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Background: Reduced social attention-looking at faces-is one of the most common manifestations of social difficulty in autism that is central to social development. Although reduced social attention is well characterized in autism, qualitative differences in how social attention unfolds across time remains unknown., Methods: We used a computational modeling (i.e., hidden Markov modeling) approach to assess and compare the spatiotemporal dynamics of social attention in a large, well-characterized sample of children with autism (n = 280) and neurotypical children (n = 119) (ages 6-11) who completed 3 social eye-tracking assays at 3 longitudinal time points (baseline, 6 weeks, 24 weeks)., Results: Our analysis supported the existence of 2 common eye movement patterns that emerged across 3 eye-tracking assays. A focused pattern was characterized by small face regions of interest, which had high a probability of capturing fixations early in visual processing. In contrast, an exploratory pattern was characterized by larger face regions of interest, with a lower initial probability of fixation and more nonsocial regions of interest. In the context of social perception, children with autism showed significantly more exploratory eye movement patterns than neurotypical children across all social perception assays and all 3 longitudinal time points. Eye movement patterns were associated with clinical features of autism, including adaptive function, face recognition, and autism symptom severity., Conclusions: Decreased likelihood of precisely looking at faces early in social visual processing may be an important feature of autism that is associated with autism-related symptomology and may reflect less visual sensitivity to face information., (Copyright © 2024 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Objective: Electroencephalography (EEG) measures of visual evoked potentials (VEPs) provide a targeted approach for investigating neural circuit dynamics. This study separately analyses phase-locked (evoked) and non-phase-locked (induced) gamma responses within the VEP to comprehensively investigate circuit differences in autism., Methods: We analyzed VEP data from 237 autistic and 114 typically developing (TD) children aged 6-11, collected through the Autism Biomarkers Consortium for Clinical Trials (ABC-CT). Evoked and induced gamma (30-90 Hz) responses were separately quantified using a wavelet-based time-frequency analysis, and group differences were evaluated using a permutation-based clustering procedure., Results: Autistic children exhibited reduced evoked gamma power but increased induced gamma power compared to TD peers. Group differences in induced responses showed the most prominent effect size and remained statistically significant after excluding outliers., Conclusions: Our study corroborates recent research indicating diminished evoked gamma responses in children with autism. Additionally, we observed a pronounced increase in induced power. Building upon existing ABC-CT findings, these results highlight the potential to detect variations in gamma-related neural activity, despite the absence of significant group differences in time-domain VEP components., Significance: The contrasting patterns of decreased evoked and increased induced gamma activity in autistic children suggest that a combination of different EEG metrics may provide a clearer characterization of autism-related circuitry than individual markers alone., (Copyright © 2024. Published by Elsevier B.V.)

Younger siblings (SIBS) of children with autism exhibit a wide range of clinical and subclinical symptoms including social, cognitive, language, and adaptive functioning delays. Identifying factors linked with this phenotypic heterogeneity is essential for improving understanding of the underlying biology of the heterogenous outcomes and for early identification of the most vulnerable SIBS. Prevalence of neurodevelopmental (NDD) and neuropsychiatric disorders (NPD) is significantly elevated in families of children with autism. It remains unknown, however, if the family history associates with the developmental outcomes among the SIBS. We quantified history of the NDDs and NPDs commonly reported in families of children with autism using a parent interview and assessed autism symptoms, verbal, nonverbal, and adaptive skills in a sample of 229 SIBS. Multiple regression analyses were used to examine links between family history and phenotypic outcomes, whereas controlling for birth year, age, sex, demographics, and parental education. Results suggest that family history of schizophrenia, depression, anxiety, bipolar disorder, and intellectual disability associate robustly with dimensional measures of social affect, verbal and nonverbal IQ, and adaptive functioning in the SIBS. Considering family history of these disorders may improve efforts to predict long-term outcomes in younger siblings of children with autism and inform about familial factors contributing to high phenotypic heterogenetity in this cohort., (© 2024 The Author(s). Autism Research published by International Society for Autism Research and Wiley Periodicals LLC.)

