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Background Sex-based neurobiological heterogeneity in autism is poorly understood. Research is disproportionately biased to males, leading to an unwarranted presumption that autism neurobiology is the same across sexes. Previous neuroimaging studies using amalgamated multicenter datasets to increase autistic female samples are characterized by large statistical noise. Methods We used a better-powered dataset of 1183 scans of 839 individuals—299 (467 scans) autistic males, 74 (102 scans) autistic females, 240 (334 scans) control males, and 226 (280 scans) control females—to test two whole-brain models of overall/global sex modulations on autism neuroanatomy, by summary measures computed across the brain: the local magnitude model, in which the same brain regions/circuitries are involved across sexes but effect sizes are larger in females, indicating quantitative sex modulation; and spatial dissimilarity model, in which the neuroanatomy differs spatially between sexes, indicating qualitative sex modulation. The male and female autism groups were matched on age, IQ, and autism symptoms. Autism brain features were defined by comparisons with same-sex control individuals. Results Across five metrics (cortical thickness, surface area, volume, mean absolute curvature, and subcortical volume), we found no evidence supporting the local magnitude model. We found indicators supporting the spatial dissimilarity model on cortical mean absolute curvature and subcortical volume, but not on other metrics. Conclusions The overall/global autism neuroanatomy in females and males does not simply differ quantitatively in the same brain regions/circuitries. They may differ qualitatively in spatial involvement in cortical curvature and subcortical volume. The neuroanatomy of autism may be partly sex specific. Sex stratification to inform autism preclinical/clinical research is needed to identify sex-informed neurodevelopmental targets.

Background Executive functioning (EF) varies in children with autism spectrum disorder (ASD) and is associated with clinical symptoms, academic, and adaptive functioning. Here, we examined whether middle-childhood EF mediates associations between early-childhood autism symptoms and adolescent outcomes in children with ASD. Methods The Pathways in ASD Cohort comprising children recruited at the time of ASD diagnosis (at 2-4 years-of-age) and followed prospectively across eight subsequent timepoints over ˜10 years was used. A subset of Pathways participants (n = 250) with Behavior Rating Inventory of Executive Function (BRIEF)-Parent Form data from at least one timepoint when participants were school-aged was analyzed. A mediation framework was used to examine whether BRIEF-measured EF across age 7-10 years (middle-childhood) mediated associations between early-childhood autism symptoms (measured using the parent-report Social Responsiveness Scale across age 2-6 years) and clinical, academic, and functional outcomes, indexed at age >10-11.8 years (early-adolescence) using the Child Behavior Checklist (CBCL)-Internalizing and Externalizing Scales, Academic Performance from the Teacher's Report Form, and Vineland Adaptive Behavior Scales. Models were rerun substituting clinician-rated and teacher-rated measures, where possible. Results Mediation models indicated a significant indirect effect of middle-childhood EF on associations between early-childhood autism symptoms and externalizing behavior, academic performance, or adaptive functioning in early adolescence; kappa squared (κ2 ) effect sizes ranged from large to small. Model findings were stable across raters. Middle-childhood EF did not mediate associations between early-childhood autism symptoms and adolescent internalizing behavior. Conclusions Among children with an ASD diagnosis, middle-childhood EF may be one pathway through which early-childhood autism symptoms influence a variety of outcomes in early-adolescence. An experimental study targeting middle-childhood EF to improve adolescent academic, emotional/behavioral, and adaptive functioning is needed to evaluate the clinical meaningfulness of these findings.

Background Although early autism spectrum disorder (ASD) detection strategies tend to focus on differences at a point in time, behavioral symptom trajectories may also be informative. Methods Developmental trajectories of early signs of ASD were examined in younger siblings of children diagnosed with ASD (n = 499) and infants with no family history of ASD (n = 177). Participants were assessed using the Autism Observation Scale for Infants (AOSI) from 6 to 18 months. Diagnostic outcomes were determined at age 3 years blind to previous assessments. Results Semiparametric group-based modeling using AOSI scores identified three distinct trajectories: Group 1 ('Low', n = 435, 64.3%) was characterized by a low level and stable evolution of ASD signs, group 2 ('Intermediate', n = 180, 26.6%) had intermediate and stable levels, and group 3 ('Inclining', n = 61, 9.3%) had higher and progressively elevated levels of ASD signs. Among younger siblings, ASD rates at age 3 varied by trajectory of early signs and were highest in the Inclining group, membership in which was highly specific (94.5%) but poorly sensitive (28.5%) to ASD. Children with ASD assigned to the inclining trajectory had more severe symptoms at age 3, but developmental and adaptive functioning did not differ by trajectory membership. Conclusions These prospective data emphasize variable early-onset patterns and the importance of a multipronged approach to early surveillance and screening for ASD.

