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Sensory modulation symptoms form a diagnostic criterion for autism spectrum disorder and are associated with significant daily functional limitations. Utilizing caregiver report on Short Sensory Profile-2 (SSP-2) for 919 autistic children (3-14.11 years), we examined the expression of sensory modulation symptoms by age and sex and investigated the existence of specific sensory modulation subtypes. Sensory modulation symptoms appeared to peak in frequency during middle childhood, particularly in sensory sensitivity and avoidance. Symptoms associated with sensory hypo-reactivity and seeking tended not differ between age cohorts. Males and females demonstrated similar overall sensory modulation profiles, however, females showed elevated symptoms relating to sensory sensitivity. Model-based cluster analysis revealed five interpretable sensory modulation subtypes which related to symptom severity (low, mid-range, high). Subtypes demonstrating mid-range symptom severity differed in focus on sensory hyper-reactivity or seeking symptoms. The findings of this study report for the first time that age-related differences in sensory modulation symptoms may be associated with sensory hyper-reactivity only. The subtyping results also suggest that sensory modulation symptom severity is a reliable means of classifying variance within autistic children, however, consideration of differences in the behavioral strategies employed by individuals to manage sensory modulation symptoms may inform tailored supportive strategies. LAY SUMMARY: We studied sensory symptoms such as over-responding, under-responding and sensation seeking behaviors in 919 autistic children and adolescents. We found that 6-12-year-olds and females displayed the most sensory over-responding symptoms. Autistic children could be grouped into mild, moderate, and severe levels of sensory symptoms, however, children differed in the type of strategies used to cope with their sensory symptoms meaning that they may require different intervention approaches.

Greater facial asymmetry has been consistently found in children with autism spectrum disorder (ASD) relative to children without ASD. There is substantial evidence that both facial structure and the recurrence of ASD diagnosis are highly heritable within a nuclear family. Furthermore, sub-clinical levels of autistic-like behavioural characteristics have also been reported in first-degree relatives of individuals with ASD, commonly known as the 'broad autism phenotype'. Therefore, the aim of the current study was to examine whether a broad autism phenotype expresses as facial asymmetry among 192 biological parents of autistic individuals (134 mothers) compared to those of 163 age-matched adults without a family history of ASD (113 females). Using dense surface-modelling techniques on three dimensional facial images, we found evidence for greater facial asymmetry in parents of autistic individuals compared to age-matched adults in the comparison group (p = 0.046, d = 0.21 [0.002, 0.42]). Considering previous findings and the current results, we conclude that facial asymmetry expressed in the facial morphology of autistic children may be related to heritability factors. LAY ABSTRACT: In a previous study, we showed that autistic children presented with greater facial asymmetry than non-autistic children. In the current study, we examined the amount of facial asymmetry shown on three-dimensional facial images of 192 parents of autistic children compared to a control group consisting of 163 similarly aged adults with no known history of autism. Although parents did show greater levels of facial asymmetry than those in the control group, this effect is statistically small. We concluded that the facial asymmetry previously found in autistic children may be related to genetic factors.

To investigate associations between functioning, community participation, and quality of life (QoL) and identify whether participation mediates the effects of functioning on QoL.The caregivers of 435 children (211 females, 224 males; mean age 12y; SD 3y 11mo; age range 5-18y) with intellectual disability and autism spectrum disorder, cerebral palsy, Down syndrome, or Rett syndrome reported on their child's functioning (dependence for managing personal needs, mobility, communication, eye contact when speaking), frequency of participation, and QoL. Linear regression and mediation analyses were used to evaluate the relationships between child functioning, participation, and QoL.Children with greater dependency for managing personal needs and limited eye contact when speaking experienced poorer QoL. Less impaired functioning was associated with more frequent participation, which, in turn, was associated with a 3-point gain in QoL for each additional point in frequency of participation (coefficient=2.67, 95% confidence interval 1.56-3.78). The effect of impaired functioning on QoL was partially mediated by participation in children with greater dependency in managing personal needs and those with mildly impaired communication.Greater levels of impairments with poorer functioning, notably a high level of dependence, were associated with poorer QoL. Poorer QoL can be partly explained by less frequent community participation.Investigar las asociaciones entre el funcionamiento, la participación comunitaria y la calidad de vida (CdV) e identificar si la participación media los efectos del funcionamiento en la CdV. MÉTODO: Participaron los cuidadores de 435 niños (211 niñas y 224 niños; media de edad 12 años DS 3 años 11 meses; rango de edad 5-18 años) con discapacidad intelectual y trastorno del espectro autista, parálisis cerebral, síndrome de Down o síndrome de Rett. Informaron sobre el funcionamiento de sus hijos (dependencia para el manejo de necesidades personales, movilidad, comunicación, contacto visual al hablar), frecuencia de participación y calidad de vida. Se realizaron análisis de mediación y regresión lineal para analizar las relaciones entre el funcionamiento, la participación y la calidad de vida de los niños.Los niños con mayor dependencia para manejar sus necesidades personales y aquellos con limitado contacto visual al hablar, experimentaron una peor calidad de vida. Un menor compromiso en el funcionamiento se asoció con una participación más frecuente, que, a su vez, se asoció con una ganancia de 3 puntos en la CdV por cada punto adicional en la frecuencia de participación (coeficiente = 2,67, intervalo de confianza del 95%: 1,56-3,78). El efecto del deterioro del funcionamiento sobre la calidad de vida fue mediado parcialmente por la participación en niños con mayor dependencia en el manejo de sus necesidades personales y en aquellos con un compromiso leve en la comunicación. INTERPRETACIÓN: Niveles mayores de deficiencias en el funcionamiento, en particular un alto nivel de dependencia, se asociaron con una peor calidad de vida. La menor calidad de vida se puede explicar, en parte, por una participación comunitaria menos frecuente.Investigar associações entre funcionamento, participação na comunidade, e qualidade de vida (QV), e identificar se a participação media os efeitos do funcionamento na QV. MÉTODO: Os cuidadores de 435 crianças (211 do sexo feminino, 224 do sexo masculino; média de idade 12a; DP 3a 11m; variação da idade: 5-18a) com deficiência intelectual e transtorno do espectro autista, paralisia cerebral, síndrome de Down, ou síndrome de Rett, relataram o funcionamento de suas crianças (dependência para manejar necessidades pessoais, mobilidade, comunicação, contato pessoal ao falar), frequência de participação, e QV. Análises de regressão linear e de mediação foram usadas para avaliar as relações entre funcionamento da criança, participação, e QV.Crianças com maior dependência para o manejo das necessidades pessoais e contato visual limitado ao falar experimentaram pior QV. Funcionamento menos comprometido foi associado com maior frequência de participação, o que, por sua vez, se associou com um ganho de 3 pontos em QV para cada ponto adicional na frequência de participação (coeficiente=2,67, intervalo de confiança a 95% 1,56-3,78). O efeito do funcionamento deficiente na QV foi parcialmente mediado pela participação em crianças com maior dependência no manejo de necessidades pessoais e naquelas com comunicação levemente comprometida. INTERPRETAÇÃO: Maiores níveis de deficiência com pior funcionamento, notavelmente um maior nível de dependência, foram associados com pior QV. Pior QV pode ser parcialmente explicda por uma participação menos frequente na comunidade.

Alcohol exposure during pregnancy has been associated with altered brain development and facial dysmorphology. While autism spectrum disorder (ASD) is not specifically related to distinct facial phenotypes, recent studies have suggested certain facial characteristics—increased facial masculinity and asymmetry—may be associated with ASD and its clinical presentations. In the present study, we conducted a preliminary investigation to examine the effects of prenatal alcohol exposure on facial morphology in autistic children with (n = 37; mean age = 8.21 years, SD = 2.72) and without (n = 100; mean age = 8.37 years, SD = 2.47) prenatal alcohol exposure. Using three-dimensional facial scans and principal component analysis, we identified a facial shape associated with prenatal alcohol exposure in autistic children. However, variations in the alcohol-related facial shape were generally not associated with behavioural and cognitive measures. These findings suggest that while early exposure to alcohol may influence the development of facial structures, it is does not appear to be associated with ASD phenotypic variability. Importantly, although these findings do not implicate a role for prenatal alcohol exposure in the etiology of ASD, further research is warranted to investigate the link between prenatal alcohol exposure and facial morphology differences among neurodevelopmental conditions.

PurposeThe aim of the study was to examine whether otitis media (OM) in early childhood has an impact on language development in later childhood.MethodsWe analyzed data from 1,344 second-generation (Generation 2) participants in the Raine Study, a longitudinal pregnancy cohort established in Perth, Western Australia, between 1989 and 1991. OM was assessed clinically at 6 years of age. Language development was measured using the Peabody Picture Vocabulary Test–Revised (PPVT-R) at 6 and 10 years of age and the Clinical Evaluation of Language Fundamentals–Third Edition at 10 years of age. Logistic regression analysis accounted for a wide range of social and environmental covariates.ResultsThere was no significant relationship between bilateral OM and language ability at 6 years of age (β = −0.56 [−3.78, 2.66],p =.732). However, while scores were within the normal range for the outcome measures at both time points, there was a significant reduction in the rate of receptive vocabulary growth at 10 years of age (PPVT-R) for children with bilateral OM at 6 years of age (β = −3.17 [−6.04, −0.31],p =.030), but not for the combined unilateral or bilateral OM group (β = −1.83 [−4.04, 0.39],p =.106).ConclusionsChildren with OM detected at 6 years of age in this cohort had average language development scores within the normal range at 6 and 10 years of age. However, there was a small but statistically significant reduction in the rate of receptive vocabulary growth at 10 years of age (on the PPVT-R measure only) in children who had bilateral OM at 6 years of age after adjusting for a range of sociodemographic factors.