The Selective Social Attention (SSA) task is a brief eye-tracking task involving experimental conditions varying along socio-communicative axes. Traditionally the SSA has been used to probe socially-specific attentional patterns in infants and toddlers who develop autism spectrum disorder (ASD). This current work extends these findings to preschool and school-age children. Children 4- to 12-years-old with ASD (N = 23) and a typically-developing comparison group (TD; N = 25) completed the SSA task as well as standardized clinical assessments. Linear mixed models examined group and condition effects on two outcome variables: percent of time spent looking at the scene relative to scene presentation time (%Valid), and percent of time looking at the face relative to time spent looking at the scene (%Face). Age and IQ were included as covariates. Outcome variables' relationships to clinical data were assessed via correlation analysis. The ASD group, compared to the TD group, looked less at the scene and focused less on the actress' face during the most socially-engaging experimental conditions. Additionally, within the ASD group, %Face negatively correlated with SRS total T-scores with a particularly strong negative correlation with the Autistic Mannerism subscale T-score. These results highlight the extensibility of the SSA to older children with ASD, including replication of between-group differences previously seen in infants and toddlers, as well as its ability to capture meaningful clinical variation within the autism spectrum across a wide developmental span inclusive of preschool and school-aged children. The properties suggest that the SSA may have broad potential as a biomarker for ASD., (© 2023 International Society for Autism Research and Wiley Periodicals LLC.)

Idiopathic autism spectrum disorder (ASD) is highly heterogeneous, and it remains unclear how convergent biological processes in affected individuals may give rise to symptoms. Here, using cortical organoids and single-cell transcriptomics, we modeled alterations in the forebrain development between boys with idiopathic ASD and their unaffected fathers in 13 families. Transcriptomic changes suggest that ASD pathogenesis in macrocephalic and normocephalic probands involves an opposite disruption of the balance between excitatory neurons of the dorsal cortical plate and other lineages such as early-generated neurons from the putative preplate. The imbalance stemmed from divergent expression of transcription factors driving cell fate during early cortical development. While we did not find genomic variants in probands that explained the observed transcriptomic alterations, a significant overlap between altered transcripts and reported ASD risk genes affected by rare variants suggests a degree of gene convergence between rare forms of ASD and the developmental transcriptome in idiopathic ASD., (© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Lay Abstract: Children with autism spectrum disorder are prescribed a variety of medications that affect the central nervous system (psychotropic medications) to address behavior and mood. In clinical trials, individuals taking concomitant psychotropic medications often are excluded to maintain homogeneity of the sample and prevent contamination of biomarkers or clinical endpoints. However, this choice may significantly diminish the clinical representativeness of the sample. In a recent multisite study designed to identify biomarkers and behavioral endpoints for clinical trials (the Autism Biomarkers Consortium for Clinical Trials), school-age children with autism spectrum disorder were enrolled without excluding for medications, thus providing a unique opportunity to examine characteristics of psychotropic medication use in a research cohort and to guide future decisions on medication-related inclusion criteria. The aims of the current analysis were (1) to quantify the frequency and type of psychotropic medications reported in school-age children enrolled in the ABC-CT and (2) to examine behavioral features of children with autism spectrum disorder based on medication classes. Of the 280 children with autism spectrum disorder in the cohort, 42.5% were taking psychotropic medications, with polypharmacy in half of these children. The most commonly reported psychotropic medications included melatonin, stimulants, selective serotonin reuptake inhibitors, alpha agonists, and antipsychotics. Descriptive analysis showed that children taking antipsychotics displayed a trend toward greater overall impairment. Our findings suggest that exclusion of children taking concomitant psychotropic medications in trials could limit the clinical representativeness of the study population, perhaps even excluding children who may most benefit from new treatment options.

Clinical trials in autism spectrum disorder (ASD) often rely on clinician rating scales and parent surveys to measure autism-related features and social behaviors. To aid in the selection of these assessments for future clinical trials, the Autism Biomarkers Consortium for Clinical Trials (ABC-CT) directly compared eight common instruments with respect to acquisition rates, sensitivity to group differences, equivalence across demographic sub-groups, convergent validity, and stability over a 6-week period. The sample included 280 children diagnosed with ASD (65 girls) and 119 neurotypical children (36 girls) aged from 6 to 11 years. Full scale IQ for ASD ranged from 60 to 150 and for neurotypical ranged from 86 to 150. Instruments measured clinician global assessment and autism-related behaviors, social communication abilities, adaptive function, and social withdrawal behavior. For each instrument, we examined only the scales that measured social or communication functioning. Data acquisition rates were at least 97.5% at T1 and 95.7% at T2. All scales distinguished diagnostic groups. Some scales significantly differed by participant and/or family demographic characteristics. Within the ASD group, most clinical instruments exhibited weak (≥ |0.1|) to moderate (≥ |0.4|) intercorrelations. Short-term stability was moderate (ICC: 0.5-0.75) to excellent (ICC: >0.9) within the ASD group. Variations in the degree of stability may inform viability for different contexts of use, such as identifying clinical subgroups for trials versus serving as a modifiable clinical outcome. All instruments were evaluated in terms of their advantages and potential concerns for use in clinical trials., (© 2023 International Society for Autism Research and Wiley Periodicals LLC.)

