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Background: Pregnancy measures of DNA methylation, an epigenetic mark, may be associated with autism spectrum disorder (ASD) development in children. Few ASD studies have considered prospective designs with DNA methylation measured in multiple tissues and tested overlap with ASD genetic risk loci. Objectives: To estimate associations between DNA methylation in maternal blood, cord blood, and placenta and later diagnosis of ASD, and to evaluate enrichment of ASD-associated DNA methylation for known ASD-associated genes. Methods: In the Early Autism Risk Longitudinal Investigation (EARLI), an ASD-enriched risk birth cohort, genome-scale maternal blood (early n = 140 and late n = 75 pregnancy), infant cord blood (n = 133), and placenta (maternal n = 106 and fetal n = 107 compartments) DNA methylation was assessed on the Illumina 450k HumanMethylation array and compared to ASD diagnosis at 36 months of age. Differences in site-specific and global methylation were tested with ASD, as well as enrichment of single site associations for ASD risk genes (n = 881) from the Simons Foundation Autism Research Initiative (SFARI) database. Results: No individual DNA methylation site was associated with ASD at genome-wide significance, however, individual DNA methylation sites nominally associated with ASD (P < 0.05) in each tissue were highly enriched for SFARI genes (cord blood P = 7.9 × 10-29, maternal blood early pregnancy P = 6.1 × 10-27, maternal blood late pregnancy P = 2.8 × 10-16, maternal placenta P = 5.6 × 10-15, fetal placenta P = 1.3 × 10-20). DNA methylation sites nominally associated with ASD across all five tissues overlapped at 144 (29.5%) SFARI genes. Conclusion: DNA methylation sites nominally associated with later ASD diagnosis in multiple tissues were enriched for ASD risk genes. Our multi-tissue study demonstrates the utility of examining DNA methylation prior to ASD diagnosis.

Gastrointestinal symptoms (GIS) are commonly reported in children with autism spectrum disorder (ASD). This multi-site study evaluated the prevalence of GIS in preschool-aged children with ASD/(n = 672), with other developmental delays (DD)/(n = 938), and children in the general population (POP)/(n = 851). After adjusting for covariates, children in the ASD group were over 3 times more likely to have parent-reported GIS than the POP group, and almost 2 times more likely than the DD group. Children with GIS from all groups had more behavioral and sleep problems. Within the ASD group, children with developmental regression had more GIS than those without; however, there were no differences in autism severity scores between children with and without GIS. These findings have implications for clinical management.

Prior studies investigating restricted and repetitive behavior (RRB) subtypes within autism spectrum disorder (ASD) have found varied factor structures for symptom groupings, in part, due to variation in symptom measurement and broad sample age ranges. This study examined RRBs among 827 preschool-age children, ages 35 to 71 months, through an exploratory factor analysis of RRB items from the Autism Diagnostic Interview-Revised (ADI-R) collected through the Study to Explore Early Development. The factor structures of RRBs among children with confirmed ASD versus those with non-autism developmental concerns were qualitatively compared. Correlations between RRB factors and participant characteristics were examined in the ASD group. Three conceptually well-defined factors characterized as repetitive sensorimotor behaviors (RSMB), insistence on sameness (IS), and a novel stereotyped speech (SPEECH) factor emerged for the ASD group only. Distinct factors were supported by different clinical correlates. Findings have implications for improving differential diagnosis and understanding of ASD symptomatology in this age range.

Background: Children with autism spectrum disorder (ASD) experience high rates of atypical eating behaviours, such as food neophobia. Mobile health (mHealth) interventions have been found to improve communication, behaviour and social skills for children with ASD. However, there is limited evidence examining mHealth nutrition interventions among children with ASD. Methods: The present study comprised a qualitative descriptive study that used qualitative content analysis to explore parent and child experiences with a novel mHealth nutrition intervention. Ten parent–child dyads provided user feedback and evaluation of the intervention. Data collection tools included a semistructured interview guide and a quantitative questionnaire with open‐ended questions. Data analysis of the interview transcripts and open‐ended questionnaire responses was an iterative process that continued until saturation was achieved. Descriptive statistics were used to analyse quantitative questionnaire data. Results: Analysis of the qualitative semistructured interviews led to emergence of three themes: (1) positive intervention outcomes; (2) parent suggestions for improvement; and (3) barriers to engagement. Each theme included subthemes. Questionnaire data revealed the ability to pick rewards and the virtual character that reinforced dietary goals ("Nutrition Ninja") were the most liked components of the application. Sending messages within the application and the Nutrition Ninja game were the least liked components of the application. Conclusions: Collectively, findings indicated that the app served as an interactive tool prompting dietary change and conversations within families. Yet, for some families, the intervention design, resistance to change or child disinterest hindered use and implementation of the intervention. Highlights: Parent and child engagement with the mHealth nutrition intervention resulted in gaining new skills, tools or knowledge for some of the participating families.Parents offered several suggestions that ranged from technical modifications to the design or functionality of the mobile app to overarching changes to the approach of the nutrition intervention itself.For some families, various components of the mobile app or family circumstances hindered parent or child engagement with the app technology or nutrition intervention. [ABSTRACT FROM AUTHOR]

