studied both in relation to anxiety and as a probe for amygdala function, was carried out in 97 children aged 9-14 years including 48 (12 female) with ASD and 49 (14 female) with typical development (TD). In addition, exploratory analyses were conducted examining the association between FPS and amygdala volume as assessed with magnetic resonance imaging in a subset of the children with ASD with or without an anxiety disorder with available MRI data. While the startle latency was increased in the children with ASD, there was no group difference in FPS. FPS was not significantly associated with traditional Diagnostic and Statistical Manual (DSM) or "autism distinct" forms of anxiety. Within the autism group, FPS was negatively correlated with amygdala volume. Multiple regression analyses revealed that the association between FPS and anxiety severity was significantly moderated by the size of the amygdala, such that the association between FPS and anxiety was significantly more positive in children with larger amygdalas than smaller amygdalas. These findings highlight the heterogeneity of emotional reactivity associated with ASD and the difficulties in establishing biologically meaningful probes of altered brain function. LAY SUMMARY: Many children with autism spectrum disorder (ASD) have additional problems such as anxiety that can greatly impact their lives. How these co-occurring symptoms develop is not well understood. We studied the amygdala, a region of the brain critical for processing fear and a laboratory method called fear potentiated startle for measuring fear conditioning, in children with ASD (with and without an anxiety disorder) and typically developing children. Results showed that the connection between fear conditioning and anxiety is dependent on the size of the amygdala in children with ASD.

Despite the clinically significant impact of executive dysfunction on the outcomes of adolescents and young adults with autism spectrum disorders (ASD), we lack a clear understanding of its prevalence, profile, and development. To address this gap, we administered the NIH Toolbox Cognition Battery to a cross-sectional Intelligence Quotient (IQ) case-matched cohort with ASD (n = 66) and typical development (TD; n = 66) ages 12-22. We used a general linear model framework to examine group differences in task performance and their associations with age. Latent profile analysis (LPA) was used to identify subgroups of individuals with similar cognitive profiles. Compared to IQ case-matched controls, ASD demonstrated poorer performance on inhibitory control (P

Despite advances in early detection, the average age of autism spectrum disorder (ASD) diagnosis exceeds 4 years and is often later in females. In typical development, biological sex predicts inter-individual variation across multiple developmental milestones, with females often exhibiting earlier progression. The goal of this study was to examine sex differences in caregiver-reported developmental milestones (first word, phrase, walking) and their contribution to timing of initial concerns expressed by caregivers and eventual age of diagnosis. 195 (105 males) children and adolescents aged 8 to 17 years with a clinical diagnosis of ASD were recruited to the study (mean IQ = 99.76). While developmental milestones did not predict timing of diagnosis or age parents first expressed concerns, females had earlier first words and phrases than males. There was a marginal difference in the age of diagnosis, with females receiving their diagnosis 1 year later than males. Despite sex differences in developmental milestones and diagnostic variables, IQ was the most significant predictor in the timing of initial concerns and eventual diagnosis, suggesting children with lower IQ, regardless of sex, are identified and diagnosed earlier. Overall, biological sex and developmental milestones did not account for a large proportion of variance for the eventual age of ASD diagnosis, suggesting other factors (such as IQ and the timing of initial concerns) are potentially more influential. LAY SUMMARY: In this study, a later age of diagnosis in females having ASD was confirmed; however, biological sex was not the stronger predictor of age of diagnosis. Parents reported that females learned language more quickly than males, and parents noted their first concerns when females were older than males. In this sample, the strongest predictor of age of diagnosis was the age of first concerns.

The prenatal period is a critical window for the development of autism spectrum disorder (ASD). The relationship between prenatal nutrients and gestational gene expression in mothers of children later diagnosed with ASD or non-typical development (Non-TD) is poorly understood. Maternal blood collected prospectively during pregnancy provides insights into the effects of nutrition, particularly one-carbon metabolites, on gene pathways and neurodevelopment. Genome-wide transcriptomes were measured with microarrays in 300 maternal blood samples in Markers of Autism Risk in Babies-Learning Early Signs. Sixteen different one-carbon metabolites, including folic acid, betaine, 5'-methyltretrahydrofolate (5-MeTHF), and dimethylglycine (DMG) were measured. Differential expression analysis and weighted gene correlation network analysis (WGCNA) were used to compare gene expression between children later diagnosed as typical development (TD), Non-TD and ASD, and to one-carbon metabolites. Using differential gene expression analysis, six transcripts (TGR-AS1, SQSTM1, HLA-C, and RFESD) were associated with child outcomes (ASD, Non-TD, and TD) with genome-wide significance. Genes nominally differentially expressed between ASD and TD significantly overlapped with seven high confidence ASD genes. WGCNA identified co-expressed gene modules significantly correlated with 5-MeTHF, folic acid, DMG, and betaine. A module enriched in DNA methylation functions showed a suggestive protective association with folic acid/5-MeTHF concentrations and ASD risk. Maternal plasma betaine and DMG concentrations were associated with a block of co-expressed genes enriched for adaptive immune, histone modification, and RNA processing functions. These results suggest that the prenatal maternal blood transcriptome is a sensitive indicator of gestational one-carbon metabolite status and changes relevant to children's later neurodevelopmental outcomes. LAY SUMMARY: Pregnancy is a time when maternal nutrition could interact with genetic risk for autism spectrum disorder. Blood samples collected during pregnancy from mothers who had a prior child with autism were examined for gene expression and nutrient metabolites, then compared to the diagnosis of the child at age three. Expression differences in gene pathways related to the immune system and gene regulation were observed for pregnancies of children with autism and non-typical neurodevelopment and were associated with maternal nutrients.