Objective: Numerous candidate EEG biomarkers have been put forward for use in clinical research on autism spectrum disorder (ASD), but biomarker development has been hindered by limited attention to the psychometric properties of derived variables, inconsistent results across small studies, and variable methodology. The authors evaluated the basic psychometric properties of a battery of EEG assays for their potential suitability as biomarkers in clinical trials., Methods: This was a large, multisite, naturalistic study in 6- to 11-year-old children who either had an ASD diagnosis (N=280) or were typically developing (N=119). The authors evaluated an EEG battery composed of well-studied assays of resting-state activity, face perception (faces task), biological motion perception, and visual evoked potentials (VEPs). Biomarker psychometrics were evaluated in terms of acquisition rates, construct performance, and 6-week stability. Preliminary evaluation of use was explored through group discrimination and phenotypic correlations., Results: Three assays (resting state, faces task, and VEP) show promise in terms of acquisition rates and construct performance. Six-week stability values in the ASD group were moderate (intraclass correlations ≥0.66) for the faces task latency of the P1 and N170, the VEP amplitude of N1 and P1, and resting alpha power. Group discrimination and phenotype correlations were primarily observed for the faces task P1 and N170., Conclusions: In the context of a large-scale, rigorous evaluation of candidate EEG biomarkers for use in ASD clinical trials, neural response to faces emerged as a promising biomarker for continued evaluation. Resting-state activity and VEP yielded mixed results. The study's biological motion perception assay failed to display construct performance. The results provide information about EEG biomarker performance that is relevant for the next stage of biomarker development efforts focused on context of use.

Background: Due to familial liability, siblings of children with ASD exhibit elevated risk for language delays. The processes contributing to language delays in this population remain unclear., Methods: Considering well-established links between attention to dynamic audiovisual cues inherent in a speaker's face and speech processing, we investigated if attention to a speaker's face and mouth differs in 12-month-old infants at high familial risk for ASD but without ASD diagnosis (hr-sib; n = 91) and in infants at low familial risk (lr-sib; n = 62) for ASD and whether attention at 12 months predicts language outcomes at 18 months., Results: At 12 months, hr-sib and lr-sib infants did not differ in attention to face (p = .14), mouth preference (p = .30), or in receptive and expressive language scores (p = .36, p = .33). At 18 months, the hr-sib infants had lower receptive (p = .01) but not expressive (p = .84) language scores than the lr-sib infants. In the lr-sib infants, greater attention to the face (p = .022) and a mouth preference (p = .025) contributed to better language outcomes at 18 months. In the hr-sib infants, neither attention to the face nor a mouth preference was associated with language outcomes at 18 months., Conclusions: Unlike low-risk infants, high-risk infants do not appear to benefit from audiovisual prosodic and speech cues in the service of language acquisition despite intact attention to these cues. We propose that impaired processing of audiovisual cues may constitute the link between genetic risk factors and poor language outcomes observed across the autism risk spectrum and may represent a promising endophenotype in autism., (© 2022 Association for Child and Adolescent Mental Health.)

Autism is a heterogeneous neurodevelopmental condition, and functional magnetic resonance imaging-based studies have helped advance our understanding of its effects on brain network activity. We review how predictive modeling, using measures of functional connectivity and symptoms, has helped reveal key insights into this condition. We discuss how different prediction frameworks can further our understanding of the brain-based features that underlie complex autism symptomatology and consider how predictive models may be used in clinical settings. Throughout, we highlight aspects of study interpretation, such as data decay and sampling biases, that require consideration within the context of this condition. We close by suggesting exciting future directions for predictive modeling in autism., (Copyright © 2022. Published by Elsevier Inc.)

The present study objectives were to examine the performance of the new M-CHAT-R algorithm to the original M-CHAT algorithm. The main purpose was to examine if the algorithmic changes increase identification of children later diagnosed with ASD, and to examine if there is a trade-off when changing algorithms. We included 54,463 screened cases from the Norwegian Mother and Child Cohort Study. Children were screened using the 23 items of the M-CHAT at 18 months. Further, the performance of the M-CHAT-R algorithm was compared to the M-CHAT algorithm on the 23-items. In total, 337 individuals were later diagnosed with ASD. Using M-CHAT-R algorithm decreased the number of correctly identified ASD children by 12 compared to M-CHAT, with no children with ASD screening negative on the M-CHAT criteria subsequently screening positive utilizing the M-CHAT-R algorithm. A nonparametric McNemar's test determined a statistically significant difference in identifying ASD utilizing the M-CHAT-R algorithm. The present study examined the application of 20-item MCHAT-R scoring criterion to the 23-item MCHAT. We found that this resulted in decreased sensitivity and increased specificity for identifying children with ASD, which is a trade-off that needs further investigation in terms of cost-effectiveness. However, further research is needed to optimize screening for ASD in the early developmental period to increase identification of false negatives., (© 2021 The Authors. Autism Research published by International Society for Autism Research and Wiley Periodicals LLC.)