We analyzed CBCL/1½-5 Pervasive Developmental Problems (DSM-PDP) scores in 3- to 5-year-olds from the Study to Explore Early Development (SEED), a multi-site case control study, with the objective to discriminate children with ASD (N = 656) from children with Developmental Delay (DD) (N = 646), children with Developmental Delay (DD) plus ASD features (DD-AF) (N = 284), and population controls (POP) (N = 827). ASD diagnosis was confirmed with the ADOS and ADI-R. With a cut-point of T = 65, sensitivity was 80% for ASD, with specificity varying across groups: POP (0.93), DD-noAF (0.85), and DD-AF (0.50). One-way ANOVA yielded a large group effect (?[superscript 2] = 0.50). Our results support the CBCL/1½-5's as a time-efficient ASD screener for identifying preschoolers needing further evaluation.

We examined associations between child body mass index at 2-5 years and maternal pre-pregnancy body mass index, gestational weight gain, and rapid weight gain during infancy in children with autism spectrum disorder, developmental delays, or population controls. The Study to Explore Early Development is a multi-site case-control study of children, aged 2-5 years, classified as autism spectrum disorder (n = 668), developmental delays (n = 914), or population controls (n = 884). Maternal gestational weight gain was compared to the Institute of Medicine recommendations. Rapid weight gain was a change in weight-for-age z-scores from birth to 6 months > 0.67 standard deviations. After adjusting for case status, mothers with pre-pregnancy overweight/obesity were 2.38 times (95% confidence interval: 1.96-2.90) more likely, and mothers who exceeded gestational weight gain recommendations were 1.48 times (95% confidence interval: 1.17-1.87) more likely, to have an overweight/obese child than other mothers (P < 0.001). Children with autism spectrum disorder showed the highest frequency of rapid weight gain (44%) and were 3.47 times (95% confidence interval: 1.85-6.51) more likely to be overweight/obese as children with autism spectrum disorder without rapid weight gain (P < 0.001). Helping mothers achieve a healthy pre-pregnancy body mass index and gestational weight gain represent important targets for all children. Healthy infant growth patterns carry special importance for children at increased risk for an autism spectrum disorder diagnosis.

This study examined caregiver-reported medically-attended injuries among 30-68 month old children with autism spectrum disorder (ASD) compared to general population (POP) and non-ASD developmental disorders (DD) controls in the Study to Explore Early Development. Injuries were common in ASD cases (32.3%) as well as POP (30.2%) and DD (27.8%) controls; most resulted in an emergency visit or hospitalization. After accounting for sociodemographic, health, IQ and behavior differences, odds of injury in ASD cases were significantly higher than DD controls but similar to POP controls. Attention problems mediated the relationships. Clinicians caring for children with both ASD and attention problems should consider providing targeted safety advice. Differences in injury risk between children with ASD vs. other developmental disorders need further study.

The Social Communication Questionnaire (SCQ) and the Social Responsiveness Scales (SRS) are commonly used screeners for autism spectrum disorder (ASD). Data from the Study to Explore Early Development were used to examine variations in the performance of these instruments by child characteristics and family demographics. For both instruments, specificity decreased as maternal education and family income decreased. Specificity was decreased with lower developmental functioning and higher behavior problems. This suggests that the false positive rates of the SRS and the SCQ are associated with child characteristics and family demographic factors. There is a need for ASD screeners that perform well across socioeconomic and child characteristics. Clinicians should be mindful of differential performance of these instruments in various groups of children.

The objective of this study was to identify homogenous classes of young children with autism spectrum disorder (ASD) to improve phenotypic characterization. Children were enrolled in the Study to Explore Early Development between 2 and 5 years of age. 707 children were classified with ASD after a comprehensive evaluation with strict diagnostic algorithms. Four classes of children with ASD were identified from latent class analysis: "mild language delay with cognitive rigidity," "mild language and motor delay with dysregulation," "general developmental delay," and "significant developmental delay with repetitive motor behaviors." We conclude that a four-class phenotypic model of children with ASD best describes our data and improves phenotypic characterization of young children with ASD. Implications for screening, diagnosis, and research are discussed.