This study examined the trajectories of autistic symptom severity in an inception cohort of 187 children with ASD assessed across four time points from diagnosis to age 10. Trajectory groups were derived using multivariate cluster analysis. A two trajectory/cluster solution was selected. Change in trajectory slopes revealed a turning point marked by plateauing in symptom reduction during the period of transition to school (age 6) for one of the two trajectories. Trajectories were labelled: Continuously Improving (27%) and Improving then Plateauing (73% of sample). Children in the two trajectories differed in levels of symptom severity, language, cognitive, and adaptive functioning skills. Study findings can inform the development of more personalized services for children with ASD transitioning into the school system. Supplementary Information The online version of this article (10.1007/s10803-021-04949-2) contains supplementary material, which is available to authorized users.

This study examined parental perceptions of the character traits of children with autism from early childhood to age 11. Parents (n = 153) provided descriptions of the "best things" about their children on the Child Behavior Checklist (CBCL) at ages 3-4, 7-8, and 10-11 years. Descriptions were coded using the framework of the Values in Action Classification of Strengths, with additional traits added as needed. Parent-endorsed traits included love, kindness, happiness, and humor in children across all ages and traits such as perseverance as children entered school. Higher CBCL scores were associated with a lower likelihood of endorsement for Humanity traits. Results are congruent with a contemporary neurodiversity perspective that emphasizes strengths and resilience.

Many neurodevelopmental disorders (NDDs) share common learning and behavioural impairments, as well as features such as dysregulation of the oxytocin hormone. Here, we examined DNA methylation (DNAm) in the 1st intron of the oxytocin receptor gene, OXTR, in patients with autism spectrum (ASD), attention deficit and hyperactivity (ADHD) and obsessive compulsive (OCD) disorders. DNAm of OXTR was assessed for cohorts of ASD (blood), ADHD (saliva), OCD (saliva), which uncovered sex-specific DNAm differences compared to neurotypical, tissue-matched controls. Individuals with ASD or ADHD exhibiting extreme DNAm values had lower IQ and more social problems, respectively, than those with DNAm within normative ranges. This suggests that OXTR DNAm patterns are altered across NDDs and may be correlated with common clinical outcomes.

The objectives were to characterize behavioral signs of autism spectrum disorder (ASD) in younger siblings of diagnosed children (high-risk; HR) and examine classification features of the Autism Observation Scale for Infants (AOSI). Participants (501 HR and 180 low-risk [LR]) were assessed between 6 and 18 months using the AOSI and at age 3 for ASD diagnoses. Total AOSI scores differentiated HR infants later diagnosed with ASD starting at 12 months. ROC analyses identified 12- and 18-month cutoff scores associated with 0.52 sensitivity and 0.74 specificity and 0.73 sensitivity and 0.65 specificity, respectively. Although classification accuracy does not support use as a standalone screen, the AOSI identifies features associated with ASD starting at 6 months and differentiates HR infants with ASD by 12 months.

Aim To examine mental health in conjunction with physical health during the COVID‐19 pandemic among youth with physical health conditions compared to those without. Methods A cross‐sectional survey of 622 youth aged 14 to 28 was conducted. Analyses were conducted to understand the changes in mental and physical health among youth in four groups: (a) participants with a friend or family member diagnosed with COVID‐19, (b) participants with symptoms associated with COVID‐19, (c) participants with atopic conditions (asthma and allergies), and (d) participants with other preexisting physical health conditions. Results Many participants with physical health concerns met screening criteria for an internalizing disorder, which was significantly higher than the rate found among participants without physical health conditions. Significantly greater declines in self‐reported mental health were observed during the COVID‐19 period compared to 3 months earlier among youth reporting physical health concerns compared to those without physical health concerns. Substance use does not appear to have been affected. Conclusions Mental health concerns are highly prevalent among youth with physical health concerns, and also appear to be exacerbated by the COVID‐19 pandemic. Physical health concerns appear to constitute risk factors for heightened mental health responses to the pandemic situation. System planners striving to adapt mental health services to meet social/physical distancing recommendations are urged to consider youth with physical health conditions and ensure that adequate integrated mental health and physical health supports are available to them.

Objectives The objective of this review was to identify outcomes reported in adolescent major depressive disorder trials and quantify outcome heterogeneity. Study Design and Setting Three databases were searched to identify trials evaluating therapies for major depressive disorder in adolescents published from 2008 to 2017. Identified outcomes were thematically grouped and mapped into predefined outcome core areas (physiological/clinical, life impact, resource use, adverse events, and death). Outcome heterogeneity was quantified using descriptive analyses. Results Of 2,686 articles yielded from the search, 42 articles describing 32 trials were included. A total of 434 outcomes measured using 118 different outcome measurement instruments were grouped into 86 unique outcome terms. Most outcome terms mapped to the physiological/clinical core area (62%), followed by the life impact (27%). Nearly half (45%) were reported in only a single trial each. Of 18 primary outcomes reported, 13 (72%) were each only reported in a single trial. “Depressive symptom severity”, reported in 30 trials (94%), was measured using 19 different outcome measurement instruments. Conclusion Heterogeneity exists in the outcomes and outcome measurement instruments used in adolescent depression trials. To enable reproducibility, comparison, and synthesis of trial results, a standard set of agreed-on outcomes and methods of measurement is needed.