This study explored the association between autistic-like traits in young adults and dietary intake in early childhood in the Gen2 Raine Study cohort. Data were available from 811 participants at years 1, 2 and 3 for the assessment of dietary intake, and at year 20 for measurement of autistic-like traits. Results showed as autistic-like traits increased, total food variety, core food variety and dairy variety decreased (p

BackgroundEmerging research suggests that maternal immune activation (MIA) may be associated with an increased risk of adverse neurodevelopmental and mental health outcomes in offspring. Using data from the Raine Study, we investigated whether MIA during pregnancy was associated with increased behavioral and emotional problems in offspring longitudinally across development.MethodsMothers (Generation 1; N = 1905) were classified into the following categories: AAAE (Asthma/Allergy/Atopy/Eczema; N = 1267); infection (during pregnancy; N = 1082); no AAAE or infection (N = 301). The Child Behavior Checklist (CBCL) was administered for offspring at ages 5, 8, 10, 14, and 17. Generalized estimating equations were used to investigate the effect of maternal immune status on CBCL scores.ResultsAAAE conditions were associated with significant increases in CBCL Total (β 2.49; CI 1.98–3.00), Externalizing (β 1.54; CI 1.05–2.03), and Internalizing (β 2.28; CI 1.80–2.76) scores. Infection conditions were also associated with increased Total (β 1.27; CI 0.77–1.78), Externalizing (β 1.18; CI 0.70–1.66), and Internalizing (β 0.76; CI 0.28–1.24) scores. Exposure to more than one AAAE and/or infection condition was associated with a greater elevation in CBCL scores than single exposures in males and females. Females showed greater increases on the Internalizing scale from MIA, while males showed similar increases on both Internalizing and Externalizing scales.ConclusionsMIA was associated with increased behavioral and emotional problems in offspring throughout childhood and adolescence. This highlights the need to understand the relationship between MIA, fetal development, and long-term outcomes, with the potential to advance early identification and intervention strategies.

Little is known about the role of family characteristics in sleep disturbance for children with autism spectrum disorder (ASD). This study involved an exploratory analysis of the association between 17 child, parent, and socioeconomic characteristics and sleep disturbance using data from 203, 2-18-year-old children with ASD whose families participated in the Western Australian Autism Biological Registry. Results suggest that greater ASD symptom severity; child seizures; maternal autism traits, anxiety, and depression; lower paternal education; and lower family income were related to increased sleep disturbance. All these characteristics, aside from maternal depression, were significant predictors within a regression model, which accounted for 33% of the total variance. Thus, child characteristics alone may not adequately explain sleep disturbance in children with ASD.

To investigate modifiable child and caregiver factors influencing community participation among children with Down syndrome.Cross-sectional data from a study investigating quality of life of children with intellectual disability were analysed. Participants were caregivers of 89 children with Down syndrome (54 females; 83 school attenders) (mean age 11 y 1 mo; SD 4 y 1 mo). Components of participation (Increased caregiver time availability was associated with higher frequency of attendance. Higher frequency of attendance was associated with greater child involvement, and having a sleep breathing disorder and less verbal communication ability was associated with less child involvement. These factors combined explained 21% of the variance.Children with Down syndrome who participated in the community more frequently enjoyed greater involvement. Supporting participation of children with poorer verbal communication and/or sleep breathing disorders could further the participation of children with Down syndrome.Implications for rehabilitationChildren with Down syndrome who more frequently attended opportunities for participation were more likely to be involved in those experiences.Healthcare providers and educators could foster involvement in participation opportunities of children with poorer verbal ability by supporting the development of prerequisite communication strategies.Rehabilitation programs and policies pertaining to accessibility of community activities need to align with modifiable determinants of participation in children, including availability of caregivers' time.

Reports linking prenatal testosterone exposure to autistic traits and to a masculinized face structure have motivated research investigating whether autism is associated with facial masculinization. This association has been reported with greater consistency for females than for males, in studies comparing groups with high and low levels of autistic traits. In the present study, we conducted two experiments to examine facial masculinity/femininity in 151 neurotypical adults selected for either low, mid-range, or high levels of autistic traits. In the first experiment, their three-dimensional facial photographs were subjectively rated by 41 raters for masculinity/femininity and were objectively analysed. In the second experiment, we generated 6-face composite images, which were rated by another 36 raters. Across both experiments, findings were consistent for ratings of photographs and composite images. For females, a linear relationship was observed where femininity ratings decreased as a function of higher levels of autistic traits. For males, we found a U-shaped function where males with mid-range levels of traits were rated lowest on masculinity. Objective facial analyses revealed that higher levels of autistic traits were associated with less feminine facial structures in females and less masculine structures in males. These results suggest sex-specific relationships between autistic traits and facial masculinity/femininity.

Preeclampsia is a pregnancy disorder characterized by hypertension. Epidemiological studies have associated preeclampsia with an increased risk of neurodevelopmental disorders in offspring, such as autism and schizophrenia. Preeclampsia has also been linked with maternal vitamin D deficiency, another candidate risk factor also associated with autism. Our laboratory has established a gestational vitamin-D-deficient rat model that shows consistent and robust behavioural phenotypes associated with autism- and schizophrenia-related animal models. Therefore, we explored here whether this model also produces preeclampsia as a possible mediator of behavioural phenotypes in offspring. We showed that gestational vitamin D deficiency was not associated with maternal blood pressure or proteinuria during late gestation. Maternal and placental angiogenic and vasculogenic factors were also not affected by a vitamin-D-deficient diet. We further showed that exposure to low vitamin D levels did not expose the placenta to oxidative stress. Overall, gestational vitamin D deficiency in our rat model was not associated with preeclampsia-related features, suggesting that well-described behavioural phenotypes in offspring born to vitamin-D-deficient rat dams are unlikely to be mediated via a preeclampsia-related mechanism.

This study aimed to explore the rates of motor difficulties in children from the Australian Autism Biobank, and how early motor concerns impacted on children functionally. Children with autism aged 2-7 years, including 441 with a Vineland Adaptive Behavior Scale (VABS-II) motor subscale and 385 with a Mullen Scales of Early Learning (MSEL) fine motor subscale were included (n total = 514; 80% male). Approximately 60% of children on the MSEL and ~ 25% on the VABS-II had clinically significant motor impairments. More children with delayed sitting and walking motor milestones had early childhood parent reported motor difficulties (p 0.001). Early motor delays or concerns may assist identifying individuals who will likely benefit from early ongoing developmental monitoring and early support.

Key Points Question Does preemptive intervention compared with usual care reduce the severity of autism symptoms and the likelihood of an autism spectrum disorder (ASD) diagnosis in infants showing early signs of ASD? Findings In this randomized clinical trial of 103 infants showing early behavioral signs of ASD, preemptive intervention led to a statistically significant reduction in the severity of ASD behaviors across early childhood. Infants who received the preemptive intervention had lower odds of meeting diagnostic criteria for ASD (7%) than those who received usual care (21%) at age 3 years, with a number needed to treat of 7 participants. Meaning This study found that a preemptive intervention reduced ASD diagnostic behaviors when used at the time atypical development first emerges during infancy., Importance Intervention for individuals with autism spectrum disorder (ASD) typically commences after diagnosis. No trial of an intervention administered to infants before diagnosis has shown an effect on diagnostic outcomes to date. Objective To determine the efficacy of a preemptive intervention for ASD beginning during the prodromal period. Design, Setting, and Participants This 2-site, single rater–blinded randomized clinical trial of a preemptive intervention vs usual care was conducted at 2 Australian research centers (Perth, Melbourne). Community sampling was used to recruit 104 infants aged 9 to 14 months showing early behaviors associated with later ASD, as measured by the Social Attention and Communication Surveillance–Revised. Recruitment occurred from June 9, 2016, to March 30, 2018. Final follow-up data were collected on April 15, 2020. Interventions Infants were randomized on a 1:1 ratio to receive either a preemptive intervention plus usual care or usual care only over a 5-month period. The preemptive intervention group received a 10-session social communication intervention, iBASIS–Video Interaction to Promote Positive Parenting (iBASIS-VIPP). Usual care comprised services delivered by community clinicians. Main Outcomes and Measures Infants were assessed at baseline (approximate age, 12 months), treatment end point (approximate age, 18 months), age 2 years, and age 3 years. Primary outcome was the combined blinded measure of ASD behavior severity (the Autism Observation Scale for Infants and the Autism Diagnostic Observation Schedule, second edition) across the 4 assessment points. Secondary outcomes were an independent blinded clinical ASD diagnosis at age 3 years and measures of child development. Analyses were preregistered and comprised 1-tailed tests with an α level of .05. Results Of 171 infants assessed for eligibility, 104 were randomized; 50 infants (mean [SD] chronological age, 12.40 [1.93] months; 38 boys [76.0%]) received the iBASIS-VIPP preemptive intervention plus usual care (1 infant was excluded after randomization), and 53 infants (mean [SD] age, 12.38 [2.02] months; 32 boys [60.4%]) received usual care only. A total of 89 participants (45 in the iBASIS-VIPP group and 44 in the usual care group) were reassessed at age 3 years. The iBASIS-VIPP intervention led to a reduction in ASD symptom severity (area between curves, −5.53; 95% CI, −∞ to −0.28; P = .04). Reduced odds of ASD classification at age 3 years was found in the iBASIS-VIPP group (3 of 45 participants [6.7%]) vs the usual care group (9 of 44 participants [20.5%]; odds ratio, 0.18; 95% CI, 0-0.68; P = .02). Number needed to treat to reduce ASD classification was 7.2 participants. Improvements in caregiver responsiveness and language outcomes were also observed in the iBASIS-VIPP group. Conclusions and Relevance Receipt of a preemptive intervention for ASD from age 9 months among a sample of infants showing early signs of ASD led to reduced ASD symptom severity across early childhood and reduced the odds of an ASD diagnosis at age 3 years. Trial Registration http://anzctr.org.au identifier: ACTRN12616000819426., This randomized clinical trial examines whether preemptive intervention compared with usual care reduces the severity of autism symptoms and the odds of an autism spectrum disorder diagnosis among infants showing early signs of autism.