In the first year of life, the ability to engage in sustained synchronous interactions develops as infants learn to match social partner behaviors and sequentially regulate their behaviors in response to others. Difficulties developing competence in these early social building blocks can impact later language skills, joint attention, and emotion regulation. For children at elevated risk for autism spectrum disorder (ASD), early dyadic synchrony and responsiveness difficulties may be indicative of emerging ASD and/or developmental concerns. As part of a prospective developmental monitoring study, infant siblings of children with ASD (high-risk group n = 104) or typical development (low-risk group n = 71), and their mothers completed a standardized play task when infants were 6, 9, and/or 12 months of age. These interactions were coded for the frequency and duration of infant and mother gaze, positive affect, and vocalizations, respectively. Using these codes, theory-driven composites were created to index dyadic synchrony and infant/maternal responsiveness. Multilevel models revealed significant risk group differences in dyadic synchrony and infant responsiveness by 12 months of age. In addition, high-risk infants with higher dyadic synchrony and infant responsiveness at 12 months received significantly higher receptive and expressive language scores at 36 months. The findings of the present study highlight that promoting dyadic synchrony and responsiveness may aid in advancing optimal development in children at elevated risk for autism. LAY SUMMARY: In families raising children with an autism spectrum disorder (ASD), younger siblings are at elevated risks for social communication difficulties. The present study explored whether social-communication differences were evident during a parent-child play task at 6, 9, and 12 months of age. For infant siblings of children with ASD, social differences during play were observed by 12 months of age and may inform ongoing monitoring and intervention efforts.

There is lack of consensus in the literature regarding sex differences in social outcomes for individuals on the autism spectrum. Furthermore, little research has focused on the social experiences of high school students with autism spectrum disorder (ASD) during the school day. Using a large racially/ethnically diverse sample of high school students with ASD receiving special education services (n = 547; 76 females, 471 males), we examined sex differences in social interactions of youth both during and after school. We also tested for sex differences in background and phenotypic characteristics including autism severity, IQ, adaptive behavior, and mental health. Results indicated few statistically significant differences between males and females in social interactions and phenotypic characteristics (including raw scores of autism symptom severity). However, analysis of standardized scores of autism symptoms suggested that symptom scores for females with ASD diverged more from same-sex peers in the normed sample than scores of males with ASD. Lack of sex difference in social participation for youth with ASD in this study stands in contrast to patterns of sex differences in the general population. Findings suggest that few differences between males and females with ASD, both in social participation and autism symptom severity, might result in females with ASD being more dissimilar to their same-sex peers than males with ASD. Implications of findings for understanding sex differences in ASD across the life course are discussed. LAY SUMMARY: The present study examined sex differences in social participation in a large, diverse sample of high school students with autism spectrum disorder (ASD). Males and females were very similar in their social interactions both at school and outside of school, based on reports by teachers and parents. Level of autism symptoms was also similar for males and females. However, standardized scores of autism symptoms, which take into account age and sex specific norms, suggested that females with ASD may have behaviors that are more divergent from their same-sex peers than males with ASD.

Although individuals with autism spectrum disorder (ASD) have been often shown to display similar memory performance on semantic memory tasks compared to typically developing (TD) children, there is ongoing debate about whether and how their ability to remember specific past events (i.e., episodic memory) is impaired. We assessed a sample of 62 children with ASD and 72 TD children, ranging in age between 8 and 12 years on 2 memory tasks. Participants encoded a series of images and their association with either where they appeared on the screen (item-space association task) or with the color of an image's border (item-color association task). Children with ASD showed worse memory in the item-space association task compared to their TD peers, but comparable memory for the item-color association task. These differences persisted when age, intellectual quotient, and general item recognition memory were accounted for statistically. We interpret these results in light of evidence for specific deficits along the dorsal stream affecting processing of spatiotemporal information in ASD. Autism Res 2020, 13: 1985-1997. © 2020 International Society for Autism Research and Wiley Periodicals LLC LAY SUMMARY: Episodic memory requires the ability to bind contextual details (such as color, location, etc.) to an item or event in order to remember the past with specific detail. Here, we compared children with autism spectrum disorder (ASD) and typically developing (TD) children on tasks examining episodic memory. Children with ASD recalled more poorly previously seen items and their associated space-related details, but they performed comparably to TD children on color details. We discuss the possible mechanisms that contribute to worse spatial processing/recall in ASD.