Understanding differences in social-emotional behavior can help identify atypical development. This study examined the differences in social-emotional development in children at increased risk of an autism spectrum disorder (ASD) diagnosis (infant siblings of children diagnosed with the disorder). Parents completed the Brief Infant-Toddler Social-Emotional Assessment (BITSEA) to determine its ability to flag children with later-diagnosed ASD in a high-risk (HR) sibling population. Parents of HR (n= 311) and low-risk (LR; no family history of ASD;n= 127) children completed the BITSEA when their children were 18 months old and all children underwent a diagnostic assessment for ASD at age 3 years. All six subscales of the BITSEA (Problems, Competence, ASD Problems, ASD Competence, Total ASD Score, and Red Flags) distinguished between those in the HR group who were diagnosed with ASD (n= 84) compared to non-ASD-diagnosed children (both HR-N and LR). One subscale (BITSEA Competence) differentiated between the HR children not diagnosed with ASD and the LR group. The results suggest that tracking early social-emotional development may have implications for all HR children, as they are at increased risk of ASD but also other developmental or mental health conditions.

Temperament is a construct that is relatively stable over time but varies between individuals. Research suggests that children with autism spectrum disorder have a ‘reactive’ temperament profile when compared to peers with or without disabilities. However, our understanding of how temperament varies within children with autism and how it relates to child symptoms and outcomes is limited. This study aimed to (a) explore the variation of individual temperament traits within a sample of school-aged children with autism to determine whether subgroups of children with similar trait profiles emerge and (b) examine whether temperament influences the relationship between autism symptoms and adaptive functioning outcomes. Results revealed that children with autism can be classified empirically into two distinct profiles – ‘Even’ and ‘Reactive’ temperaments. Correlational and hierarchical regression analyses indicated that both temperament profiles and baseline symptom severity predicted adaptive functioning outcomes 1 year later. There was a significant interaction between temperament and symptom severity, suggesting temperament can influence the impact of increasing symptom severity on adaptive functioning skills in children with autism. Study findings highlight the importance of considering temperament in understanding the individual differences that influence the development of daily functioning and developmental outcomes in children with autism. Lay Abstract Temperament is often thought of as behavioural traits that are relatively stable over time but can vary between individuals. Children diagnosed with autism spectrum disorder are often characterized as having ‘reactive’ and ‘negative’ temperaments when compared to same-aged peers with or without disabilities, which can negatively impact the development of adaptive functioning skills but little is known about variations of temperament between individual children diagnosed with autism spectrum disorder. This study aimed to (a) explore the variation of individual temperament traits within a sample of school-aged children with autism spectrum disorder to determine whether subgroups with similar trait profiles emerge and (b) examine whether temperament influences the relationship between autism symptoms and adaptive functioning outcomes. Results from our dataset suggest that children diagnosed with autism spectrum disorder fit under two profiles: ‘even’ and ‘reactive’. Furthermore, our analysis shows that temperament can influence the impact of increasing symptom severity on adaptive functioning skills in children with autism spectrum disorder. Study findings highlight the importance of considering temperament when trying to understand the individual differences that influence the development of functioning and developmental outcomes in children with autism spectrum disorder.

The new coronavirus disease (COVID-19) pandemic is changing how society operates. Environmental changes, disrupted routines, and reduced access to services and social networks will have a unique impact on autistic individuals and their families and will contribute to significant deterioration in some. Access to support is crucial to address vulnerability factors, guide adjustments in home environments, and apply mitigation strategies to improve coping. The current crisis highlights that our regular care systems are not sufficient to meet the needs of the autism communities. In many parts of the world, people have shifted to online school and increased use of remote delivery of healthcare and autism supports. Access to these services needs to be increased to mitigate the negative impact of COVID-19 and future epidemics/pandemics. The rapid expansion in the use of telehealth platforms can have a positive impact on both care and research. It can help to address key priorities for the autism communities including long waitlists for assessment and care, access to services in remote locations, and restricted hours of service. However, system-level changes are urgently needed to ensure equitable access and flexible care models, especially for families and individuals who are socioeconomically disadvantaged. COVID-19 mandates the use of technology to support a broader range of care options and better meet the diverse needs of autistic people and their families. It behooves us to use this crisis as an opportunity to foster resilience not only for a given individual or their family, but also the system: to drive enduring and autism-friendly changes in healthcare, social systems, and the broader socio-ecological contexts.