Supplemental Digital Content is available in the text., Background and Purpose: Management of stroke risk factors might reduce later dementia. In ASCOT (Anglo-Scandinavian Outcome Trial), we determined whether dementia or stroke were associated with different blood pressure (BP)–lowering regimens; atorvastatin or placebo; and mean BP, BP variability, and mean cholesterol levels. Methods: Participants with hypertension and ≥3 cardiovascular disease risk factors were randomly allocated to amlodipine- or atenolol-based BP-lowering regimen targeting BP

Motor impairment is not currently included in the diagnostic criteria or evaluation of autism. This reflects the lack of large-scale studies demonstrating its prominence to advocate for change. We examined the prevalence of motor difficulties at the time of diagnosis in a large sample of children with autism utilizing standardized assessment, and the relationship between motor difficulties, core autism symptomology, and other prominent clinical features. Vineland Adaptive Behavior Scales were administered to children from the Western Australian Register for Autism Spectrum Disorders aged ≤6 years (N = 2,084; 81.2% males, 18.8% females). Prevalence of motor difficulties was quantified based on scores from the motor domain of the Vineland and then compared to other domains of functioning within the Vineland (communication, daily living, and socialization), the DSM criteria, intellectual level, age, and gender. Scores on the Vineland indicated that 35.4% of the sample met criteria for motor difficulties (standard score70), a rate almost as common as intellectual impairment (37.7%). Motor difficulties were reported by diagnosing clinicians in only 1.34% of cases. Motor difficulties were common in those cases meeting diagnostic criteria for impairments in nonverbal behavior and the presence of restricted and repetitive behaviors. The prevalence of motor difficulties also increased with increasing age of diagnosis (P 0.001). Findings from the present study highlight the need for further consideration of motor difficulties as a distinct specifier within the diagnostic criteria for ASD. Autism Res 2020, 13: 298-306. © 2019 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: In this population-based cohort that included 2,084 children with autism aged ≤6 years, over one-third met the criteria for motor difficulties, a rate almost as common as intellectual disability. This study demonstrates that motor difficulties are a prominent feature of the autism phenotype requiring further consideration in both the diagnostic criteria and evaluation of autism.

BackgroundGreat interest exists in the potential efficacy of prediagnostic interventions within the autism spectrum disorder prodrome, but available evidence relates to children at high familial risk. We aimed to test the efficacy of a pre-emptive intervention designed for infants showing early behavioural signs of autism spectrum disorder.MethodsIn this single-blind, randomised controlled trial done at two specialist centres in Australia, infants aged 9–14 months were enrolled if they were showing at least three early behavioural signs of autism spectrum disorder on the Social Attention and Communication Surveillance-Revised (SACS-R) 12-month checklist. Infants were randomly assigned (1:1) to receive a parent-mediated video-aided intervention (iBASIS-VIPP) or treatment as usual. Group allocation was done by minimisation, stratified by site, sex, age, and the number of SACS-R risk behaviours. Assessments were done at baseline (before treatment allocation) and at the 6 month endpoint. The primary outcome was Autism Observation Scale for Infants (AOSI), which measures early behavioural signs associated with autism spectrum disorder. Secondary outcomes were a range of infant and caregiver outcomes measured by Manchester Assessment of Caregiver–Infant interaction (MACI), Mullen Scales of Early Learning (MSEL), Vineland Adaptive Behaviour Scales, 2nd edition (VABS-2), MacArthur-Bates Communicative Development Inventory (MCDI), and Parenting Sense of Competence (PSOC) scale. This trial is registered with Australian New Zealand Clinical Trials Registry, number ANZCTR12616000819426.FindingsBetween June 9, 2016, and March 30, 2018, 103 infants were randomly assigned, 50 to the iBASIS-VIPP group and 53 to the treatment-as-usual group. After the intervention, we observed no significant differences between groups on early autism spectrum disorder behavioural signs measured by the AOSI (difference estimate −0·74, 95% CI −2·47 to 0·98). We also observed no significant differences on secondary outcomes measuring caregiver non-directiveness (0·16, −0·33 to 0·65), caregiver sensitive responding (0·24, −0·15 to 0·63), and infant attentiveness (−0·19, −0·63 to 0·25) during parent–child interactions (MACI), as well as on researcher-administered measures of receptive (1·30, −0·48 to 3·08) and expressive language (0·54, −0·73 to 1·80), visual reception (0·31, −0·77 to 1·40), and fine motor skills (0·55, −0·32 to 1·41) using the MSEL. Compared with the treatment-as-usual group, the iBASIS-VIPP group had lower infant positive affect (−0·69, −1·27 to −0·10) on the MACI, but higher caregiver-reported receptive (37·17, 95% CI 10·59 to 63·75) and expressive vocabulary count (incidence rate ratio 2·31, 95% CI 1·22 to 4·33) on MCDI, and functional language use (difference estimate 6·43, 95% CI 1·06 to 11·81) on VABS. There were no significant group differences on caregiver-reported measures of MCDI infant gesture use (3·22, −0·60 to 7·04) and VABS social behaviour (3·28, −1·43 to 7·99). We observed no significant differences between groups on self-reported levels of parenting satisfaction (difference estimate 0·21, 95% CI −0·09 to 0·52), interest (−0·23, −0·62 to 0·16) and efficacy (−0·08, −0·38 to 0·22) on PSOC.InterpretationA pre-emptive intervention for the autism spectrum disorder prodrome had no immediate treatment effect on early autism spectrum disorder symptoms, the quality of parent–child interactions, or researcher-administered measures of developmental skills. However, we found a positive effect on parent-rated infant communication skills. Ongoing follow-up of this infant cohort will assess longer-term developmental effects.FundingWestern Australia Children's Research Fund, Autism Cooperative Research Centre, La Trobe University, and Angela Wright Bennett Foundation.

The Autism-Spectrum Quotient (AQ) is a psychometric scale that is commonly used to assess autistic-like traits and behaviors expressed by neurotypical individuals. A potential strength of the AQ is that it provides subscale scores that are specific to certain dimensions associated with autism such as social difficulty and restricted interests. However, multiple psychometric evaluations of the AQ have led to substantial disagreement as to how many factors exist in the scale, and how these factors are defined. These challenges have been exacerbated by limitations in study designs, such as insufficient sample sizes as well as a reliance on Pearson, rather than polychoric, correlations. In addition, several proposed models of the AQ suggest that some factors are uncorrelated, or negatively correlated, which has ramifications for whether total-scale scores are meaningfully interpretable-an issue not raised by previous work. The aims of the current study were to provide: (a) guidance as to which models of the AQ are viable for research purposes, and (b) evidence as to whether total-scale scores are adequately interpretable for research purposes. We conducted a comprehensive series of confirmatory factor analyses on 11 competing AQ models using two large samples drawn from an undergraduate population (n = 1,702) and the general population (n = 1,280). Psychometric evidence largely supported using the three-factor model described by Russell-Smith et al. [Personality and Individual Differences 51(2), 128-132 (2011)], but did not support the use of total-scale scores. We recommend that researchers consider using AQ subscale scores instead of total-scale scores. Autism Res 2020, 13: 45-60. © 2019 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: We examined 11 different ways of scoring subscales in the popular Autism-Spectrum Quotient (AQ) questionnaire in two large samples of participants (i.e., general population and undergraduate students). We found that a three-subscale model that used "Social Skill," "Patterns/Details," and "Communication/Mindreading" subscales was the best way to examine specific types of autistic traits in the AQ. We also found some weak associations between the three subscales-for example, being high on the "Patterns/Details" subscale was not predictive of scores on the other subscales. This means that meaningful interpretation of overall scores on the AQ is limited.