Diminished visual attention to faces of social partners represents one of the early characteristics of autism spectrum disorder (ASD). Here we examine if the introduction of puppets as social partners alters attention to speakers' faces in young children with ASD and typically developing (TD) controls. Children with ASD (N = 37; M age  = 49.44 months) and TD (N = 27; M age  = 40.66 months) viewed a video depicting a puppet and a human engaged in a conversation. Dwell time on these faces was analyzed as a function of group and speaker's identity. Unlike TD controls, the ASD group exhibited limited visual attention to and chance-level visual preference for the human speaker. However, attention to and preference for the puppet speaker's face was greater than chance and comparable across the two groups. While there was a strong association between low human speaker preference and high autism severity, no association with autism severity was found for puppet speaker preference. Unlike humans, expressive and verbal puppets attracted the attention of children with ASD at levels comparable to that of TD controls. Considering that puppets can engage in reciprocal interactions and deliver simplified, salient social-communicative cues, they may facilitate therapeutic efforts in children with ASD. LAY SUMMARY: While studies have shown support for therapeutic uses of robots with children with autism, other similar agents such as puppets remain to be explored. When shown a video of a conversation between a puppet and a person, young children with ASD paid as much attention to the puppet's face as typically-developing (TD) children. Since puppets can engage in back-and-forth interactions and model social interactions and communication, they may play a promising role in therapeutic efforts for young children with ASD., (© 2021 International Society for Autism Research and Wiley Periodicals LLC.)

Differential emotional reactivity to social and nonsocial stimuli has been hypothesized but rarely examined empirically in ASD despite its potential importance for development of social motivation, cognition, and comorbid psychopathology. This study examined emotional reactivity, regulation, and attention to social and nonsocial threat in toddlers with ASD (n = 42, M age : 22 months) and typically developing (TD) toddlers (n = 22, M age : 23 months), and their mutual associations with autism symptom severity. Participants were exposed to social (stranger), nonsocial (mechanical objects), and ambiguous (masks) threats, and their intensity of distress (iDistress), attention to threat (Attention), and presence of emotion regulation (ER) strategies were measured. Autism symptom severity was quantified using the Autism Diagnostic Observation Schedule-2. In response to social threat, toddlers with ASD exhibited elevated iDistress (P < 0.038) but lower Attention (P < 0.002) and a wider variety of ER strategies (P < 0.040) compared to TD controls, though their ER strategies were less likely to be social. However, nonsocial and ambiguous threat elicited lower iDistress in ASD than in TD toddlers (P = 0.012 and P = 0.034, respectively), but comparable Attention and ER strategy use. Autism severity was not associated with iDistress. The study demonstrates elevated emotional salience but diminished attentional salience of social threat in ASD. A failure to attend adequately to social threats may restrict opportunities to appraise their threat value and engender often observed in ASD negative emotional responses to novel social situations. Early atypical emotional reactivity may independently contribute to the shaping of complex autism phenotypes and may be linked with later emerging affective and behavioral symptoms. LAY SUMMARY: Compared to typically developing toddlers, toddlers with ASD show diminished attention yet enhanced distress in response to social threat. Poor attention to potential social threat may limit opportunities to assess its threat value and thus contribute to often observed negative emotional responses to novel social situations. Identifying the precursors of atypical emotional reactivity in infancy and its links with later psychopathology will inform about novel treatment targets and mechanisms of change in the early stages of ASD. Autism Res 2021, 14: 1025-1036. © 2020 International Society for Autism Research, Wiley Periodicals, LLC., (© 2020 International Society for Autism Research, Wiley Periodicals, LLC.)