Gastrointestinal (GI) symptoms are frequently reported in children with autism spectrum disorder (ASD). We evaluated the frequency and severity of GI symptoms in preschool-aged children with ASD compared to participants with typical development (TD). Our goal was to ascertain whether GI symptoms are associated with differences in sex or developmental and behavioral measures. Participants were between 2 and 3.5 years of age and included 255 children with ASD (184 males/71 females) and 129 age-matched TD controls (75 males/54 females). A parent interview was used to assess GI symptoms (abdominal pain, gaseousness/bloating, diarrhea, constipation, pain on stooling, vomiting, difficulty swallowing, blood in stool or in vomit). Children with GI symptoms in each diagnostic group were compared to children without GI symptoms on measures of developmental, behavioral, and adaptive functioning. GI symptoms were reported more frequently in children with ASD compared to the TD group (47.8% vs. 17.8%, respectively). Children with ASD were also more likely to experience multiple GI symptoms (30.6% vs. 5.4%). GI symptoms were equally common in males and females across both diagnostic groups. There were no statistically significant differences in developmental or adaptive measures based on presence of GI symptoms in either ASD or TD children. Co-occurring GI symptoms were, however, associated with increased self-injurious behaviors, restricted stereotyped behaviors, aggressive behaviors, sleep problems and attention problems in both ASD and TD children. In children with ASD, a higher number of GI symptoms was associated with an increase in self-injurious behaviors, somatic complaints, reduced sleep duration, and increased parasomnias. LAY SUMMARY: ASD is characterized by challenges in social communication and repetitive behaviors. But, people with autism have many other difficulties including gastrointestinal problems. Children with ASD were three times more likely to experience GI symptoms than typically developing peers. Increased GI symptoms are associated with increased problem behaviors such as sleep problems, self-injury, and body aches. Since GI symptoms are often treatable, it is important to recognize them as soon as possible. Both clinicians and parents should become more aware of the high occurrence of GI problems in autistic people. Autism Res 2020, 13: 1778-1789. © 2020 International Society for Autism Research and Wiley Periodicals LLC.

Individuals with autism spectrum disorder (ASD) are significantly more likely to experience sensory over-responsivity (SOR) compared to neurotypical controls. SOR in autism has been shown to be related to atypical functional connectivity in the salience network (SN), a brain network thought to help direct attention to the most relevant stimuli in one's environment. However, all studies to date which have examined the neurobiological basis of sensory processing in ASD have used primarily male samples so little is known about sex differences in the neural processing of sensory information. This study examined the relationship between SOR and resting-state functional connectivity in the SN for 37 males and 16 females with autism, ages 8-17 years. While there were no sex differences in parent-rated SOR symptoms, there were significant sex differences in how SOR related to SN connectivity. Relative to females with ASD, males with ASD showed a stronger association between SOR and increased connectivity between the salience and primary sensory networks, suggesting increased allocation to sensory information. Conversely, for females with ASD, SOR was more strongly related to increased connectivity between the SN and prefrontal cortex. Results suggest that the underlying mechanisms of SOR in ASD are sex specific, providing insight into the differences seen in the diagnosis rate and symptom profiles of males and females with ASD. LAY SUMMARY: Sensory over-responsivity (SOR) is common in autism. Most research on the neural basis of SOR has focused on males, so little is known about SOR or its neurobiology in females with autism spectrum disorder. Here despite no sex differences in SOR symptoms, we found sex differences in how SOR related to intrinsic connectivity in a salience detection network. Results show sex differences in the neural mechanisms underlying SOR and inform sex differences seen in diagnosis rates and symptom profiles in autism. Autism Res 2020, 13: 1489-1500. © 2020 International Society for Autism Research, Wiley Periodicals, Inc.

Naturally low-social rhesus macaques exhibit social impairments with direct relevance to autism spectrum disorder (ASD). To more efficiently identify low-social individuals in a large colony, we exploited, refined, and psychometrically assessed the macaque Social Responsiveness Scale (mSRS), an instrument previously derived from the human ASD screening tool. We performed quantitative social behavior assessments and mSRS ratings on a total of N = 349 rhesus macaques (Macaca mulatta) housed in large, outdoor corrals. In one cohort (N = 116), we conducted inter-rater and test-retest reliabilities, and in a second cohort (N = 233), we evaluated the convergent construct and predictive validity of the mSRS-Revised (mSRS-R). Only 17 of the original 36 items demonstrated inter-rater and test-retest reliability, resulting in the 17-item mSRS-R. The mSRS-R showed strong validity: mSRS-R scores robustly predicted monkeys' social behavior frequencies in home corrals. Monkeys that scored 1.5 standard deviations from the mean on nonsocial behavior likewise exhibited significantly more autistic-like traits, and mSRS-R scores predicted individuals' social classification (low-social vs. high-social) with 96% accuracy (likelihood ratio chi-square = 25.07; P