BackgroundEvidence-based health care is informed by results of randomized clinical trials (RCTs) and their syntheses in meta-analyses. When the trial outcomes measured are not clearly described in trial publications, knowledge synthesis, translation, and decision-making may be impeded. While heterogeneity in outcomes measured in adolescent major depressive disorder (MDD) RCTs has been described, the comprehensiveness of outcome reporting is unknown. This study aimed to assess the reporting of primary outcomes in RCTs evaluating treatments for adolescent MDD.MethodsRCTs evaluating treatment interventions in adolescents with a diagnosis of MDD published between 2008 and 2017 specifying a single primary outcome were eligible for outcome reporting assessment. Outcome reporting assessment was done independently in duplicate using a comprehensive checklist of 58 reporting items. Primary outcome information provided in each RCT publication was scored as “fully reported”, “partially reported”, or “not reported” for each checklist item, as applicable.ResultsEighteen of 42 identified articles were found to have a discernable single primary outcome and were included for outcome reporting assessment. Most trials (72%) did not fully report on over half of the 58 checklist items. Items describing masking of outcome assessors, timing and frequency of outcome assessment, and outcome analyses were fully reported in over 70% of trials. Items less frequently reported included outcome measurement instrument properties (ranging from 6 to 17%), justification of timing and frequency of outcome assessment (6%), and justification of criteria used for clinically significant differences (17%). The overall comprehensiveness of reporting appeared stable over time.ConclusionsHeterogeneous reporting exists in published adolescent MDD RCTs, with frequent omissions of key details about their primary outcomes. These omissions may impair interpretability, replicability, and synthesis of RCTs that inform clinical guidelines and decision-making in this field. Consensus on the minimal criteria for outcome reporting in adolescent MDD RCTs is needed.

Background In youth and young adults with autism spectrum disorder (ASD), executive function (EF) deficits may be a promising treatment target with potential impact on everyday functioning. Objective To conduct a pilot randomized, double-blind, parallel, controlled trial evaluating repetitive transcranial magnetic stimulation (rTMS) for EF deficits in ASD. Method In Toronto, Ontario (November 2014 to June 2017), a 20-session, 4-week course of 20 Hz rTMS targeting dorsolateral prefrontal cortex (DLPFC) (90%RMT) was compared to sham stimulation in 16–35 year-olds with ASD (28 male/12 female), without intellectual disability, who had impaired everyday EF performance (n = 20 active/n = 20 sham). Outcome measures evaluated protocol feasibility and clinical effects of active vs. sham rTMS on EF performance. The moderating effect of baseline functioning was explored. Results Of eligible participants, 95% were enrolled and 95% of randomized participants completed the protocol. Adverse events across treatment arms were mild-to-moderate. There was no significant difference between active vs. sham rTMS on EF performance. Baseline adaptive functioning moderated the effect of rTMS, such that participants with lower baseline functioning experienced significant EF improvement in the active vs. sham group. Conclusions Our pilot RCT demonstrated the feasibility and acceptability of using high frequency rTMS targeting DLPFC in youth and young adults with autism. No evidence for efficacy of active versus sham rTMS on EF performance was found. However, we found promising preliminary evidence of EF performance improvement following active versus sham rTMS in participants with ASD with more severe adaptive functioning deficits. Future work could focus on examining efficacy of rTMS in this higher-need population. Clinical trial registration Repetitive Transcranial Magnetic Stimulation (rTMS) for Executive Function Deficits in Autism Spectrum Disorder and Effects on Brain Structure: A Pilot Study; https://clinicaltrials.gov/ct2/show/NCT02311751?term = ameisr NCT02311751. The trial was funded by: an American Academy of Child and Adolescent Psychiatry (AACAP) Pilot Research Award, the Innovation Fund from the Alternate Funding Plan of the Academic Health Sciences Centres of Ontario, and an Ontario Mental Health Foundation (OMHF) Project A Grant and New Investigator Fellowship.

Objective: The purpose of the study was to identify profiles and predictors of academic and social functioning in a sample of school-age children with autism spectrum disorder.Method: The study inc...