A growing body of evidence supports a potential link between autism spectrum disorder (ASD) and gender dysphoria, yet few studies have looked at sex differences in the co-occurrence of gender diversity and ASD. The aim of this study was to characterize sex differences in gender-diverse expressions and identities, as well as gender-related concerns, in youth with ASD. Parents of youth with ASD ages 6-21 (n = 163) completed an online questionnaire about their child's gender expression and identity. Sex-typed behaviors during childhood were measured using the Gender Identity Questionnaire (GIQ). Semi-partial Kendall correlations and chi-square tests were used to compare gender non-conformity, gender-diverse identities, and gender-related concerns between sexes. Sex-based differences in mean GIQ score and individual GIQ items were evaluated using a linear regression and semi-partial Kendall correlations, respectively. All regressions and correlations controlled for child age. Parents of girls were more likely to report child appearances and mannerisms that were less concordant with their child's birth sex. Based on parent-report, girls had lower mean GIQ scores, indicating greater cross-gendered/fewer same-gendered behaviors in childhood. Lastly, parents of girls with ASD were more likely to report that their daughters experienced anxiety due to gender-related concerns and discomfort during puberty than parents of boys. These findings suggest that girls with ASD seem more likely have gender-diverse preferences, mannerisms, and appearances that fall outside of traditional gender norms. Gender-related concerns appear to be a source of real distress in girls with ASD, highlighting the need for individualized support, especially during puberty. LAY SUMMARY: Despite evidence of a potential link between autism and gender diversity, few studies have explored differences in gender identity/expression between boys and girls with autism. Based on parent responses, we found that girls with autism are more likely than boys to have appearances and mannerisms, as well as behaviors during childhood, that fall outside of the traditional gender role. The unique profile of girls with autism and their elevated distress over gender-related concerns call for individualized support during adolescence., (© 2020 International Society for Autism Research, Wiley Periodicals, LLC.)

Background: In typical development, the unfolding of social and communicative skills hinges upon the ability to allocate and sustain attention toward people, a skill present moments after birth. Deficits in social attention have been well documented in autism, though the underlying mechanisms are poorly understood., Methods: In order to parse the factors that are responsible for limited social attention in toddlers with autism, we manipulated the context in which a person appeared in their visual field with regard to the presence of salient social (child-directed speech and eye contact) and nonsocial (distractor toys) cues for attention. Participants included 13- to 25-month-old toddlers with autism (autism; n = 54), developmental delay (DD; n = 22), and typical development (TD; n = 48). Their visual responses were recorded with an eye-tracker., Results: In conditions devoid of eye contact and speech, the distribution of attention between key features of the social scene in toddlers with autism was comparable to that in DD and TD controls. However, when explicit dyadic cues were introduced, toddlers with autism showed decreased attention to the entire scene and, when they looked at the scene, they spent less time looking at the speaker's face and monitoring her lip movements than the control groups. In toddlers with autism, decreased time spent exploring the entire scene was associated with increased symptom severity and lower nonverbal functioning; atypical language profiles were associated with decreased monitoring of the speaker's face and her mouth., Conclusions: While in certain contexts toddlers with autism attend to people and objects in a typical manner, they show decreased attentional response to dyadic cues for attention. Given that mechanisms supporting responsivity to dyadic cues are present shortly after birth and are highly consequential for development of social cognition and communication, these findings have important implications for the understanding of the underlying mechanisms of limited social monitoring and identifying pivotal targets for treatment., (© 2012 The Authors. Journal of Child Psychology and Psychiatry © 2012 Association for Child and Adolescent Mental Health.)

Context: Multiple studies have reported an overgrowth in head circumference (HC) in the first year of life in autism. However, it is unclear whether this phenomenon is independent of overall body growth and whether it is associated with specific social or cognitive features., Objectives: To examine the trajectory of early HC growth in autism compared with control groups; to assess whether HC growth in autism is independent of height and weight growth during infancy; and to examine HC growth from birth to 24 months in relationship to social, verbal, cognitive, and adaptive functioning levels., Design: Retrospective study., Setting: A specialized university-based clinic., Participants: Boys diagnosed as having autistic disorder (n = 64), pervasive developmental disorder-not otherwise specified (n = 34), global developmental delay (n = 13), and other developmental problems (n = 18) and typically developing boys (n = 55)., Main Outcome Measures: Age-related changes in HC, height, and weight between birth and age 24 months; measures of social, verbal, and cognitive functioning at age 2 years., Results: Compared with typically developing controls, boys with autism were significantly longer by age 4.8 months, had a larger HC by age 9.5 months, and weighed more by age 11.4 months (P = .05 for all). None of the other clinical groups showed a similar overgrowth pattern. Boys with autism who were in the top 10% of overall physical size in infancy exhibited greater severity of social deficits (P = .009) and lower adaptive functioning (P = .03)., Conclusions: Boys with autism experienced accelerated HC growth in the first year of life. However, this phenomenon reflected a generalized process affecting other morphologic features, including height and weight. The study highlights the importance of studying factors that influence not only neuronal development but also skeletal growth in autism.