Abstract Infant sibling studies have been at the vanguard of autism spectrum disorders (ASD) research over the past decade, providing important new knowledge about the earliest emerging signs of ASD and expanding our understanding of the developmental course of this complex disorder. Studies focused on siblings of children with ASD also have unrealized potential for contributing to ASD etiologic research. Moving targeted time of enrollment back from infancy toward conception creates tremendous opportunities for optimally studying risk factors and risk biomarkers during the pre-, peri- and neonatal periods. By doing so, a traditional sibling study, which already incorporates close developmental follow-up of at-risk infants through the third year of life, is essentially reconfigured as an enriched-risk pregnancy cohort study. This review considers the enriched-risk pregnancy cohort approach of studying infant siblings in the context of current thinking on ASD etiologic mechanisms. It then discusses the key features of this approach and provides a description of the design and implementation strategy of one major ASD enriched-risk pregnancy cohort study: the Early Autism Risk Longitudinal Investigation (EARLI).

This study examined the phenotypic profiles of children aged 30-68 months in the Study to Explore Early Development (SEED). Children classified as autism spectrum disorder (ASD), developmental delay (DD) with ASD symptoms, DD without ASD symptoms, and population comparison (POP) differed significantly from each other on cognitive, adaptive, behavioral, and social functioning and the presence of parent-reported conditions. Children with ASD and DD with ASD symptoms had mild to severe ASD risk on several measures compared to children with other DD and POP who had little ASD risk across measures. We conclude that children in SEED have varying degrees of ASD impairment and associated deficits. SEED thus provides a valuable sample to explore ASD phenotypes and inform risk factor analyses.

The Study to Explore Early Development (SEED) is a multi-site case-control study designed to explore the relationship between autism spectrum disorder (ASD) phenotypes and etiologies. The goals of this paper are to (1) describe the SEED algorithm that uses the Autism Diagnostic Interview-Revised (ADI-R) and Autism Diagnostic Observation Schedule (ADOS) to classify children with ASD, (2) examine psychometric properties of different ASD classification methods, including the SEED method that incorporates rules for resolving ADI-R and ADOS discordance, and (3) determine whether restricted interests and repetitive behaviors were noted for children who had instrument discordance resolved using ADI-R social and communication scores. Results support the utility of SEED criteria when well-defined groups of children are an important clinical or research outcome.

Recent reports suggest certain behaviors among children with autism spectrum disorders (ASD) may indicate underlying gastro-intestinal (GI) problems, and that the presence of these behaviors may help alert primary care providers to the need to evaluate a child with ASD for GI problems. The purpose of this population-based study of 487 children with ASD, including 35 (7.2%) with a medically documented history of GI problems, was to compare behavioral features of children with and without a history of GI problems. Unusual sleeping or eating habits and oppositional behavior were significantly associated with GI problems. These behaviors, however, were frequent in both children with and without GI problems, suggesting they may have limited utility in a screening capacity for GI problems.

This study estimated differences by ethnicity in the diagnoses assigned prior to the diagnosis of autism. In this sample of 406 Medicaid-eligible children, African-Americans were 2.6 times less likely than white children to receive an autism diagnosis on their first specialty care visit. Among children who did not receive an autism diagnosis on their first visit, ADHD was the most common diagnosis. African-American children were 5.1 times more likely than white children to receive a diagnosis of adjustment disorder than of ADHD, and 2.4 times more likely to receive a diagnosis of conduct disorder than of ADHD. Differences in diagnostic patterns by ethnicity suggest possible variations in parents' descriptions of symptoms, clinician interpretations and expectations, or symptom presentation.

In no area of developmental pediatric practice is there more controversy regarding the choice of treatment than related to children with autistic spectrum disorders (ASD). Complementary and alternative medical therapies (CAM) are often elected because they are perceived as treating the cause of symptoms rather than the symptoms themselves. CAM used for autism can be divided by proposed mechanism: immune modulation, gastrointestinal, supplements that affect neurotransmitter function, and nonbiologic intervention. Secretin as a therapy for autism is discussed as an example of how a clinical observation rapidly grew to a widespread treatment before well-designed studies demonstrated absence of effect. The plausibility for behavioral effect was not substantiated by clinical studies. CAM used for treatment of autism is examined in terms of rationale, evidence of efficacy, side effects, and additional commentary. Families and clinicians need access to well-designed clinical evidence to assist them in choice of therapies. (Contains 1 table.)