Background Focus is shifting to better understand the lived experiences of children with intellectual disability in relation to their quality of life (QOL). Yet no available QOL measures are grounded in the domains important for this population. We previously conducted qualitative parent caregiver interviews identifying QOL domains in children with intellectual disability to constitute a new measure of QOL. This study describes the content validity of the Quality of Life Inventory-Disability (QI-Disability), a parent-report measure developed for children with intellectual disability. Methods and results Questionnaire items were extracted from a qualitative dataset of 77 parent caregiver interviews. To establish content validation, a draft of QI-Disability was administered to 16 parent caregivers of children with intellectual disability (Down syndrome, Rett syndrome, cerebral palsy, or autism spectrum disorder). Parents participated in a cognitive interviewing procedure known as the "think-aloud" method. The process of item generation, cognitive debriefing, and refinement of QI-Disability prior to its pilot testing are described. A conceptual framework is presented. Conclusions Satisfactory content validity is reported, where ongoing consumer feedback shaped the dataset from which the final items were selected. Use of QI-Disability for children with intellectual disability will allow for greater insight into service utility and targeted intervention.

‘High functioning autism’ is a term often used for individuals with autism spectrum disorder without an intellectual disability. Over time, this term has become synonymous with expectations of greater functional skills and better long-term outcomes, despite contradictory clinical observations. This study investigated the relationship between adaptive behaviour, cognitive estimates (intelligence quotient) and age at diagnosis in autism spectrum disorder. Participants ( n = 2225, 1–18 years of age) were notified at diagnosis to a prospective register and grouped by presence ( n = 1041) or absence ( n = 1184) of intellectual disability. Functional abilities were reported using the Vineland Adaptive Behaviour Scales. Regression models suggested that intelligence quotient was a weak predictor of Vineland Adaptive Behaviour Scales after controlling for sex. Whereas the intellectual disability group’s adaptive behaviour estimates were close to reported intelligence quotients, Vineland Adaptive Behaviour Scales scores fell significantly below intelligence quotients for children without intellectual disability. The gap between intelligence quotient and Vineland Adaptive Behaviour Scales scores remained large with increasing age at diagnosis for all children. These data indicate that estimates from intelligence quotient alone are an imprecise proxy for functional abilities when diagnosing autism spectrum disorder, particularly for those without intellectual disability. We argue that ‘high functioning autism’ is an inaccurate clinical descriptor when based solely on intelligence quotient demarcations and this term should be abandoned in research and clinical practice.

BACKGROUND: Angiotensin-converting enzyme inhibitors and calcium channel blockers in combination are widely recommended in hypertension guidelines. The advantages of single-pill combinations (SPCs) are increasingly recognized, so a dosage-adapted combination of perindopril and amlodipine was developed for the initial management of hypertension. OBJECTIVE: This randomized trial evaluated the blood pressure (BP)-lowering efficacy of four incremental doses of perindopril/amlodipine SPC in adults with mild-to-severe hypertension. METHODS: Eligible patients (N = 1617) were randomized to SPC perindopril 3.5 mg/amlodipine 2.5 mg (i.e., 3.5/2.5 mg) daily, uptitrating as required on a monthly basis up to 14/10 mg until BP

BACKGROUND Exposure to surgery and anesthesia in early childhood has been found to be associated with an increased risk of behavioral deficits. While the US Food and Drug Administration (FDA) has warned against prenatal exposure to anesthetic drugs, little clinical evidence exists to support this recommendation. This study evaluates the association between prenatal exposure to general anesthesia due to maternal procedures during pregnancy and neuropsychological and behavioral outcome scores at age 10. METHODS This is an observational cohort study of children born in Perth, Western Australia, with 2 generations of participants contributing data to the Raine Study. In the Raine Study, the first generation (Gen1) are mothers enrolled during pregnancy, and the second generation (Gen2) are the children born to these mothers from 1989 to 1992 with neuropsychological and behavioral tests at age 10 (n=2024). In the primary analysis, 6 neuropsychological and behavioral tests were evaluated at age 10: Raven's Colored Progressive Matrices (CPM), McCarron Assessment of Neuromuscular Development (MAND), Peabody Picture Vocabulary Test (PPVT), Symbol Digit Modality Test (SDMT) with written and oral scores, Clinical Evaluation of Language Fundamentals (CELF) with Expressive, Receptive, and Total language scores, and Child Behavior Checklist (CBCL) with Internalizing, Externalizing, and Total behavior scores. Outcome scores of children prenatally exposed to general anesthesia were compared to children without prenatal exposure using multivariable linear regression models adjusting for demographic and clinical covariates (sex, race, income, and maternal education, alcohol or tobacco use, and clinical diagnoses: diabetes, epilepsy, hypertension, psychiatric disorders, or thyroid dysfunction). Bonferroni adjustment was used for the 6 independent tests in the primary analysis, so a corrected P value

Childhood aggressive behavior (AGG) has a substantial heritability of around 50%. Here we present a genome-wide association meta-analysis (GWAMA) of childhood AGG, in which all phenotype measures across childhood ages from multiple assessors were included. We analyzed phenotype assessments for a total of 328 935 observations from 87 485 children aged between 1.5 and 18 years, while accounting for sample overlap. We also meta-analyzed within subsets of the data, i.e., within rater, instrument and age. SNP-heritability for the overall meta-analysis (AGGoverall) was 3.31% (SE = 0.0038). We found no genome-wide significant SNPs for AGGoverall. The gene-based analysis returned three significant genes: ST3GAL3 (P = 1.6E–06), PCDH7 (P = 2.0E–06), and IPO13 (P = 2.5E–06). All three genes have previously been associated with educational traits. Polygenic scores based on our GWAMA significantly predicted aggression in a holdout sample of children (variance explained = 0.44%) and in retrospectively assessed childhood aggression (variance explained = 0.20%). Genetic correlations (rg) among rater-specific assessment of AGG ranged from rg = 0.46 between self- and teacher-assessment to rg = 0.81 between mother- and teacher-assessment. We obtained moderate-to-strong rgs with selected phenotypes from multiple domains, but hardly with any of the classical biomarkers thought to be associated with AGG. Significant genetic correlations were observed with most psychiatric and psychological traits (range $$\left| {r_g} \right|$$ r g : 0.19–1.00), except for obsessive-compulsive disorder. Aggression had a negative genetic correlation (rg = ~−0.5) with cognitive traits and age at first birth. Aggression was strongly genetically correlated with smoking phenotypes (range $$\left| {r_g} \right|$$ r g : 0.46–0.60). The genetic correlations between aggression and psychiatric disorders were weaker for teacher-reported AGG than for mother- and self-reported AGG. The current GWAMA of childhood aggression provides a powerful tool to interrogate the rater-specific genetic etiology of AGG.

Background Autism spectrum disorder (ASD) is a group of neurodevelopmental disorders which are more common in males. The ‘prenatal sex steroid’ hypothesis links excessive sex-steroid exposure during foetal life with the behavioural differences observed in ASD. However, the reason why sex steroid exposure may be excessive remains unclear. Epidemiological studies have identified several environmental risk factors associated with ASD, including developmental vitamin D (DVD) deficiency. We have demonstrated in an animal model that DVD-deficiency is associated with a hyper-inflammatory response in placentas from male but not female foetuses. Vitamin D also regulates the expression of several steroidogenic enzymes in vitro. Therefore using this animal model, we have examined whether DVD-deficiency leads to increased sex-steroid levels in both the maternal and foetal compartments. Methods Female rats are fed a vitamin D deficient diet from 6 weeks before mating until tissue collection at embryonic day 18. We examined the levels of testosterone, androstenedione and corticosterone in maternal plasma, foetal brains and amniotic fluid. We further examined gene expressions of steroidogenic enzymes and DNA methylation of aromatase promoters in foetal brains as a potential molecular mechanism regulating testosterone expression. Results We show that DVD-deficiency increases testosterone levels in maternal blood. We also show elevated levels of testosterone and androstenedione in the amniotic fluid of female but not male DVD-deficient foetuses. Testosterone levels were also elevated in DVD-deficient male brains. Vitamin D, like other steroid-related hormones, regulates gene expression via methylation. Therefore we examined whether the significant elevation in testosterone in male brains was due to such a potential gene-silencing mechanism. We show that the promoter of aromatase was hyper-methylated compared to male controls. Limitations A reduction in aromatase, in addition to causing excessive testosterone, could also lead to a reduction in estradiol which was not examined here. Conclusions This study is the first to show how an epidemiologically established environmental risk factor for ASD may selectively elevate testosterone in male embryonic brains. These findings provide further mechanistic support for the prenatal sex steroid theory of ASD.

Economic preferences may be shaped by exposure to sex hormones around birth. Prior studies of economic preferences and numerous other phenotypic characteristics use digit ratios (2D : 4D), a purported proxy for prenatal testosterone exposure, whose validity has recently been questioned. We use direct measures of neonatal sex hormones (testosterone and oestrogen), measured from umbilical cord blood ( n = 200) to investigate their association with later-life economic preferences (risk preferences, competitiveness, time preferences and social preferences) in an Australian cohort (Raine Study Gen2). We find no significant associations between testosterone at birth and preferences, except for competitiveness, where the effect runs opposite to the expected direction. Point estimates are between 0.05–0.09 percentage points (pp) and 0.003–0.14 s.d. We similarly find no significant associations between 2D : 4D and preferences ( n = 533, point estimates 0.003–0.02 pp and 0.001–0.06 s.d.). Our sample size allows detecting effects larger than 0.11 pp or 0.22 s.d. for testosterone at birth, and 0.07 pp or 0.14 s.d. for 2D : 4D ( α = 0.05 and power = 0.90). Equivalence tests show that most effects are unlikely to be larger than these bounds. Our results suggest a reinterpretation of prior findings relating 2D : 4D to economic preferences, and highlight the importance of future large-sample studies that permit detection of small effects.