Context: Toddlers with autism spectrum disorders (ASD) exhibit poor face recognition and atypical scanning patterns in response to faces. It is not clear if face-processing deficits are also expressed on an attentional level. Typical individuals require more effort to shift their attention from faces compared with other objects. This increased disengagement cost is thought to reflect deeper processing of these socially relevant stimuli., Objective: To examine if attention disengagement from faces is atypical in the early stages of ASD., Design: Attention disengagement was tested in a variation of the cued attention task in which participants were required to move their visual attention from face or nonface central fixation stimuli and make a reactive saccade to a peripheral target. The design involved diagnosis as a between-group factor and central fixation stimuli type as a within-group factor., Setting: Participants were taken from a cohort of patients at a university-based specialized clinic or from a pool of subjects participating in a prospective study of social cognition in ASD., Participants: Toddlers with ASD (mean age, 32 months [n = 42]) were compared with toddlers with nonautistic developmental delays (mean age, 29 months [n = 31]) and with typically developing toddlers (mean age, 29 months [n = 46])., Main Outcome Measure: Saccadic reaction time., Results: Developmentally delayed and typically developing toddlers had more difficulties disengaging visual attention from faces than toddlers with ASD. This effect was not present in response to nonfacial stimuli. These results suggest that toddlers with ASD are not captivated by faces to the same extent as toddlers without ASD and that this effect is not driven by a generalized impairment in disengagement of attention., Conclusion: The results suggest that face-processing difficulties in toddlers with ASD involve disruption of an attentional mechanism that typically supports deeper processing of these highly socially relevant stimuli.

With increased public awareness of the early signs and recent American Academy of Pediatrics recommendations that all 18- and 24-month-olds be screened for autism spectrum disorders, there is an increasing need for diagnostic assessment of very young children. However, unique challenges exist in applying current diagnostic guidelines for autism spectrum disorders to children under the age of 2 years. In this article, we address challenges related to early detection, diagnosis, and treatment of autism spectrum disorders in this age group. We provide a comprehensive review of findings from recent studies on the early development of children with autism spectrum disorders, summarizing current knowledge on early signs of autism spectrum disorders, the screening properties of early detection tools, and current best practice for diagnostic assessment of autism spectrum disorders before 2 years of age. We also outline principles of effective intervention for children under the age of 2 with suspected/confirmed autism spectrum disorders. It is hoped that ongoing studies will provide an even stronger foundation for evidence-based diagnostic and intervention approaches for this critically important age group.

The Modified Checklist for Autism in Toddlers (M-CHAT) was used to screen younger (16-23 months) versus older (24-30 months) high- and low-risk toddlers. Refusal rates for follow-up interview showed no group differences, but parents of younger/low-risk children were more likely to refuse evaluation than parents of high-risk children. PPP for an ASD diagnosis was: younger/high-risk 0.79, older/high-risk 0.74, younger/low-risk 0.28, and older/low-risk 0.61, with PPP differing by age within the low-risk group. Most of the children in all groups, however, were diagnosed with a developmental disorder. Symptom severity generally did not differ among groups. Cognitive and adaptive measures showed minimal group differences. Therefore, older and younger toddlers had similar symptomatology and developmental delays; PPP for ASD is better at 24 than 18 months for low-risk children; however, these children are still highly likely to show a developmental disorder. Clinical decision making should balance early identification against the lower specificity of M-CHAT screening for the younger/low-risk group.

Autism spectrum disorders (ASD) often go undetected in toddlers. The Modified Checklist for Autism in Toddlers (M-CHAT) was used to screen 3,793 children aged 16-30 months from low- and high-risk sources; screen positive cases were diagnostically evaluated. Rescreening was performed on 1,416 children aged 42-54 months. Time 1 Positive Predictive Value (PPV) was .36 for the initial screening and .74 for the screening plus follow-up telephone interview; values were similar for Time2 PPV. When separating referral sources, PPV was low for the low-risk sample but acceptable with the followup telephone interview. Children with ASD from the low-risk and high-risk samples were highly similar. Results indicate that the M-CHAT continues to be a promising instrument for the early detection of ASD.

Thirty-seven children 15-25 months of age received clinical diagnoses of autism spectrum disorder (ASD) and were re-evaluated two years later. All subjects were judged to have retained a diagnosis of ASD at the follow-up evaluation. Communication scores for the group as a whole during the first visit were significantly lower than nonverbal IQ. However, by the second visit, verbal and nonverbal scores were no longer significantly different. The group was divided into two subgroups, based on expressive language (EL) outcome at the second visit. The two groups were similar in the second year of life in terms of expressive communication skills and autistic symptoms, except for a trend toward more stereotypic and repetitive behavior in the worse outcome group. By the second visit, however, the groups differed significantly on all standard measures of expression and reception, as well as on autistic symptomotology and nonverbal IQ. When assessed during their second year, children who ended up in the better outcome group showed higher average nonverbal cognitive level, receptive language (RL) scores, number of sounds and words produced, use of symbolic play schemes, and response to joint attention bids. Regression analysis revealed that the variables for which significant differences between the two outcome groups in their second year of life were found provided significant prediction of EL outcome at age four. Stepwise regression identified RL and presence of stereotypic and repetitive at the first visit as significantly associated with EL outcome. Implications of these findings for early identification and intervention are discussed.