Motor impairments occur frequently in genetic syndromes highly penetrant for autism spectrum disorder (syndromic ASD) and in individuals with ASD without a genetic diagnosis (nonsyndromic ASD). In particular, abnormalities in gait in ASD have been linked to language delay, ASD severity, and likelihood of having a genetic disorder. Quantitative measures of motor function can improve our ability to evaluate motor differences in individuals with syndromic and nonsyndromic ASD with varying levels of intellectual disability and adaptive skills. To evaluate this methodology, we chose to use quantitative gait analysis to study duplication 15q syndrome (dup15q syndrome), a genetic disorder highly penetrant for motor delays, intellectual disability, and ASD. We evaluated quantitative gait variables in individuals with dup15q syndrome (n = 39) and nonsyndromic ASD (n = 21) and compared these data to a reference typically developing cohort. We found a gait pattern of slow pace, poor postural control, and large gait variability in dup15q syndrome. Our findings improve characterization of motor function in dup15q syndrome and nonsyndromic ASD. Quantitative gait analysis can be used as a translational method and can improve our identification of clinical endpoints to be used in treatment trials for these syndromes. Autism Res 2020, 13: 1102-1110. © 2020 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: Motor impairments, particularly abnormalities in walking, occur frequently in genetic syndromes highly penetrant for autism spectrum disorder (syndromic ASD). Here, using quantitative gait analysis, we find that individuals with duplication 15q syndrome have an atypical gait pattern that differentiates them from typically developing and nonsyndromic ASD individuals. Our findings improve motor characterization in dup15q syndrome and nonsyndromic ASD.

Advanced parental age is a well-replicated risk factor for autism spectrum disorder (ASD), a neurodevelopmental condition with a complex and not well-defined etiology. We sought to determine parental age associations with ASD-related outcomes in subjects at high familial risk for ASD. A total of 397 younger siblings of a child with ASD, drawn from existing prospective high familial risk cohorts, were included in these analyses. Overall, we did not observe significant associations of advanced parental age with clinical ASD diagnosis, Social Responsiveness Scale, or Vineland Adaptive Behavior Scales scores. Instead, increased odds of ASD were found with paternal age

Emerging research suggests social attention in autism spectrum disorder (ASD) girls is enhanced relative to ASD boys but may also be affected by the type of social and nonsocial content presented. This study examined how biological sex and gender norms interact to influence visual attention in 79 school-aged children observing scenes that included gender-associated toys and actors of both sexes. Attention to social (faces) and object activity (hands with toys) stimuli was measured. Previously described distinctions between social attention in ASD boys and girls were replicated, with ASD girls looking more at faces than ASD boys. Irrespective of diagnosis, males and females attended more to actors that shared their same sex, and attended more to toys with gender-associations that were consistent with their own sex, suggesting that social and object salience increases for children under sex-consistent conditions. Importantly, ASD and typically developing (TD) children increased their gaze to faces when male actors were shown playing with female-associated toys, suggesting that both groups of children are sensitive to societal messages about the acceptability of males playing with female-associated toys. Our findings provide further evidence of heightened attention to faces in ASD girls relative to ASD boys, and indicate that social attention in ASD and TD children is influenced by who (male or female actor) and what (male- or female-associated toy) is being observed. Collectively, these results present a nuanced profile of attention in ASD that adds to a growing body of research indicating subtle phenotypic differences in ASD girls that may impact identification, assessment, and intervention. Autism Res 2020, 13: 763-776.. © 2019 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: Sex differences observed in typical development may also be present in individuals with autism. In this study, we developed an eye-tracking paradigm featuring videos of boys and girls playing with toys that varied in their gender associations. Attention to faces differed between autistic and non-autistic children but was also influenced by the sex of the actor and gender-association of toys. Autistic females demonstrated subtle attention differences that distinguished them from autistic males and may influence referral, diagnosis, and intervention.

The Social Responsiveness Scale (SRS) has been validated in high-income countries but not yet in low- and middle-income countries. We aimed to assess the reliability of the SRS in a community sample and its validity to discriminate between children with and without autism spectrum disorder (ASD) in Vietnam. We used a three-phase study: piloting the translated SRS, reliability testing, and validation of the SRS in 158 Vietnamese caretakers and their children (ages 4-9 years). We examined reliability, validity and sensitivity, and specificity to ASD diagnosis. We applied receiver operator characteristic (ROC) analysis to determine optimal cutoff scores discriminating the children with ASD from those without ASD. We also assessed the performance of the SRS short form. We found that reliability was good with high internal consistency (0.88-0.89), test-retest reliability (0.82-0.83), sensitivity (93%), and specificity (98%) for identification of children with ASD. The ROC curves were similar for total raw score and total T-score, with the area under the curve (AUC) values reaching 0.98 and the optimal cutoff of 62 for raw scores and 60 for T-scores. The SRS short form also performed well in distinguishing children with ASD from children without ASD, with high AUC (0.98), sensitivity (90%), and specificity (98%) when using a raw score of 15 as a cutoff. In conclusion, the translated and culturally adapted SRS shows good reliability, validity, and sensitivity for identification of children with ASD in Vietnam. Both SRS long and short forms performed adequately to discriminate between children with and without ASD. Autism Res 2019, 00: 1-13. © 2019 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: Middle-income countries often lack validated tools to evaluate autism symptoms. The Social Responsiveness Scale (SRS) translated to Vietnamese was reliable and performed well to distinguish between children with and without autism spectrum disorder in Vietnam. The Vietnamese SRS, and translations of the tool to other languages with this methodology, may be useful in pediatric practice, potentially allowing providers to make more appropriate referrals for diagnostic evaluations and identify children for intervention to help them fulfill their developmental potential.