Background Birth order effects have been linked to variability in intelligence, educational attainment and sexual orientation. First- and later-born children have been linked to an increased likelihood of an Autism Spectrum Disorder (ASD) diagnosis, with a smaller body of evidence implicating decreases in cognitive functioning with increased birth order. The present study investigated the potential association between birth order and ASD diagnostic phenotypes in a large and representative population sample. Methods Data were obtained from an ongoing prospective diagnostic registry, collected between 1999 and 2017, including children (1-18 years of age, n = 5,404) diagnosed with ASD in the state of Western Australia. Children with ASD were ranked relative to sibling's birth to establish birth order within families at time of ASD diagnosis. Information reported to the registry by health professionals at the time of diagnostic evaluation included demographic and family characteristics, functional abilities and intellectual capacity. Results Adaptive functioning and intelligence scores decreased with increasing birth order, with later-born children more likely to have an intellectual disability. Compared to first-born children with siblings, first-born children without siblings at the time of diagnosis also exhibited decreased cognitive functioning. Conclusions These findings demonstrate for the first time an association between increasing birth order and variability in ASD clinical phenotypes at diagnosis, with potential evidence of reproductive curtailment in children without siblings. Taken together, these findings have significant implications for advancing understanding about the potential mechanisms that contribute to heterogeneity in ASD clinical presentations as a function of birth order and family size.

The aim of this study was to understand the challenges experienced by families obtaining a diagnosis and therapy for developmental coordination disorder (DCD).Parents of 435 children aged 4-18 years with persistent motor difficulties consistent with a diagnosis of DCD completed an online survey. Diagnostic timeline and diagnostic label/s received were examined, along with therapies accessed.There was inconsistent diagnostic terminology (nine separate terms) with more children diagnosed with dyspraxia (64.7%) than DCD (48.8%). Even though most parents (87.0%) reported that receiving a diagnosis was helpful, children did not receive a diagnosis until years after seeking help (mean 2.8 ± 2.3 years). Many children were diagnosed with at least one co-occurring neurodevelopmental, language or learning disorder (70.0%). Almost all families had accessed therapy for their child's movement difficulties (93.9%), but more than half did not have access to funding to support therapy costs (57.8%) and reported that the costs caused financial strain (52.6%). Two out of every three families reported that they did not feel the current level of therapy was sufficient.This critical advocacy research highlights inconsistent and incorrect terminology and the challenges families experience in obtaining a diagnosis and adequate access to therapy for their child's movement difficulties.This is the first comprehensive study to examine the challenges families experience gaining a diagnosis and therapy for their child with DCD. Families regularly experienced prolonged diagnosis; 45% waited between 2 and 4 years. There is no clear diagnostic pathway, with children more likely to be diagnosed with dyspraxia than the correct clinical diagnosis of DCD. More extensive implementation of the diagnostic guidelines into clinical practice is needed.

Atypical facial morphology, particularly increased facial asymmetry, has been identified in some individuals with Autism Spectrum Conditions (ASC). Many cognitive, behavioural and biological features associated with ASC also occur on a continuum in the general population. The aim of the present study was to examine subthreshold levels of autistic traits and facial morphology in non-autistic individuals. Facial asymmetry was measured using three-dimensional facial photogrammetry, and the Autism-spectrum Quotient was used to measure autistic-like traits in a community-ascertained sample of young adults (n = 289). After accounting for covariates, there were no significant associations observed between autistic-like traits and facial asymmetry, suggesting that any potential facial morphology differences linked to ASC may be limited to the clinical condition.

Probiotics may be neuroprotective for preterm neonates due to their anti-inflammatory effects and ability to facilitate nutrition.To assess long-term effects of early probiotic supplementation on neuropsychological development in preterm infants.Follow up study.Children at age 3 to 5 years who had participated as preterm infants (33 week) in the randomised controlled trial.Primary: Continuous early learning composite measure derived from the Mullen's Scale of Early Learning (MSEL). Other outcomes were assessed by the Developmental, Dimensional and Diagnostic Interview, Developmental NEuroPSYchological assessment-2nd Edition, Parental questionnaires using children's communication checklist-2nd edition, social responsiveness scale, and Vineland Adaptive Behavioural Scales-2nd edition.Continuous scores derived from all the measures.67 children of the 159 participants (42%) (Probiotic: 36/79, Placebo: 31/80) were followed-up for at least one neuropsychological assessment. All six assessments were completed in 18/31 (58.1%) of the control vs. 11/36 (30.6%) probiotic group children. Multivariable analysis of MSEL composite score showed no evidence of probiotic effect univariately, or after adjustment for gestation, intrauterine growth restriction, Apgar7 at 5 min and age at assessment (adjusted mean effect in probiotic group: -2.7, 95% CI -8.5-3.0, p = 0.349).There was no significant effect on neurodevelopment of children assessed at the age of 3 to 5 years who participated as preterm neonates in the RCT of B. breve M-16V. The validity of these results is limited by the reduced sample size due to high rate of loss to follow up.

Links between temperament and social-emotional difficulties are well-established in normative child development but remain poorly characterized in autism. We sought to characterize distinct temperament subgroups and their associations with concurrent internalizing and externalizing symptoms in a sample of 103 infants (Mage = 12.39 months, SD = 1.97; 68% male) showing early signs of autism. Latent profile analysis was used to identify subgroups of infants with distinct temperament trait configurations on the Infant Behavior Questionnaire-Revised. Derived subgroups were then compared in terms of internalizing and externalizing symptoms on the Infant-Toddler Social and Emotional Assessment. Three distinct temperament subgroups were identified: (a) inhibited/low positive (n = 22), characterized by low Smiling and Laughter, low High-Intensity Pleasure, low Vocal Reactivity, and low Approach; (b) active/negative reactive (n = 23), characterized by high Activity Level, high Distress to Limitations, high Sadness, high Fear, and low Falling Reactivity; and (c) well-regulated (n = 51), characterized by high Cuddliness, high Soothability, and high Low-Intensity Pleasure. There were no differences in infant sex ratio, mean age or developmental/cognitive ability. Inhibited/low-positive infants had significantly more behavioral autism signs than active/negative reactive and well-regulated infants, who did not differ. Inhibited/low-positive and active/negative reactive infants had higher internalizing symptoms, relative to well-regulated infants, and active/negative reactive infants also had higher externalizing symptoms. These findings align closely with those garnered in the context of normative child development, and point to child temperament as a putative target for internalizing and externalizing interventions. LAY SUMMARY: This study explored whether infants with early signs of autism could be grouped according to temperament characteristics (i.e., emotional, behavioral, and attentional traits). Three subgroups were identified that differed with respect to emotional and behavioral difficulties. Specifically, "inhibited/low-positive" infants had high emotional difficulties, "active/negative reactive" infants had high emotional and behavioral difficulties, while "well-regulated" infants had the lowest difficulties.

This pilot research investigated the effects of a community-based organized football program on behavioral, social and communicative outcomes in children with Autism Spectrum Disorder. In a non-randomized design, 19 children completed the football program and were compared pre- and post-intervention with 21 children who received no comparable intervention (ages 5–12 years). Caregiver-report using the child behavior checklist indicated a significant decrease in total, internalizing, DSM-oriented anxiety and social problems for children who participated in the program, with no change in the comparison group. There were no group differences in socialization and communication scores on the Vineland Adaptive Behavior scale. Results provide preliminary evidence in support of the program, justifying the need for further, more rigorous trials in this area.

Recent evidence suggests the link between caregiver psychological distress and offspring social-emotional difficulties may be accounted for by offspring temperament characteristics. However, existing studies have only focused on neurotypical children; thus, the current study sought to provide an initial examination of this process among children with varying levels of early autism features. Participants included 103 infants aged 9-16 months (M = 12.39, SD = 1.97; 68% male) and their primary caregiver (96% mothers) referred to a larger study by community healthcare professionals. We utilized caregiver-reported measures of psychological distress (Depression Anxiety Stress Scales), infant temperament (Infant Behavior Questionnaire-Revised) and internalizing and externalizing symptoms (Infant-Toddler Social and Emotional Assessment) and administered the Autism Observation Schedule for Infants (AOSI) at an assessment visit to quantify autism features. Infant negative affectivity was found to mediate positive concurrent relations between caregiver psychological distress and infant internalizing and externalizing symptoms, irrespective of the infants' AOSI score. While preliminary and cross-sectional, these results replicate and extend previous findings suggesting that the pathway from caregiver psychological distress to negative affectivity to social-emotional difficulties might also be apparent among infants with varying levels of autism features. More rigorous tests of causal effects await future longitudinal investigation. LAY SUMMARY: Offspring of caregivers experiencing psychological distress (i.e., symptoms of depression, anxiety, and/or stress) may themselves be at increased risk of poor mental health outcomes. Several previous studies conducted with neurotypical children suggest that this link from caregiver-to-child may be facilitated by children's temperament qualities. This study was a preliminary cross-sectional exploration of these relationships in infants with features of autism. We found that infants' elevated negative emotions were involved in the relation between caregiver heightened psychological distress and children's mental health difficulties, consistent with neurotypical development. Autism Res 2020, 13: 1349-1357. © 2020 International Society for Autism Research, Wiley Periodicals, Inc.