Alpha circuits (8-12 Hz), necessary for basic and complex brain processes, are abnormal in autism spectrum disorder (ASD). The present study obtained estimates of resting-state (RS) alpha activity in children with ASD and examined associations between alpha activity, age, and clinical symptoms. Given that the thalamus modulates cortical RS alpha rhythms, associations between thalamic structure and alpha activity were examined. RS magnetoencephalography was obtained from 47 typically-developing children (TDC) and 41 children with ASD. RS alpha activity was measured using distributed source localization. Left and right thalamic volume measurements were also obtained. In both groups, the strongest alpha activity was observed in Calcarine Sulcus regions. In Calcarine regions, only TDC showed the expected association between age and alpha peak frequency. ASD had more alpha activity than TDC in regions bordering the Central Sulcus as well as parietal association cortices. In ASD, whereas greater left Central Sulcus relative alpha activity was associated with higher Social Responsiveness Scale (SRS) scores, greater Calcarine region relative alpha activity was associated with lower SRS scores. Although thalamic volume group differences were not observed, relationships between thalamic volume and Calcarine alpha power were unique to TDC. The present study also identified a failure to shift peak alpha frequency as a function of age in primary alpha-generating areas in children with ASD. Findings suggested that increased RS alpha activity in primary motor and somatosensory as well as parietal multimodal areas-with increased alpha thought to reflect greater inhibition-might impair the ability to identify or interpret social cues. Finally, to our knowledge, this is the first study to report associations between thalamic volume and alpha power, an association observed only in TDC. The lack of thalamic and alpha associations in ASD suggests thalamic contributions to RS alpha abnormalities in ASD. Electronic supplementary material The online version of this article (doi:10.1007/s10803-014-2236-1) contains supplementary material, which is available to authorized users., Author(s): J. Christopher Edgar[sup.1] , Kory Heiken[sup.1] , Yu-Han Chen[sup.2] , John D. Herrington[sup.3] , Vivian Chow[sup.1] , Song Liu[sup.1] , Luke Bloy[sup.1] , Mingxiong Huang[sup.4] , Juhi Pandey[sup.3] , [...]

Previous studies have observed evoked response latency as well as gamma band superior temporal gyrus (STG) auditory abnormalities in individuals with autism spectrum disorders (ASD). A limitation of these studies is that associations between these two abnormalities, as well as the full extent of oscillatory phenomena in ASD in terms of frequency and time, have not been examined. Subjects were presented pure tones at 200, 300, 500, and 1,000 Hz while magnetoencephalography assessed activity in STG auditory areas in a sample of 105 children with ASD and 36 typically developing controls (TD). Findings revealed a profile such that auditory STG processes in ASD were characterized by pre-stimulus abnormalities across multiple frequencies, then early high-frequency abnormalities followed by low-frequency abnormalities. Increased pre-stimulus activity was a 'core' abnormality, with pre-stimulus activity predicting post Electronic supplementary material The online version of this article (doi:10.1007/s10803-013-1904-x) contains supplementary material, which is available to authorized users. stimulus neural abnormalities, group membership, and clinical symptoms (CELF-4 Core Language Index). Deficits in synaptic integration in the auditory cortex are associated with oscillatory abnormalities in ASD as well as patient symptoms. Increased pre-stimulus activity in ASD likely demonstrates a fundamental signal-to-noise deficit in individuals with ASD, with elevations in oscillatory activity suggesting an inability to maintain an appropriate 'neural tone' and an inability to rapidly return to a resting state prior to the next stimulus. Keywords Auditory * Autism spectrum disorders * M100 * Gamma * Evoked * Inter-trial coherence * Phase-locking * Magnetoencephalography, Superior Temporal Gyrus Spectro-temporal Abnormalities in Autism Spectrum Disorders Magnetoencephalography (MEG) studies examining superior temporal gyrus (STG) auditory activity in individuals with Autism Spectrum Disorders (ASD) almost uniformly report abnormalities. [...]