Maternal infection and fever during pregnancy have been implicated in the etiology of autism spectrum disorder (ASD); however, studies have not been able to separate the effects of fever itself from the impact of a specific infectious organism on the developing brain. We utilized data from the Study to Explore Early Development (SEED), a case-control study among 2- to 5-year-old children born between 2003 and 2006 in the United States, to explore a possible association between maternal infection and fever during pregnancy and risk of ASD and other developmental disorders (DDs). Three groups of children were included: children with ASD (N = 606) and children with DDs (N = 856), ascertained from clinical and educational sources, and children from the general population (N = 796), randomly sampled from state birth records. Information about infection and fever during pregnancy was obtained from a telephone interview with the mother shortly after study enrollment and maternal prenatal and labor/delivery medical records. ASD and DD status was determined by an in-person standardized developmental assessment of the child at 3-5 years of age. After adjustment for covariates, maternal infection anytime during pregnancy was not associated with ASD or DDs. However, second trimester infection accompanied by fever elevated risk for ASD approximately twofold (aOR = 2.19, 95% confidence interval 1.14-4.23). These findings of an association between maternal infection with fever in the second trimester and increased risk of ASD in the offspring suggest that the inflammatory response to the infectious agent may be etiologically relevant. Autism Res 2019, 12: 1551-1561. © 2019 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: Using data from a large multisite study in the United States-the Study to Explore Early Development-we found that women who had an infection during the second trimester of pregnancy accompanied by a fever are more likely to have children with ASD. These findings suggest the possibility that only more severe infections accompanied by a robust inflammatory response increase the risk of ASD.

Efforts to decrease disparity in diagnosis and treatment for under-resourced children with developmental delays, such as autism spectrum disorder, have led to increased interest in developing programs in community settings. One potential setting that has already demonstrated feasibility in conducting universal screening is the childcare setting. The current study conducted developmental screening in a total of 116 children ages 16-80 months of age in an urban low-income community childcare center. Parents of 20 children who screened positive were enrolled in the intervention phase of the study, where children received a staff-delivered targeted early intervention or a waitlist control condition. Given the small and imbalanced sample sizes, confidence intervals from mixed effect models were used to measure changes across time for each group. Of the children who received treatment, there was an average increase in child initiated joint engagement, symbolic play, and language use. This study provides initial feasibility data for the implementation of a screening and early intervention program to service a predominantly low-resource and ethnically diverse population within the childcare system in a large metropolitan city. Autism Res 2019, 12: 1423-1433. © 2019 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: Identifying and delivering treatment services for young children with developmental delays, such as autism spectrum disorder, may be most successful in community settings, especially for those children from under-resourced areas. This study found preliminary evidence that the childcare setting is a good place to conduct screening and deliver early interventions for children at risk for autism and other developmental delays.

Autism spectrum disorder (ASD), characterized by impairments in social communication and repetitive behaviors, often includes altered responses to sensory inputs as part of its phenotype. The neurobiological basis for altered sensory processing is not well understood. The UC Davis Medical Investigation of Neurodevelopmental Disorders Institute Autism Phenome Project is a longitudinal, multidisciplinary study of young children with ASD and age-matched typically developing (TD) controls. Previous analyses of the magnetic resonance imaging data from this cohort have shown that ∼15% of boys with ASD have disproportionate megalencephaly (DM) or brain size to height ratio, that is 1.5 standard deviations above the TD mean. Here, we investigated electrophysiological responses to auditory stimuli of increasing intensity (50-80 dB) in young toddlers (27-48 months old). Analyses included data from 36 age-matched boys, of which 24 were diagnosed with ASD (12 with and 12 without DM; ASD-DM and ASD-N) and 12 TD controls. We found that the two ASD subgroups differed in their electrophysiological response patterns to sounds of increasing intensity. At early latencies (55-115 ms), ASD-N does not show a loudness-dependent response like TD and ASD-DM, but tends to group intensities by soft vs. loud sounds, suggesting differences in sensory sensitivity in this group. At later latencies (145-195 ms), only the ASD-DM group shows significantly higher amplitudes for loud sounds. Because no similar effects were found in ASD-N and TD groups, this may be related to their altered neuroanatomy. These results contribute to the effort to delineate ASD subgroups and further characterize physiological responses associated with observable phenotypes. Autism Res 2019, 12: 1236-1250. © 2019 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: Approximately 15% of boys with ASD have much bigger brains when compared to individuals with typical development. By recording brain waves (electroencephalography) we compared how autistic children, with or without big brains, react to sounds compared to typically developing controls. We found that brain responses in the big-brained group are different from the two other groups, suggesting that they represent a specific autism subgroup.