Children with intellectual disability encounter daily challenges beyond those captured in current quality of life measures. This study evaluated a new parent-report measure for children with intellectual disability, the Quality of Life Inventory-Disability (QI-Disability). QI-Disability was administered to 253 primary caregivers of children (aged 5–18 years) with intellectual disability across four diagnostic groups: Rett syndrome, Down syndrome, cerebral palsy or autism spectrum disorder. Exploratory and confirmatory factor analyses were conducted and goodness of fit of the factor structure assessed. Associations between QI-Disability scores, and diagnostic and age groups were examined with linear regression. Six domains were identified: physical health, positive emotions, negative emotions, social interaction, leisure and the outdoors, and independence. Goodness-of-fit statistics were satisfactory and similar for the whole sample and when the sample was split by ability to walk or talk. On 100 point scales and compared to Rett syndrome, children with Down syndrome had higher leisure and the outdoors (coefficient 10.6, 95% CI 3.4,17.8) and independence (coefficient 29.7, 95% CI 22.9, 36.5) scores, whereas children with autism spectrum disorder had lower social interaction scores (coefficient − 12.8, 95% CI − 19.3, − 6.4). Scores for positive emotions (coefficient − 6.1, 95% CI − 10.7, − 1.6) and leisure and the outdoors (coefficient 5.4, 95% CI − 10.6, − 0.1) were lower for adolescents compared with children. Initial evaluation suggests that QI-Disability is a reliable and valid measure of quality of life across the spectrum of intellectual disability. It has the potential to allow clearer identification of support needs and measure responsiveness to interventions.

PurposeThe current study aimed to compare traditional logistic regression models with machine learning algorithms to investigate the predictive ability of (a) communication performance at 3 years old on language outcomes at 10 years old and (b) broader developmental skills (motor, social, and adaptive) at 3 years old on language outcomes at 10 years old.MethodParticipants (N= 1,322) were drawn from the Western Australian Pregnancy Cohort (Raine) Study (Straker et al., 2017). A general developmental screener, the Infant Monitoring Questionnaire (Squires, Bricker, & Potter, 1990), was completed by caregivers at the 3-year follow-up. Language ability at 10 years old was assessed using the Clinical Evaluation of Language Fundamentals–Third Edition (Semel, Wiig, & Secord, 1995). Logistic regression models and interpretable machine learning algorithms were used to assess predictive abilities of early developmental milestones for later language outcomes.ResultsOverall, the findings showed that prediction accuracies were comparable between logistic regression and machine learning models using communication-only performance as well as performance on communication and broader developmental domains to predict language performance at 10 years old. Decision trees are incorporated to visually present these findings but must be interpreted with caution because of the poor accuracy of the models overall.ConclusionsThe current study provides preliminary evidence that machine learning algorithms provide equivalent predictive accuracy to traditional methods. Furthermore, the inclusion of broader developmental skills did not improve predictive capability. Assessment of language at more than 1 time point is necessary to ensure children whose language delays emerge later are identified and supported.Supplemental Materialhttps://doi.org/10.23641/asha.6879719

BACKGROUND The neuropeptide and hormone oxytocin is known to have a significant impact on social cognition and behaviour in humans. There is growing concern regarding the influence of exogenous oxytocin (OT) administration in early life on later social and emotional development, including autism spectrum disorder (ASD). No study has examined offspring development in relation to the dose of exogenous oxytocin administered during labour. METHODS Between 1989 and 1992, 2,900 mothers were recruited prior to the 18th week of pregnancy, delivering 2,868 live offspring. The Child Behaviour Checklist was used to measure offspring behavioural difficulties at ages 5, 8, 10, 14 and 17 years. Autism spectrum disorder was formally diagnosed by consensus of a team of specialists. At 20 years, offspring completed a measure of autistic-like traits, the Autism Spectrum Quotient (AQ). Oxytocin exposure prior to birth was analysed using categorical and continuous approaches (maternal oxytocin dose) with univariate and multivariate statistical techniques. RESULTS Categorical analyses of oxytocin exposure prior to birth demonstrated no group differences in any measures of child behaviour. A small in magnitude dose-response association was observed for clinically significant total behaviour symptoms (adjusted odds ratio 1.03; 95% CI: 1.01-1.06, p

Background Autism spectrum disorders (ASDs) are complex, pervasive, and heterogeneous neurodevelopmental conditions with varying trajectories, significant male bias and largely unknown etiology. However, an understanding of the biological mechanisms driving pathophysiology is evolving. Immune system aberrations, as identified through cytokine profiles, are believed to have a role in ASD. Altered cytokine levels may facilitate identification of ASD subtypes as well as provide biological markers of response to effective treatments. Research exploring the relationship between cytokine profiles and ASD symptoms is, however, in its infancy. The objective of this study was to explore relationships between cytokine levels and the severity of ASD and other clinical traits. Methods Multiplex assay techniques were used to measure levels of 27 cytokines in plasma samples from a cohort of 144 children diagnosed with ASD. Results Overall, results showed a significant negative association between platelet-derived growth factor (PDGF)-BB, and the severity of ASD symptoms. Furthermore, a significant interaction with sex suggested a different immune profile for females compared to males. ASD symptom severity was negatively associated with levels of 4 cytokines, IL-1β, IL-8, MIP-1β, and VEGF, in females, but not in males. Conclusions Results of the present study suggest that an altered cytokine response or profile is associated with the severity of ASD-related symptoms, with sex a potential modifier of this relationship. Further research in larger populations which recognizes the importance of sex comparisons and longitudinal assessments are now required to extend and further describe the role of the immune system in ASD. Electronic supplementary material The online version of this article (10.1186/s13229-017-0176-2) contains supplementary material, which is available to authorized users.

Domains of quality of life in children with autism spectrum disorder have not previously been explored and there has been no quality of life measure developed for this population. Our study investigated parent observations to identify the domains important to children with autism spectrum disorder who also had an intellectual disability. In all, 21 parents (19 mothers, 2 fathers) of children with autism spectrum disorder (aged 6–17 years) participated in a qualitative study to discuss their child’s quality of life. Thematic analysis using a grounded theory framework was conducted and 10 domains emerged in relation to health and well-being, capacity to perform and develop skills in daily life, and connections with the community and environment. Unique aspects of quality of life included varying levels of social desire, consistency of routines, and time spent in nature and the outdoors, which are not comprehensively captured in existing measures. Parent observations provide an initial framework for understanding quality of life in autism spectrum disorder and support the development of a new measure for this population.

Background The anaesthetic dose causing neurotoxicity in animals has been evaluated, but the relationship between duration of volatile anaesthetic (VA) exposure and neurodevelopment in children remains unclear. Methods Data were obtained from the Western Australian Pregnancy Cohort (Raine) Study, with language (Clinical Evaluation of Language Fundamentals: Receptive [CELF-R] and Expressive [CELF-E] and Total [CELF-T]) and cognition (Coloured Progressive Matrices [CPM]) assessed at age 10 yr. Medical records were reviewed, and children divided into quartiles based on total VA exposure duration before age three yr. The association between test score and exposure duration quartile was evaluated using linear regression, adjusting for patient characteristics and comorbidity. Results Of 1622 children with available test scores, 148 had documented VA exposure and were split into the following quartiles: ≤25, >25 to ≤35, >35 to ≤60 and >60 min. Compared with unexposed children, CELF-T scores for children in the first and second quartiles did not differ, but those in the third and fourth quartiles had significantly lower scores ([3rd quartile – Unexposed] -5.3; 95% confidence interval [CI], (-10.2 – -0.4), [4th quartile – Unexposed] -6.2; 95% CI, (-11.6 – -0.9). CELF-E showed similar findings, but significant differences were not found in CELF-R or CPM for any quartile. Conclusions Children with VA exposures ≤35 min did not differ from unexposed children, but those with exposures >35 min had lower total and expressive language scores. It remains unclear if this is a dose-response relationship, or if children requiring longer exposures for longer surgeries have other clinical reasons for lower scores.

Background Although it is estimated that half of all children with cerebral palsy also have comorbid intellectual disability, the domains of quality of life (QOL) important for these children are not well understood. The aim of this study was to identify important domains of QOL for these children and adolescents. Methods Due to the children's communication impairments, qualitative semi-structured interviews were conducted with 18 parents. The children (9 males) had a median age of 12 (range 7 to 17) years at interview and nearly two thirds were classified as Gross Motor Function Classification System IV or V. A grounded theory approach was used to identify domains of QOL. Results The 11 domains identified as important to QOL were physical health, body comfort, behaviour and emotion, communication, predictability and routine, movement and physical activity, nature and outdoors, variety of activity, independence and autonomy, social connectedness, and access to services. Conclusions The domains of QOL that emerged from this study will be useful for professionals who support children with cerebral palsy and their families. They will also be important for developing a QOL instrument essential for informing the development of interventions and their monitoring and evaluation.