Autism spectrum disorders (ASDs) represent a group of childhood neurodevelopmental and neuropsychiatric disorders characterized by deficits in verbal communication, impairment of social interaction, and restricted and repetitive patterns of interests and behaviour. To identify common genetic risk factors underlying ASDs, here we present the results of genome-wide association studies on a cohort of 780 families (3,101 subjects) with affected children, and a second cohort of 1,204 affected subjects and 6,491 control subjects, all of whom were of European ancestry. Six single nucleotide polymorphisms between cadherin 10 (CDH10) and cadherin 9 (CDH9)-two genes encoding neuronal cell-adhesion molecules-revealed strong association signals, with the most significant SNP being rs4307059 (P = 3.4 X [10.sup.-8], odds ratio =1.19). These signals were replicated in two independent cohorts, with combined Pvalues ranging from 7.4 X [10.sup.-8] to 2.1 X [10.sup.-10]. Our results implicate neuronal cell-adhesion molecules in the pathogenesis of ASDs, and represent, to our knowledge, the first demonstration of genome-wide significant association of common variants with susceptibility to ASDs., ASDs encompass a range of clinically defined conditions, including autism and pervasive developmental disorder not otherwise specified, which are more common and severe, as well as Asperger's syndrome, which appears [...]

Autism spectrum disorders (ASDs) are childhood neurodevelopmental disorders with complex genetic origins(1-4). Previous studies focusing on candidate genes or genomic regions have identified several copy number variations (CNVs) that are associated with an increased risk of ASDs(5-9). Here we present the results from a whole-genome CNV study on a cohort of 859 ASD cases and 1,409 healthy children of European ancestry who were genotyped with 550,000 single nucleotide polymorphism markers, in an attempt to comprehensively identify CNVs conferring susceptibility to ASDs. Positive findings were evaluated in an independent cohort of 1,336 ASD cases and 1,110 controls of European ancestry. Besides previously reported ASD candidate genes, such as NRXNI (ref. 10) and CNTN4 (refs 11, 12), several new susceptibility genes encoding neuronal cell-adhesion molecules, including NLGNI and ASTN2, were enriched with CNVs in ASD cases compared to controls (P = 9.5 x [10.sup.-3]). Furthermore, CNVs within or surrounding genes involved in the ubiquitin pathways, including UBE3A, PARKZ RFWD2 and FBX040, were affected by CNVs not observed in controls (P= 3.3 x [10.sup.-3]). We also identified duplications 55 kilobases upstream of complementary DNA AK123120 (P=3.6 x [10.sup.-6]). Although these variants may be individually rare, they target genes involved in neuronal cell-adhesion or ubiquitin degradation, indicating that these two important gene networks expressed within the central nervous system may contribute to the genetic susceptibility of ASD., ASDs, including autism, are neurodevelopmental disorders characterized by impairments in social and communication skills, as well as stereotyped and repetitive behaviours and/or a restricted range of interests. Current prevalence estimates [...]

The heterogeneous nature of children with symptoms of autism spectrum disorder (ASD) makes it difficult to identify risk factors and effective treatment options. We sought to identify behavioral and developmental features that best define the heterogeneity and homogeneity in 2–5‐year‐old children classified with ASD and subthreshold ASD characteristics. Children were enrolled in a multisite case–control study of ASD. Detailed behavioral and developmental data were gathered by maternal telephone interview, parent‐administered questionnaires, child cognitive evaluation, and ASD diagnostic measures. Participants with a positive ASD screen score or prior ASD diagnosis were referred for comprehensive evaluation. Children in the ASD group met study criteria based on this evaluation; children who did not meet study criteria were categorized as having subthreshold ASD characteristics. There were 1480 children classified as ASD (81.6% boys) and 594 children classified as having subthreshold ASD characteristics (70.2% boys) in the sample. Factors associated with dysregulation (e.g., aggression, anxiety/depression, sleep problems) followed by developmental abilities (e.g., expressive and receptive language skills) most contributed to heterogeneity in both groups of children. Atypical sensory response contributed to homogeneity in children classified as ASD but not those with subthreshold characteristics. These findings suggest that dysregulation and developmental abilities are clinical features that can impact functioning in children with ASD and other DD, and that documenting these features in pediatric records may help meet the needs of the individual child. Sensory dysfunction could be considered a core feature of ASD and thus used to inform more targeted screening, evaluation, treatment, and research efforts. Lay summary: The diverse nature of autism spectrum disorder (ASD) makes it difficult to find risk factors and treatment options. We identified the most dissimilar and most similar symptom(s) in children classified as ASD and as having subthreshold ASD characteristics. Factors associated with dysregulation and developmental abilities contributed to diversity in both groups of children. Sensory dysfunction was the most common symptom in children with ASD but not those with subthreshold characteristics. Findings can inform clinical practice and research. [ABSTRACT FROM AUTHOR]