Vitamin D appears essential for normal neurodevelopment and cognitive and behavioral function. We examined neonatal vitamin D in relation to the child's later diagnosis of autism spectrum disorder (ASD) or developmental delay (DD). Children aged 24-60 months enrolled in the population-based CHARGE case-control study were evaluated clinically for ASD (n = 357), DD (n = 134), or typical development (TD, n = 234) at the MIND Institute (Sacramento, CA) using standardized assessments. Total 25-hydroxyvitamin D (25[OH]D) was measured using sensitive isotope dilution liquid chromatography-tandem mass spectrometry in archived dried blood spots collected for the California Department of Public Health's Newborn Screening Program. Multinomial logistic regression was used to calculate ORs as measures of the associations between 25 nmol/L change in 25(OH)D and ASD and DD. Associations between 25(OH)D and scores on Mullen Scales of Early Learning and Vineland Adaptive Behavior Scales were assessed using robust linear regression. Effect modification was examined using stratified models and interaction product terms. Unadjusted mean (SD) 25(OH)D was lower for DD (73.2 [37.6]) than for TD (82.7 [39.3]) and ASD (80.1 [37.4]). After adjustment for maternal prepregnancy body mass index and education, a 25 nmol/L increase in total 25(OH)D was not associated with ASD (OR = 0.97; CI: 0.87-1.08) or DD (OR = 0.91; 95% CI: 0.78-1.06). Neonatal 25(OH)D was associated with significantly reduced ASD only in females (adjusted OR = 0.74; 95% CI: 0.55-0.99, Pinteraction  = 0.03), and significantly reduced DD only in non-Hispanic white children (adjusted OR = 0.79; 95% CI: 0.63-0.98, Pinteraction  = 0.11 for Hispanic, Pinteraction  = 0.31 for other), driven by DD children with trisomy 21. This study provides evidence that neonatal vitamin D could be associated with ASD in females and with DD in non-Hispanic white children. Autism Res 2019, 12: 976-988. © 2019 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: Vitamin D appears essential for brain development and function. We examined neonatal total 25-hydroxyvitamin D (25[OH]D) measured in dried blood spots in relation to later diagnoses of autism spectrum disorder (ASD) or developmental delay (DD) and related assessment scores. Higher neonatal 25(OH)D was associated with a 26% reduction in the odds for ASD only in females. After taking into account factors that could contribute to vitamin D status, a significant association with 21% reduced odds for DD was found only in non-Hispanic white children. Though results were nonsignificant overall, certain subgroups might benefit from higher neonatal vitamin D.

There is a pressing need for objective, quantifiable outcome measures in intervention trials for children with autism spectrum disorder (ASD). The current study investigated the use of eye tracking as a biomarker of treatment response in the context of a pilot randomized clinical trial of treatment for young children with ASD. Participants included 28 children with ASD, aged 18-48 months, who were randomized to one of two conditions: Pivotal Response Intervention for Social Motivation (PRISM) or community treatment as usual (TAU). Eye-tracking and behavioral assessment of developmental functioning were administered at Time 1 (prior to randomization) and at Time 2 (after 6 months of intervention). Two well-established eye-tracking paradigms were used to measure social attention: social preference and face scanning. As a context for understanding relationships between social attention and developmental ability, we first examined how scanning patterns at Time 1 were associated with concurrent developmental functioning and compared to those of 23 age-matched typically developing (TD) children. Changes in scanning patterns from Time 1 to Time 2 were then compared between PRISM and TAU groups and associated with behavioral change over time. Results showed that the social preference paradigm differentiated children with ASD from TD children. In addition, attention during face scanning was associated with language and adaptive communication skills at Time 1 and change in language skills from Time 1 to Time 2. These findings highlight the importance of examining targeted biomarkers that measure unique aspects of child functioning and that are well-matched to proposed mechanisms of change. Autism Research 2019, 12: 779-793. © 2019 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: Biomarkers have the potential to provide important information about how and why early interventions effect positive change for young children with ASD. The current study suggests that eye-tracking measures of social attention can be used to track change in specific areas of development, such as language, and points to the need for targeted eye-tracking paradigms designed to measure specific behavioral changes. Such biomarkers could inform the development of optimal, individualized, and adaptive interventions for young children with ASD.