Background Although there is high co-occurrence between ASD and ADHD, the nature of this co-occurrence remains unclear. Our study aimed to examine the underlying relationship between ASD and ADHD symptoms in a combined sample of children with a primary clinical diagnosis of ASD or ADHD. Methods Participants included children and youth (aged 3-20 years) with a clinical diagnosis of ASD (n = 303) or ADHD (n = 319) for a total of 622 participants. Parents of these children completed the social communication questionnaire (SCQ), a measure of autism symptoms, and the strengths and weaknesses of ADHD and normal behavior (SWAN) questionnaire, a measure of ADHD symptoms. A principal component analysis (PCA) was performed on combined SCQ and SWAN items, followed by a profile analysis comparing normalized component scores between diagnostic groups and gender. Results PCA revealed a four-component solution (inattention, hyperactivity/impulsivity, social-communication, and restricted, repetitive, behaviors, and interests (RRBI)), with no overlap between SCQ and SWAN items in the components. Children with ASD had higher component scores in social-communication and RRBI than children with ADHD, while there was no difference in inattentive and hyperactive/impulsive scores between diagnostic groups. Males had higher scores than females in social-communication, RRBI, and hyperactivity/impulsivity components in each diagnostic group. Limitations We did not formally assess children with ASD for ADHD using our research-criteria for ADHD, and vice versa. High rates of co-occurring ADHD in ASD, for example, may have inflated component scores in inattention and hyperactivity/impulsivity. A disadvantage with using single informant-based reports (i.e., parent-rated questionnaires) is that ASD and ADHD symptoms may be difficult to distinguish by parents, and may be interpreted differently between parents and clinicians. Conclusions ASD and ADHD items loaded on separate components in our sample, suggesting that the measurement structure cannot explain the covariation between the two disorders in clinical samples. High levels of inattention and hyperactivity/impulsivity were seen in both ASD and ADHD in our clinical sample. This supports the need for a dimensional framework that examines neurodevelopmental domains across traditional diagnostic boundaries. Females also had lower component scores across social-communication, RRBI, and hyperactivity/impulsivity than males, suggesting that there may be gender-specific phenotypes related to the two conditions.

Purpose of review With increasing awareness of potential differences of autism presentation in nonmale versus male individuals, this review summarizes the rapidly evolving literature on sex and gender impacts on autism across nosology, behavioural presentation, developmental change and contextual recognition biases. Recent findings Most studies have not differentiated sex versus gender impacts. Regarding behavioural presentation, measurement invariance across sex/gender was found in several standard measures. On this basis, diagnosed females overall showed lower restricted/repetitive behaviour/interests/activities (RRBI) than males, with small and variable effects depending on age, developmental level and kinds of RRBI. Differences insufficiently captured by standard measures may include autistic females displaying female-gender-typical narrow interests, higher social attention, linguistic abilities, motivation for friendship and more camouflaging than autistic males. Regarding developmental change, diagnosed young girls were more likely to have better cognitive development, less intense autistic symptoms and reduction of symptoms over time. Difficulties in adaptive functioning and social challenges, however, may emerge more for females in adolescence. Regarding diagnosis, general expectancy biases and gender-stereotypes may impede timely recognition of autism in females. Summary Appreciating the multilevel sex and gender impacts on presentation, development, and diagnosis is key to sex-equitable and gender-equitable care for autistic individuals. A holistic approach to understanding the person in the contexts of sex and gender is essential for timely and accurate diagnosis and support.

Background This paper is a systematic review and meta-analysis of the efficacy of available medications for the treatment of restricted/repetitive behavior (RRBs) in Autism Spectrum Disorder (ASD). Method We searched MEDLINE, Embase, PsycINFO, The Cochrane Library (Cochrane Database of Systematic Reviews (CDRS), the Cochrane Central Register of Controlled Trials (CENTRAL), database of Abstracts of Reviews of Effects (DARE)), Scopus, Epistimonikos, Clinicaltrials.gov, and included all randomized controlled trials published after 1993 that were directed at RRBs in patients with ASD of all ages. We extracted the relevant data from the published studies with a predefined data extraction form and assessed the risk of bias. The primary outcomes were change in restricted/repetitive behavior. We performed a meta-analysis using the random effect model and included studies with given mean and standard deviation. This study is registered with PROSPERO number CRD42018092660). Results We identified 14 randomized controlled trials that met initial inclusion criteria. After closer inspection, nine trials – involving 552 patients in total – were included in the final analysis. The meta-analysis found no significant difference between medications (including fluvoxamine, risperidone, fluoxetine, citalopram, oxytocin, N-Acetylcysteine, buspirone) and placebo in the treatment of RRBs in ASD (P = 0.20). Similarly, the sub-group meta-analysis also showed no significant difference between Selective Serotonin Reuptake Inhibitor (SSRIs) and placebo in the treatment of RRBs in ASD (P = 0.68). There was no evidence of publication bias. Conclusion This meta-analysis finds little support for the routine use of medications to treat restricted/repetitive behaviors in Autism Spectrum Disorder. Further research of large, balanced trials with precise assessment tools and long-term follow-up are needed. Trial registration The study protocol is registered in PROSPERO (Reference number: CRD42018092660).

This study investigated rates of suicidal ideation (SI) and suicidal and/or self-injurious behaviour (SSIB) reported by parents on the Child Behavior Checklist for 178 children with ASD over four annual assessments (ages 7-11 years). Analyses examined the frequency and persistence of SI and SSIB, and the association of SI and SSIB at any time point with child characteristics and internalizing and externalizing problems at age 7. SI occurred in 9.6% of children and was associated with fewer ASD symptoms and better adaptive functioning at age 7. SSIB occurred in 14.6% and was associated with poorer adaptive functioning and more externalizing behaviour at age 7. Internalizing problems were not associated with SI or SSIB at any time point. SI and SSIB rarely co-occurred (4%).