Summary Background In blinded randomised controlled trials, statin therapy has been associated with few adverse events (AEs). By contrast, in observational studies, larger increases in many different AEs have been reported than in blinded trials. Methods In the Lipid-Lowering Arm of the Anglo-Scandinavian Cardiac Outcomes Trial, patients aged 40–79 years with hypertension, at least three other cardiovascular risk factors, and fasting total cholesterol concentrations of 6·5 mmol/L or lower, and who were not taking a statin or fibrate, had no history of myocardial infarction, and were not being treated for angina were randomly assigned to atorvastatin 10 mg daily or matching placebo in a randomised double-blind placebo-controlled phase. In a subsequent non-randomised non-blind extension phase (initiated because of early termination of the trial because efficacy of atorvastatin was shown), all patients were offered atorvastatin 10 mg daily open label. We classified AEs using the Medical Dictionary for Regulatory Activities. We blindly adjudicated all reports of four prespecified AEs of interest—muscle-related, erectile dysfunction, sleep disturbance, and cognitive impairment—and analysed all remaining AEs grouped by system organ class. Rates of AEs are given as percentages per annum. Results The blinded randomised phase was done between February, 1998, and December, 2002; we included 101 80 patients in this analysis (5101 [50%] in the atorvastatin group and 5079 [50%] in the placebo group), with a median follow-up of 3·3 years (IQR 2·7–3·7). The non-blinded non-randomised phase was done between December, 2002, and June, 2005; we included 9899 patients in this analysis (6409 [65%] atorvastatin users and 3490 [35%] non-users), with a median follow-up of 2·3 years (2·2–2·4). During the blinded phase, muscle-related AEs (298 [2·03% per annum] vs 283 [2·00% per annum]; hazard ratio 1·03 [95% CI 0·88–1·21]; p=0·72) and erectile dysfunction (272 [1·86% per annum] vs 302 [2·14% per annum]; 0·88 [0·75–1·04]; p=0·13) were reported at a similar rate by participants randomly assigned to atorvastatin or placebo. The rate of reports of sleep disturbance was significantly lower among participants assigned atorvastatin than assigned placebo (149 [1·00% per annum] vs 210 [1·46% per annum]; 0·69 [0·56–0·85]; p=0·0005). Too few cases of cognitive impairment were reported for a statistically reliable analysis (31 [0·20% per annum] vs 32 [0·22% per annum]; 0·94 [0·57–1·54]; p=0·81). We observed no significant differences in the rates of all other reported AEs, with the exception of an excess of renal and urinary AEs among patients assigned atorvastatin (481 [1·87%] per annum vs 392 [1·51%] per annum; 1·23 [1·08–1·41]; p=0·002). By contrast, during the non-blinded non-randomised phase, muscle-related AEs were reported at a significantly higher rate by participants taking statins than by those who were not (161 [1·26% per annum] vs 124 [1·00% per annum]; 1·41 [1·10–1·79]; p=0·006). We noted no significant differences between statin users and non-users in the rates of other AEs, with the exception of musculoskeletal and connective tissue disorders (992 [8·69% per annum] vs 831 [7·45% per annum]; 1·17 [1·06–1·29]; p=0·001) and blood and lymphatic system disorders (114 [0·88% per annum] vs 80 [0·64% per annum]; 1·40 [1·04–1·88]; p=0·03), which were reported more commonly by statin users than by non-users. Interpretation These analyses illustrate the so-called nocebo effect, with an excess rate of muscle-related AE reports only when patients and their doctors were aware that statin therapy was being used and not when its use was blinded. These results will help assure both physicians and patients that most AEs associated with statins are not causally related to use of the drug and should help counter the adverse effect on public health of exaggerated claims about statin-related side-effects. Funding Pfizer, Servier Research Group, and Leo Laboratories.

Purpose: The aim of the current study was to investigate the risk factors present at 2 years for children who showed language difficulties that persisted from 2 to 10 years and difficulties that emerged later, at 10 years. Method: Participants (n = 783) were drawn from the Raine Study in Western Australia. Patterns of change from 2 to 10 years were identified based on child performance on the Language Development Survey and the Clinical Evaluation of Language Fundamentals, respectively. Logistic regression analyses were conducted to test whether parental, family and child characteristics present at 2 years predicted poorer language outcomes at age 10. Result: Across the 8 year period, 5.6% of the children displayed consistently low language skills, 5.9% improved skills and 23.2% deteriorated skills. Compared to children with consistently typical skills, the deteriorated group was more likely to have mothers who smoked during pregnancy, fathers with incomplete secondary education, low family income, poor early literacy environment and be male. Children showing consistently low language skills were more likely to have mothers who smoked during pregnancy than late talkers whose early delays improved. Conclusion: Results provide evidence of some modifiable risk factors at 2 years which are associated with language outcome.

There is preliminary evidence that infant siblings of children with Autism Spectrum Disorder (ASD) have an atypical pattern of cry, characterized by higher fundamental frequency and increased dysphonation. This prospective study collected multiple cry samples of 12-month old siblings of children with ASD (n = 22, 'high-risk' group) and 12-month olds with no family history of ASD (n = 27, 'low risk' group). While there was no difference between groups in the fundamental frequency or degree of phonation of the cry samples, the duration of each cry unit was significantly shorter in the high-risk siblings (p

Objective Restricted and repetitive pattern of behaviours and interests (RRB) are a cardinal feature of autism spectrum disorder (ASD), but there remains uncertainty about how these diverse behaviours vary according to individual characteristics. This study provided the largest exploration to date of the relationship between Repetitive Motor Behaviours, Rigidity/Insistence on Sameness and Circumscribed Interests with other individual characteristics in newly diagnosed individuals with ASD. Method Participants (N = 3,647; 17.7% females; Mage = 6.6 years [SD = 4.7]) were part of the Western Australian (WA) Register for ASD, an independent, prospective collection of demographic and diagnostic data of newly diagnosed cases of ASD in WA. Diagnosticians rated each of the DSM‐IV‐TR criteria on a 4‐point Likert severity scale, and here we focused on the Repetitive Motor Behaviours, Insistence on Sameness and Circumscribed Interests symptoms. Results The associations between RRB domains, indexed by Kendall's Tau, were weak, ranging from non‐significant for both Circumscribed Interests and Repetitive Motor Behaviours to significant (.20) for Insistence on Sameness and Repetitive Motor Behaviours. Older age at diagnosis was significantly associated with lower Circumscribed Interests and significantly associated with higher Insistence on Sameness and Repetitive Motor Behaviours. Male sex was significantly associated with higher Repetitive Motor Behaviours but not Insistence on Sameness or Circumscribed Interests. Conclusions The pattern of associations identified in this study provides suggestive evidence for the distinctiveness of Repetitive Motor Behaviours, Insistence on Sameness and Circumscribed Interests, highlighting the potential utility of RRB domains for stratifying the larger ASD population into smaller, more phenotypically homogeneous subgroups that can help to facilitate efforts to understand diverse ASD aetiology and inform design of future interventions.

A key research priority in the study of autism spectrum conditions (ASC) is the discovery of biological markers that may help to identify and elucidate etiologically distinct subgroups. One physical marker that has received increasing research attention is facial structure. Although there remains little consensus in the field, findings relating to greater facial asymmetry (FA) in ASC exhibit some consistency. As there is growing recognition of the importance of replicatory studies in ASC research, the aim of this study was to investigate the replicability of increased FA in autistic children compared to nonautistic peers. Using three-dimensional photogrammetry, this study examined FA in 84 autistic children, 110 typically developing children with no family history of the condition, and 49 full siblings of autistic children. In support of previous literature, significantly greater depth-wise FA was identified in autistic children relative to the two comparison groups. As a further investigation, increased lateral FA in autistic children was found to be associated with greater severity of ASC symptoms on the Autism Diagnostic Observation Schedule, second edition, specifically related to repetitive and restrictive behaviors. These outcomes provide an important and independent replication of increased FA in ASC, as well as a novel contribution to the field. Having confirmed the direction and areas of increased FA in ASC, these findings could motivate a search for potential underlying brain dysmorphogenesis. Autism Res 2019, 12: 1774-1783. © 2019 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: This study looked at the amount of facial asymmetry (FA) in autistic children compared to typically developing children and children who have siblings with autism. The study found that autistic children, compared to the other two groups, had greater FA, and that increased FA was related to greater severity of autistic symptoms. The face and brain grow together during the earliest stages of development, and so findings of facial differences in autism might inform future studies of early brain differences associated with the condition.

Weight status on children and youth with autism spectrum disorder is limited. We examined the prevalence of overweight/obesity in children and youth with autism spectrum disorder, and associations between weight status and range of factors. Children and youth with autism spectrum disorder aged 2–16 years ( n = 208) and their parents participated in this study. Body mass index was calculated using the Centers for Disease Control and Prevention growth charts and the International Obesity Task Force body mass index cut-offs. The Autism Diagnostic Observation Schedule was administered. Parents completed questionnaires about socio-demographics, diagnosed comorbidities, sleep disturbances, social functioning and medication of youth with autism spectrum disorder. The prevalence of overweight/obesity in participants with autism spectrum disorder was 35%. One quarter of obese children and youth (25.6%) had obese parents. There was a significant association between children and youth’s body mass index and maternal body mass index ( r = 0.25, n = 199, p

Autism spectrum disorder (ASD) and intellectual disability (ID) are neurodevelopmental disorders with strong genetic components. Increasingly, research attention has focused on whether genetic factors conveying susceptibility for these conditions, also influence the risk of other health conditions, such as cancer. We examined the occurrence of hospital admissions and treatment/services for cancer in mothers of children with ASD with or without ID compared with other mothers. After linking Western Australian administrative health databases, we used Cox regression to estimate the hazard ratios (HRs) of any hospitalisations and treatment/services for cancer in these groups of mothers. Mothers of children with ASD without ID had greater risk of admissions for cancer (HR 1.29 [95 % CI 1.1, 1.7]), and for treatment/services in particular (HR 1.41 [95 % CI 1.0, 2.0]), than mothers of children with no ASD/ID, while mothers of children with ASD with ID were no more likely to have a cancer-related hospital admission than other mothers. Mothers of children with autism without ID had increased risk of cancer, which may relate to common genetic pathways.