Autism spectrum disorder is a neurodevelopmental syndrome diagnosed primarily by persistent deficits in social interactions and communication, unusual sensory reactivity, motor stereotypies, repetitive behaviors, and restricted interests. No FDA-approved medical treatments exist for the diagnostic symptoms of autism. Here we interrogate multiple pharmacological targets in two distinct mouse models that incorporate well-replicated autism-relevant behavioral phenotypes. Compounds that modify inhibitory or excitatory neurotransmission were selected to address hypotheses based on previously published biological abnormalities in each model. Shank3B is a genetic model of a mutation found in autism and Phelan-McDermid syndrome, in which deficits in excitatory neurotransmission and synaptic plasticity have been reported. BTBR is an inbred strain model of forms of idiopathic autism in which reduced inhibitory neurotransmission and excessive mTOR signaling have been reported. The GABA-A receptor agonist gaboxadol significantly reduced repetitive self-grooming in three independent cohorts of BTBR. The TrkB receptor agonist 7,8-DHF improved spatial learning in Shank3B mice, and reversed aspects of social deficits in BTBR. CX546, a positive allosteric modulator of the glutamatergic AMPA receptor, and d-cycloserine, a partial agonist of the glycine site on the glutamatergic NMDA receptor, did not rescue aberrant behaviors in Shank3B mice. The mTOR inhibitor rapamycin did not ameliorate social deficits or repetitive behavior in BTBR mice. Comparison of positive and negative pharmacological outcomes, on multiple phenotypes, evaluated for replicability across independent cohorts, enhances the translational value of mouse models of autism for therapeutic discovery. GABA agonists present opportunities for personalized interventions to treat components of autism spectrum disorder. Autism Res 2019, 12: 401-421 © 2019 The Authors. Autism Research published by International Society for Autism Research published by Wiley Periodicals, Inc. LAY SUMMARY: Many of the risk genes for autism impair synapses, the connections between nerve cells in the brain. A drug that reverses the synaptic effects of a mutation could offer a precision therapy. Combining pharmacological and behavioral therapies could reduce symptoms and improve the quality of life for people with autism. Here we report reductions in repetitive behavior by a GABA-A receptor agonist, gaboxadol, and improvements in social and cognitive behaviors by a TrkB receptor agonist, in mouse models of autism.

Diminished attention to socially relevant information appears to be an early emerging risk factor associated with autism spectrum disorders (ASD). However, inconsistencies across studies suggest that atypicalities in visual social attention in infants at high-risk for ASD during the first postnatal year may be subtle and more apparent under certain contexts. Here we explore factors that may moderate developmental trajectories in attention to faces, including the social complexity of the dynamic visual stimuli used to measure visual social attention and the early social environment of the infant as indexed by parental affectedness of ASD-related traits. Across infants at both high (HR) and low risk for ASD, attention to faces increased during the first postnatal year, with overall greater attention being allocated to schematic faces in the simpler video stimulus. Moreover, greater parental affectedness of ASD-related traits was associated with reduced developmental gains in attention to faces. For HR infants, greater attention to faces was positively associated with social communicative competence, including better joint attention skills and lower social impairments. Altogether, our findings highlight the importance of considering developmental level when selecting stimuli to longitudinally examine visual social attention, and the clinical relevance of including measures of infant's social environment in understanding early markers of ASD risk. Autism Res 2019, 12: 445-457 © 2019 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: Attention to faces is an important means for infants to learn about the social world. The complexity of the social scene and an infant's early social environment both affect the amount of time infants at high- and low-risk for ASD look at faces during the first postnatal year. For infants at high-risk for ASD, greater attention to faces was associated with better social skills. Understanding an infant's social environment may have a positive impact on social communicative development.

Interest in autonomic arousal in autism spectrum disorder (ASD) is increasing; however, reliability of these measures in ASD is unknown, and previously reported associations with social and cognitive abilities are inconsistent. This study assesses heart rate (HR) and HR variability (HRV) in preschoolers with ASD or typical development (TD) while they passively watched naturalistic videos. Measurement reliability, group differences, and the relationship with social and cognitive abilities were evaluated. Seventy one ASD and 66 TD children (2-4 years) provided cardiac data from two sessions. Test-retest intraclass correlations of HR and HRV over a 3-week period were moderate to good in both groups. Groups did not differ in mean level of HR or HRV. Intra-individual variability of HR between video segments within a session was higher in the ASD group, but intraclass correlations of this metric were low. Higher HR related to better language skills in TD children, but not after accounting for age and nonverbal ability. Higher HRV related to better expressive and receptive language in ASD children after controlling for age and nonverbal ability. HR/HRV were not related to social or executive functioning skills and did not explain any additional variance in abilities at a 12-month follow-up visit. In summary, variation in language abilities is associated with HR in the TD group and HRV in the ASD group. While preliminary, these results are promising for consideration of autonomic control as a biomarker for individual differences in ASD and may help us understand the mechanisms that contribute to communication skills. Autism Research 2019, 12: 39-52. © 2018 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: Cardiac activity, such as heart rate and heart rate variability, is linked to a wide range of psychological functions. This study shows that there is an association between heart rate and heart rate variability and language skills in young children with autism spectrum disorder (ASD). These results may help us understand what underlies individual differences in developmental abilities in young children with ASD.