Autism spectrum disorders (ASD) are a group of related neurodevelopmental syndromes with complex genetic etiology. We identified a de novo chromosome 7q inversion disrupting Autism susceptibility candidate 2 (AUTS2) and Contactin Associated Protein-Like 2 (CNTNAP2) in a child with cognitive and social delay. We focused our initial analysis on CNTNAP2 based on our demonstration of disruption of Contactin 4 (CNTN4) in a patient with ASD; the recent finding of rare homozygous mutations in CNTNAP2 leading to intractable seizures and autism; and in situ and biochemical analyses reported herein that confirm expression in relevant brain regions and demonstrate the presence of CNTNAP2 in the synaptic plasma membrane fraction of rat forebrain lysates. We comprehensively resequenced CNTNAP2 in 635 patients and 942 controls. Among patients, we identified a total of 27 nonsynonymous changes; 13 were rare and unique to patients and 8 of these were predicted to be deleterious by bioinformatic approaches and/or altered residues conserved across all species. One variant at a highly conserved position, I869T, was inherited by four affected children in three unrelated families, but was not found in 4010 control chromosomes (p = 0.014). Overall, this resequencing data demonstrated a modest nonsignificant increase in the burden of rare variants in cases versus controls. Nonetheless, when viewed in light of two independent studies published in this issue of AJHG showing a relationship between ASD and common CNTNAP2 alleles, the cytogenetic and mutation screening data suggest that rare variants may also contribute to the pathophysiology of ASD, but place limits on the magnitude of this contribution.

Purpose: This study tests the hypothesis that toddlers with autism spectrum disorders (ASD) will show differences from contrast groups in preferences for attending to speech., Method: This study examined auditory preferences in toddlers with ASD and matched groups of (a) typical age-mates, (b) age-mates with nonautistic developmental disabilities, and (c) younger children matched for language age. The experimental procedure measured time spent oriented to auditory stimuli that were created to exemplify language patterns that had been studied in typically developing infants., Results: Findings suggest that toddlers with ASD show a reduced preference for child-directed speech, compared with typical age-mates, but few differences from children with nonautistic developmental disorders. Correlational analysis revealed that time spent listening to child-directed speech by children with ASD was related to their concurrent receptive language ability as well as to receptive language abilities 1 year later. This relationship did not hold for the other groups., Conclusion: The present study supports the hypothesis that children with ASD perform differently from typical peers in auditory preference paradigms and that performance in these tasks is related to concurrent and later language development.

This study compared behavioral presentation of toddlers with autistic spectrum disorders (ASD) and toddlers with global developmental delay (DD) or developmental language disorder (DLD) who display some characteristics of ASD using the diagnostic algorithm items from the Autism Diagnostic Observation Schedule, Generic (ADOS), the Childhood Autism Rating Scale (CARS), and Modified Checklist for Autism in Toddlers (M-CHAT). To date, 195 children have failed the M-CHAT and have been diagnosed with ASD, DD or DLD. Children with ASD had prominent and consistent impairments in socialization skills, especially joint attention skills and were more impaired in some aspects of communication, play, and sensory processing. Children with ASD and children with DD/DLD shared common features, but certain behavioral markers differentiated the two groups.

Face recognition impairments are well documented in older children with Autism Spectrum Disorders (ASD); however, the developmental course of the deficit is not clear. This study investigates the progressive specialization of face recognition skills in children with and without ASD. Experiment 1 examines human and monkey face recognition in 2-year-old children with ASD, matched for nonverbal mental age (NVMA) with developmentally delayed (DD) children, and typically developing children (TD), using the Visual Paired Comparison (VPC) paradigm. Results indicate that, consistent with the other-species effect, TD controls show enhanced recognition of human but not monkey faces; however, neither the ASD nor the DD group show evidence of face recognition regardless of the species. Experiment 2 examines the same question in a group of older 3- to 4-year-old developmentally disabled (ASD and DD) children as well as in typical controls. In this experiment, both human and monkey faces are recognized by all three groups. The results of Experiments 1 and 2 suggest that difficulties in face processing, as measured by the VPC paradigm, are common in toddlers with ASD as well as DD, but that these deficits tend to disappear by early preschool age. In addition, the experiments show that higher efficacy of incidental encoding and recognition of facial identity in a context of passive exposure is positively related to nonverbal cognitive skills and age, but not to overall social interaction skills or greater attention to faces exhibited in naturalistic contexts.