Despite considerable progress in characterizing the early signs of autism spectrum disorder (ASD), more remains to be learned about how symptoms emerge in the first year of life. Parents with a new baby who already had at least one biological child diagnosed with ASD (high-risk) or no family history of ASD (low-risk) completed two measures when their baby was 9 months of age, the Autism Parent Screen for Infants (APSI) questionnaire and the interview-based Parent Concerns Form. Children underwent a blinded independent diagnostic assessment for ASD at age 3 years. Total scores on the APSI and the Parent Concerns Form were both able to independently differentiate high-risk children who were later diagnosed with ASD from other high-risk and low-risk children who were not. Using logistic regression, we found that the total score on the APSI predicted ASD outcomes at age 3 with 70% accuracy, but the Parent Concerns Form did not contribute any unique variance when the APSI was already in the model. The results suggest that the APSI identifies early features predictive of ASD in high-risk infants and can be used to flag them for targeted follow-up and screening.

BackgroundThe longitudinal course of multiple symptom domains in adolescents treated for major depression is not known. Revealing the temporal course of general and specific psychopathology factors, including potential differences between psychotherapies, may aid therapeutic decision‐making.MethodsParticipants were adolescents with major depressive disorder (aged 11–17; 75% female; N = 465) who were part of the IMPACT trial, a randomized controlled trial comparing cognitive behavioral therapy, short‐term psychoanalytic psychotherapy, and brief psychosocial intervention. Self‐reported symptoms at baseline and 6, 12, 36, 52, and 86 weeks postrandomization were analyzed with bifactor modeling.ResultsGeneral psychopathology factor scores decreased across treatment and one‐year follow‐up. Specific melancholic features and depressive cognitions factors decreased from baseline to 6 weeks. Conduct problems decreased across treatment and follow‐up. Anxiety increased by 6 weeks and then reverted to baseline levels. Obsessions–compulsions did not change. Changes in general and specific factors were not significantly different between the three psychotherapies during treatment. During follow‐up, however, conduct problems decreased more in brief psychosocial intervention versus cognitive behavioral therapy (1.02, 95% Bayes credible interval 0.25, 1.96), but not versus short‐term psychoanalytic psychotherapy.ConclusionsThe clinical response signature in this trial is best revealed by rapid reductions in depression symptoms and general psychopathology. Protracted improvements in general psychopathology and conduct problems subsequently occur. Psychosocial treatments for adolescent depression have comparable effects on general and specific psychopathology, although a psychoeducational, goal‐focused approach may be indicated for youth with comorbid conduct problems.

AIMS Depression in adolescents is common and debilitating. Treatment approaches vary widely across clinics and may not reflect evidence-based care. Integrated care pathways (ICPs) are implementation tools to facilitate bridging the gap between rigorous but often complex clinical practice guidelines and what is actually practiced. We describe the development of an ICP for the treatment of Adolescents with Major Depressive Disorder (MDD-A) based on the best-available clinical practice guidelines and derived in collaboration with clinicians, administrators, youth partners and caregivers. METHODS With clinician and health service manager input, we took the recommendations from a high quality clinical practice guideline (the National Institute of Health and Care Excellence Clinical Practice Guideline for Depression in Children and Young People) and translated them into an ICP. Feedback from youth partners and clinicians was iteratively incorporated into the current version of the pathway using a collaborative approach. RESULTS The current iteration of the pathway at a Canadian tertiary care teaching hospital is described. All youth (and caregivers, if applicable) are offered a multi-family psychoeducation session, a 16-session Group Cognitive Behaviour Therapy and team reviews every 4 weeks that include measurement-based care. Conditional branches of the pathway include a medication algorithm and an 8-session group for caregivers. CONCLUSIONS The resulting ICP provides a tool to facilitate bridging the gap between evidence and clinical practice.

Autism Spectrum Disorder (ASD) is genetically complex with ~100 copy number variants and genes involved. To try to establish more definitive genotype and phenotype correlations in ASD, we searched genome sequence data, and the literature, for recurrent predicted damaging sequence-level variants affecting single genes. We identified 18 individuals from 16 unrelated families carrying a heterozygous guanine duplication (c.3679dup; p.Ala1227Glyfs*69) occurring within a string of 8 guanines (genomic location [hg38]g.50,721,512dup) affecting SHANK3, a prototypical ASD gene (0.08% of ASD-affected individuals carried the predicted p.Ala1227Glyfs*69 frameshift variant). Most probands carried de novo mutations, but five individuals in three families inherited it through somatic mosaicism. We scrutinized the phenotype of p.Ala1227Glyfs*69 carriers, and while everyone (17/17) formally tested for ASD carried a diagnosis, there was the variable expression of core ASD features both within and between families. Defining such recurrent mutational mechanisms underlying an ASD outcome is important for genetic counseling and early intervention.