Numerous studies have reported immune system disturbances in individuals with autism and their family members; however, there is considerable variability in findings with respect to the specific immune conditions involved, their timing, and the family members affected and little understanding of variation by autism subphenotype. Using data from the Study to Explore Early Development (SEED), a multi-site case-control study of children born 2003-2006 in the United States, we examined the role of family history of autoimmune diseases, asthma, and allergies in autism spectrum disorder (ASD) as well as other developmental disorders (DD). We investigated maternal immune conditions during the pregnancy period, as well as lifetime history of these conditions in several family members (mother, father, siblings, and study child). Logistic regression analyses included 663 children with ASD, 984 children with DD, and 915 controls ascertained from the general population (POP). Maternal history of eczema/psoriasis and asthma was associated with a 20%-40% increased odds of both ASD and DD. Risk estimates varied by specific ASD subphenotypes in association with these exposures. In addition, children with ASD were more likely to have a history of psoriasis/eczema or allergies than POP controls. No association was observed for paternal history or family history of these immune conditions for either ASD or DD. These data support a link between maternal and child immune conditions and adverse neurodevelopmental outcomes, and further suggest that associations may differ by ASD phenotype of the child. Autism Research 2019, 12: 123-135. © 2018 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: Using data from a large multi-site study in the US-the Study to Explore Early Development-we found that women with a history of eczema/psoriasis and asthma are more likely to have children with ASD or DD. In addition, children with ASD are more likely to have a history of psoriasis/eczema or allergies than typically developing children. These data support a link between maternal and child immune conditions and adverse neurodevelopmental outcomes.

While previous studies suggested that regressive forms of onset were not common in autism spectrum disorder (ASD), more recent investigations suggest that the rates are quite high and may be under-reported using certain methods. The current study undertook a systematic investigation of how rates of regression differed by measurement method. Infants with (n = 147) and without a family history of ASD (n = 83) were seen prospectively for up to 7 visits in the first three years of life. Reports of symptom onset were collected using four measures that systematically varied the informant (examiner vs. parent), the decision type (categorical [regression absent or present] vs. dimensional [frequency of social behaviors]), and the timing of the assessment (retrospective vs. prospective). Latent class growth models were used to classify individual trajectories to see whether regressive onset patterns were infrequent or widespread within the ASD group. A majority of the sample was classified as having a regressive onset using either examiner (88%) or parent (69%) prospective dimensional ratings. Rates of regression were much lower using retrospective or categorical measures (from 29 to 47%). Agreement among different measurement methods was low. Declining trajectories of development, consistent with a regressive onset pattern, are common in children with ASD and may be more the rule than the exception. The accuracy of widely used methods of measuring onset is questionable and the present findings argue against their widespread use. Autism Res 2018, 11: 788-797. © 2018 International Society for Autism Research, Wiley Periodicals, Inc.Lay summaryThis study examines different ways of measuring the onset of symptoms in autism spectrum disorder (ASD). The present findings suggest that declining developmental skills, consistent with a regressive onset pattern, are common in children with ASD and may be more the rule than the exception. The results question the accuracy of widely used methods of measuring symptom onset and argue against their widespread use.

To evaluate the effects of a 26-week, high-intensity, parent-implemented Early Start Denver Model (P-ESDM) intervention on developmental outcomes, severity of autism spectrum disorder (ASD), and parental stress of ASD toddlers in China. Subjects in P-ESDM group (n = 23) were recruited from 1.5- to 2.5-year-old toddlers who were screened positive in Xuhui and Minhang Districts and were diagnosed with ASD. A community (comparison) group of age-matched toddlers with ASD (n = 20) was recruited from other areas. Subjects of the P-ESDM group attended 1.5-hr parent coaching per week for 26 weeks, and those in the community group received interventions available from communities. Assessments were conducted at baseline (T1) and 26 weeks later (T2). After adjusting for baseline differences between the two groups, P-ESDM group demonstrated greater improvement than the community group in general development, especially in Language domain. Neither group demonstrated significant change in ASD severity, but the P-ESDM group showed greater improvement in social affect, parent-reported social communication and symbolic play than community group did. Finally, parents in P-ESDM group experienced decreased parenting stress while those in community group showed an opposite trend, though the differences did not reach significant association with the P-ESDM intervention. Chinese toddlers with ASD receiving 26 weeks of P-ESDM via regular coaching sessions showed significant greater improvement than those receiving community interventions in multiple aspects of development including social communications. These findings add support to the importance of providing early screening, diagnosis, and immediate referral for evidence-based interventions to improve outcome of young children with ASD. Autism Res 2018, 11: 654-666. © 2017 International Society for Autism Research, Wiley Periodicals, Inc.Lay summaryThe development of early screening and diagnosis of autism spectrum disorder (ASD) in China has highlighted the importance of early intervention for young children with ASD. Our current study demonstrated that parent-implemented Early Start Denver Model (P-ESDM) via coaching from professionals improved developmental outcomes, especially in the language domain, and social communicational behaviors of Chinese toddlers with ASD. P-ESDM may help parents in China provide effective early intervention to their children with ASD via improving their skills when they are still at a waiting list for services or lack access to intervention, and has the potential to alleviate their parenting stress.