Background: Microscopic examination of placental tissue may provide a route to assessing risk and understanding underlying biology of autism., Methods: Occurrence of a distinctive microscopic placental morphological abnormality, the trophoblast inclusion, was assessed using archived placental tissue. The rate of occurrence of trophoblast inclusion-positive slides observed for 13 individuals with autism spectrum disorder (ASD) was compared to the rate in an anonymous consecutive birth cohort., Results: The occurrence of inclusion positive slides was significantly greater in the ASD group compared to the control group (6/27 slides, 22.2% vs. 12/154, 7.8%; Fisher Exact Test, two-tailed p = .033; relative risk 2.85). The proportion of positive cases was also greater in the ASD group (5/13 cases, 38.5% vs. 8/61, 13.1%; Fisher Exact, two-tailed p = .044; relative risk 2.93). Behavioral severity scores did not differ across groups of inclusion positive (N = 4) and negative (N = 8) ASD individuals., Conclusions: Although probably not functionally detrimental or causative, the greater occurrence of placental trophoblast inclusions observed in ASD individuals may reflect altered early developmental processes. Further research is required to replicate the basic finding, to understand the basis for the trophoblastic abnormality, and to determine the utility of the measure in early detection of ASD.

Objectives: Increasing numbers of young children referred for a differential diagnosis of autism spectrum disorders (ASD) necessitates better understanding of the early syndrome expression and the utility of the existing state-of-the art diagnostic methods in this population., Method: Out of 31 infants under the age of 2 years referred for a differential diagnosis, 19 were diagnosed with autism, and 9 with pervasive developmental disorder - not otherwise specified (PDD-NOS) when reassessed at 3 years. We examined 1) the symptoms of ASD in the second year and changes in the syndrome expression by the age of three; 2) relationship between expert-assigned clinical diagnosis and diagnostic classification based on Autism Diagnostic Observation Schedule-Generic (ADOS-G) and Autism Diagnostic Interview-Revised (ADI-R) in the second year; 3) the relationship between direct observation and parental report of ASD symptoms., Results: Symptoms of autism and PDD-NOS in the second year were pronounced and stability of the clinical diagnosis was high. The agreement between clinician-assigned autism but not PDD-NOS diagnosis and the ADOS-G was high. However, sensitivity of the ADI-R diagnostic classification of autism was poor. Comparison of concurrent parental report and direct observation revealed discrepancies in severity ratings of key dyadic social behaviors. Changes in communication reflected acquisition of language accompanied by the emergence of unusual language characteristics. Symptoms of social dysfunction were relatively stable over time, and so was the severity of stereotyped behaviors., Conclusions: The study provides support for stability of clinical diagnosis and syndrome expression in the second year and highlights advantages and limitations of the ADI-R and ADOS-G for diagnosing and documenting symptoms of ASD in infants.

Symptoms of Autism Spectrum Disorders (ASD) begin to manifest during the first 2 years; there is limited evidence regarding type and timing of symptom onset. We examined factors related to parental age of recognition (AOR) of early abnormalities and the association between AOR and diagnosis and levels of functioning at 2 and 4 years in 75 toddlers with ASD. Results suggest significant differences between autism and PDD-NOS in the AOR and type of first concerns. Early social and motor delays as well as maternal age was associated with AOR. Later AOR was associated with poorer social-communicative and nonverbal cognitive functioning at 2 and 4. The findings are discussed in a context of identifying distinct developmental trajectories within the autism spectrum.

Although initially described as an inborn disorder of affective contact, information on autism as it exists in infants has been limited. Delays in diagnosis, lack of information about the condition, and reliance on retrospective research strategies have been problematic. An awareness of the increased risk for siblings is now allowing the development of new, prospective approaches. Consistent with Kanner's original hypothesis, the available information strongly suggests a fundamental difficulty in the earliest social processes, which, in turn, impacts many other areas of development. New approaches to screening have lowered the age of initial diagnosis; this presents new challenges for early intervention. Directions for future research are highlighted.

Automatic attention cueing by perceived changes in gaze direction was studied in 2-year-old children with autism and typically developing (TD) controls using a visual attention cueing paradigm. In Experiments 1 and 2 the cue consisted of an eye movement (Eyes) and a nonbiological movement (SimEyes), respectively. The results suggest that visual attention in children with autism and their TD counterparts is cued by perceived eye movement. Thus, although in naturalistic situations toddlers with autism do not follow the gaze of others, they are sensitive to directional cues inherent in eye movement. Cue-specific differences in performance related to the level of engagement and cue-processing time may suggest reliance on different underlying strategies for gaze processing in autism.