Individual differences in aggressive behavior emerge in early childhood and predict persisting behavioral problems and disorders. Studies of antisocial and severe aggression in adulthood indicate substantial underlying biology. However, little attention has been given to genome-wide approaches of aggressive behavior in children. We analyzed data from nine population-based studies and assessed aggressive behavior using well-validated parent-reported questionnaires. This is the largest sample exploring children's aggressive behavior to date (N = 18,988), with measures in two developmental stages (N = 15,668 early childhood and N = 16,311 middle childhood/early adolescence). First, we estimated the additive genetic variance of children's aggressive behavior based on genome-wide SNP information, using genome-wide complex trait analysis (GCTA). Second, genetic associations within each study were assessed using a quasi-Poisson regression approach, capturing the highly right-skewed distribution of aggressive behavior. Third, we performed meta-analyses of genome-wide associations for both the total age-mixed sample and the two developmental stages. Finally, we performed a gene-based test using the summary statistics of the total sample. GCTA quantified variance tagged by common SNPs (10-54%). The meta-analysis of the total sample identified one region in chromosome 2 (2p12) at near genome-wide significance (top SNP rs11126630, P = 5.30 x 10(-8)). The separate meta-analyses of the two developmental stages revealed suggestive evidence of association at the same locus. The gene-based analysis indicated association of variation within AVPR1A with aggressive behavior. We conclude that common variants at 2p12 show suggestive evidence for association with childhood aggression. Replication of these initial findings is needed, and further studies should clarify its biological meaning. (C) 2015 Wiley Periodicals, Inc.

Objective We examined the academic performance at age 12 years of children of mothers diagnosed with schizophrenia or other severe mental illness using a large whole-population birth cohort born in Western Australia. We investigated the association between academic performance and the subsequent development of psychotic illness. Method The sample comprised 3169 children of mothers with severe mental illness (schizophrenia, bipolar disorder, unipolar major depression, delusional disorder or other psychoses; ICD-9 codes 295–298), and 88 353 children of comparison mothers without known psychiatric morbidity. Academic performance of children was indexed on a mandatory state-wide test of reading, spelling, writing and numeracy. Results A larger proportion of children (43.1%) of mothers with severe mental illness performed below the acceptable standard than the reference group (30.3%; children of mothers with no known severe mental illness). After adjusting for covariates, children of mothers with any severe mental illness were more likely than the reference group to perform below-benchmark on all domains except reading. For all children, poor spelling was associated with the later development of psychosis, but particularly for those at familial risk for severe mental illness (hazard ratio [HR] = 1.81; 95% CI for HR = 1.21, 2.72). Conclusions Children of mothers with a severe mental illness are at increased risk for sub-standard academic achievement at age 12 years, placing these children at disadvantage for the transition to secondary school. For children with familial risk for severe mental illness, very poor spelling skills at age 12 years may be an indicator of risk for later psychotic disorder.

Rett syndrome is a neurodevelopmental disorder mainly affecting females and associated with a mutation on the MECP2 gene. There has been no systematic evaluation of the domains of quality of life (QOL) in Rett syndrome. The aims of this study were to explore QOL in school-aged children with Rett syndrome and compare domains with those identified in other available QOL scales. The sample comprised 21 families registered with the Australian Rett Syndrome Database whose daughter with Rett syndrome was aged 6-18 years. Semi-structured telephone interviews were conducted with each parent caregiver (19 mothers, 2 fathers) to investigate aspects of their daughter's life that were satisfying or challenging to her. Qualitative thematic analysis using a grounded theory framework was conducted, and emerging domains compared with those in two generic and three disability parent-report child QOL measures. Ten domains were identified: physical health, body pain, and discomfort, behavioral and emotional well-being, communication skills, movement and mobility, social connectedness, variety of activities, provision of targeted services, stability of daily routines, and the natural environment. The two latter domains were newly identified and each domain contained elements not represented in the comparison measures. Our data articulated important aspects of life beyond the genetic diagnosis. Existing QOL scales for children in the general population or with other disabilities did not capture the QOL of children with Rett syndrome. Our findings support the construction of a new parent-report measure to enable measurement of QOL in this group.

Summary Background In patients with hypertension, the long-term cardiovascular and all-cause mortality effects of different blood pressure-lowering regimens and lipid-lowering treatment are not well documented, particularly in clinical trial settings. The Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT) Legacy Study reports mortality outcomes after 16 years of follow-up of the UK participants in the original ASCOT trial. Methods ASCOT was a multicentre randomised trial with a 2 × 2 factorial design. UK-based patients with hypertension were followed up for all-cause and cardiovascular mortality for a median of 15·7 years (IQR 9·7–16·4 years). At baseline, all patients enrolled into the blood pressure-lowering arm (BPLA) of ASCOT were randomly assigned to receive either amlodipine-based or atenolol-based blood pressure-lowering treatment. Of these patients, those who had total cholesterol of 6·5 mmol/L or lower and no previous lipid-lowering treatment underwent further randomisation to receive either atorvastatin or placebo as part of the lipid-lowering arm (LLA) of ASCOT. The remaining patients formed the non-LLA group. A team of two physicians independently adjudicated all causes of death. Findings Of 8580 UK-based patients in ASCOT, 3282 (38·3%) died, including 1640 (38·4%) of 4275 assigned to atenolol-based treatment and 1642 (38·1%) of 4305 assigned to amlodipine-based treatment. 1768 of the 4605 patients in the LLA died, including 903 (39·5%) of 2288 assigned placebo and 865 (37·3%) of 2317 assigned atorvastatin. Of all deaths, 1210 (36·9%) were from cardiovascular-related causes. Among patients in the BPLA, there was no overall difference in cardiovascular mortality between treatments (adjusted hazard ratio [HR] 0·90, 95% CI 0·81–1·01, p=0·0776]), although significantly fewer deaths from stroke (adjusted HR 0·71, 0·53–0·97, p=0·0305) occurred in the amlodipine-based treatment group than in the atenolol-based treatment group. There was no interaction between treatment allocation in the BPLA and in the LLA. However, in the 3975 patients in the non-LLA group, there were fewer cardiovascular deaths (adjusted HR 0·79, 0·67–0·93, p=0·0046) among those assigned to amlodipine-based treatment compared with atenolol-based treatment (p=0·022 for the test for interaction between the two blood pressure treatments and allocation to LLA or not). In the LLA, significantly fewer cardiovascular deaths (HR 0·85, 0·72–0·99, p=0·0395) occurred among patients assigned to statin than among those assigned placebo. Interpretation Our findings show the long-term beneficial effects on mortality of antihypertensive treatment with a calcium channel blocker-based treatment regimen and lipid-lowering with a statin: patients on amlodipine-based treatment had fewer stroke deaths and patients on atorvastatin had fewer cardiovascular deaths more than 10 years after trial closure. Overall, the ASCOT Legacy study supports the notion that interventions for blood pressure and cholesterol are associated with long-term benefits on cardiovascular outcomes. Funding Pfizer.

Background Nausea and vomiting during pregnancy (NVP) is thought to be caused by changes in maternal hormones during pregnancy. Differences in hormone exposure during prenatal life have been implicated in the causal pathways for some cases of autism spectrum disorder (ASD). However, no study has investigated whether the presence and severity of NVP may be related to symptom severity in offspring with ASD. Methods A large sample of children with ASD (227 males and 60 females, aged 2 to 18 years) received a clinical assessment, during which parents completed questionnaires regarding their child’s social (Social Responsiveness Scale, SRS) and communication (Children’s Communication Checklist–2nd edition, CCC-2) symptoms. Parents also reported on a 5-point scale the frequency and severity of NVPs during the pregnancy of the child being assessed: (1) no NVP during the pregnancy, (2) occasional nausea, but no vomiting, (3) daily nausea, but no vomiting, (4) occasional vomiting, with or without nausea, and (5) daily nausea and vomiting. Results Impairments in social responsiveness in offspring, as indexed by SRS total score, significantly increased as a function of the frequency and severity of their mothers’ NVP, as did the level of language difficulties as indexed by the Global Communication Composite of the CCC-2. Conclusions The strong, positive association between increasing frequency and severity of NVP and ASD severity in offspring provides further evidence that exposure to an atypical hormonal environment during prenatal life may affect neurodevelopment and contribute to the ASD phenotype. Given that the measure of NVP symptoms in the current study was based on retrospective recall, replication of this finding is required before strong conclusions can be drawn. Electronic supplementary material The online version of this article (10.1186/s13229-018-0223-7) contains supplementary material, which is available to authorized users.