Up to 80% of children with autism spectrum disorder (ASD) experience sleep disturbance. Poor sleep impairs executive functioning (EF), a lifelong difficulty in ASD. Evidence suggests EF difficulties in ASD are exacerbated by poor sleep. We examine whether early childhood sleep disturbances are associated with worsening EF trajectories in school-aged children with ASD. A subsample (n = 217) from the Pathways in ASD longitudinal study was analyzed. The Children’s Sleep Habits Questionnaire captured sleep duration, onset, and night awakenings before age 5 (mean = 3.5 years). Metacognition (MI) and Behavioral Regulation (BRI) indices, on the Teacher Behavior Rating Inventory of Executive Functioning, were used to measure cognitive and affective components of EF respectively at four time-points (7.8–11.8 years). We applied latent growth curve models to examine associations between sleep and EF, accounting for relevant covariates, including school-age sleep (mean = 6.7 years). Sleep traits had different age-related impacts on behavioral regulation, but not metacognition. Longer sleep onset at 3.5 years was associated with a worsening BRI difficulties slope (b = 2.07, p < 0.04), but conversely associated with lower BRI difficulties at 7.7 years (b = −4.14, p = 0.04). A longer sleep onset at 6.7 years was related to higher BRI difficulties at 7.7 years (b = 7.78, p < 0.01). Longer sleep duration at 6.7 years was associated with higher BRI difficulties at age 7.7 (b = 3.15, p = 0.01), but subscale analyses revealed shorter sleep duration at age 6.7 was linked to a worsening inhibition slope (b = −0.60, p = 0.01). Sleep onset is a robust early correlate of behavior regulation in children with ASD, whereas sleep duration is a later childhood correlate.

International audience; We present the largest exome sequencing study of autism spectrum disorder (ASD) to date (n = 35,584 total samples, 11,986 with ASD). Using an enhanced analytical framework to integrate de novo and case-control rare variation, we identify 102 risk genes at a false discovery rate of 0.1 or less. Of these genes, 49 show higher frequencies of disruptive de novo variants in individuals ascertained to have severe neurodevelopmental delay, whereas 53 show higher frequencies in individuals ascertained to have ASD; comparing ASD cases with mutations in these groups reveals phenotypic differences. Expressed early in brain development, most risk genes have roles in regulation of gene expression or neuronal communication (i.e., mutations effect neurodevelopmental and neurophysiological changes), and 13 fall within loci recurrently hit by copy number variants. In cells from the human cortex, expression of risk genes is enriched in excitatory and inhibitory neuronal lineages, consistent with multiple paths to an excitatory-inhibitory imbalance underlying ASD.

We report results from a large qualitative study regarding the process of parents coming to understand the child has autism starting from the time of initial developmental concerns. Specifically, we present findings relevant to understanding how parents become motivated and prepared for engaging in care at this early stage. The study included primary data from 45 intensive interviews with 32 mothers and 9 expert professionals from urban and rural regions of Ontario, Canada. Grounded theory methods were used to guide data collection and analysis. Parents’ readiness (motivation and capacity) for engagement develops progressively at different rates as they follow individual paths of meaning making. Four optional steps account for their varied trajectories: forming an image of difference, starting to question the signs, knowing something is wrong, and being convinced it’s autism. Both the nature of the information and professional help parents seek, and the urgency with which they seek them, evolve in predictable ways depending on how far they have progressed in understanding their child has autism. Results indicate the need for sensitivity to parents’ varying awareness and readiness for involvement when engaging with them in early care, tailoring parent support interventions, and otherwise planning family-centered care pathways. Lay Abstract What is already known about the topic? Parents of children with autism often learn about their child’s autism before diagnosis and can spend long periods seeking care (including assessment) before receiving a diagnosis. Meanwhile, parents’ readiness to engage in care at this early stage can vary from parent to parent. What this paper adds? This study revealed how parents come to understand their child has autism—on their own terms, rather than from just talking to professionals. It also explained how parents’ growing awareness of their child’s autism leads them to feel more motivated to engage in care by seeking information and pursuing services. Four “optional steps” described how parents’ growing readiness to engage in care at this early stage can vary, depending on their personal process. Implications for practice, research, or policy The results suggest ways that professionals can be more sensitive (a) to parents’ varying awareness of autism and (b) to their varying readiness for being involved in early care. They also suggest ways to tailor parent supports to their individual situation and design care that is more family centered. Not all parents want high levels of involvement. Depending on their personal process, some parents may need care and support that is directed at them before feeling ready for professionals to engage them in care directed at the child.

Preschool children with autism spectrum disorder (ASD) experience slower development of daily living skills (DLS) that are essential for independent functioning compared to typically developing children. Few studies have examined the trajectories of DLS in preschoolers with ASD and the existing literature has reported conflicting results. This study examined DLS trajectories and potential covariates for preschoolers with ASD from a multi-site longitudinal study following children from diagnosis to the end of grade 1. Multi-level modeling was conducted with DLS domain scores from the Vineland Adaptive Behavior Scales-2. The results demonstrated a positive trajectory of increasing scores over time, associations of age of diagnosis, developmental level, stereotypy, and language skills with the mean score at T4 or age 6 years, whereas rate of change was only associated with ASD symptom severity, such that an improvement in DLS trajectory was associated with lower and improving ASD symptom severity.

Clinical practice guidelines (CPG) provide a framework for evidence-based practice; however, few studies have assessed the methodological quality of CPGs relevant to child and youth mental health. This study was a systematic review of CPGs for the assessment, prevention and treatment of disruptive behavior, including attention-deficit hyperactivity disorder (ADHD), oppositional defiant disorder (ODD), conduct disorder (CD) and aggression in children and youth. Systematic review identified 29 CPGs meeting inclusion criteria that were appraised using the Appraisal of Guidelines for Research and Evaluation II (AGREE II) validated tool. Twenty-two guidelines addressed ADHD, 2 CD, 1 ODD, 2 for Behavior Disorders collectively and 2 for Aggression. Among the 29 guidelines, two that were developed for ADHD (NICE 2013a; Spanish Ministry of Health, 2010) and one practice guideline developed for CD (NICE 2013b) met high quality criteria; one guideline for behavior disorders (Gorman et al. 2015), two for ADHD (AAP 2011a, b; SIGN 2009a, b, c, d, e), and two for aggression (Knapp et al. 2012; Scotto Rosato et al. 2012a, b) met minimum quality criteria. Findings from this review provide important information for clinicians and organizations who want to utilize guidelines to implement best-practice clinical services for children and youth with disruptive behavior.

Social-emotional behavior in autism spectrum disorder (ASD) was examined among high-risk (HR; siblings of children diagnosed with ASD) and low-risk (LR; no family history of ASD) toddlers. Caregivers completed the Infant-Toddler Social Emotional Assessment (ITSEA) at 18 months, and blind diagnostic assessment for ASD was conducted at 36 months. Results indicated impairment in social-emotional functioning among HR toddlers subsequently diagnosed with ASD compared to other HR and LR toddlers, such that ITSEA domains (Internalizing, Dysregulation, Competence) and subdomains predicted later ASD symptoms and diagnosis. Receiver operating curves of optimal ITSEA cutoffs ranged from 0.23 to 0.44 for sensitivity, and 0.74 to 0.89 for specificity. Although classification accuracy for ASD was limited, group differences highlight the importance of considering social-emotional development when assessing ASD risk.

Most research regarding youth with autism spectrum disorder has not focused on their first-person perspectives providing limited insight into methodologies best suited to eliciting their voices. We conducted a synthesis of methods previously used to obtain the first-person perspectives of youth with various disabilities, which may be applicable to youth with autism spectrum disorder. Two-hundred and eighty-four articles met the inclusion criteria of our scoping review. We identified six distinct primary methods (questionnaires, interviews, group discussion, narratives, diaries, and art) expressed through four communication output modalities (language, sign language and gestures, writing, and images). A group of parents who have children with autism spectrum disorder were then presented with a synthesis of results. This parent consultation was used to build on approaches identified in the literature. Parents identified barriers that may be encountered during participant engagement and provided insights on how best to conduct first-person research with youth with autism spectrum disorder. Based on our findings, we present a novel methodological framework to capture the perspectives of youth with various communication and cognitive abilities, while highlighting family, youth, and expert contributions.

Background Attention-deficit/hyperactivity disorder (ADHD) is a major sequela of traumatic brain injury (TBI) in youths. The objective of this study was to examine whether ADHD symptoms are differentially associated with genetic risk and brain structure in youths with and without a history of TBI. Methods Medical history, ADHD symptoms, genetic data, and neuroimaging data were obtained from a community sample of youths. ADHD symptom severity was compared between those with and without TBI (TBI n = 418, no TBI n = 3193). The relationship of TBI history, genetic vulnerability, brain structure, and ADHD symptoms was examined by assessing 1) ADHD polygenic score (discovery sample ADHD n = 19,099, control sample n = 34,194), 2) basal ganglia volumes, and 3) fractional anisotropy in the corpus callosum and corona radiata. Results Youths with TBI reported greater ADHD symptom severity compared with those without TBI. Polygenic score was positively associated with ADHD symptoms in youths without TBI but not in youths with TBI. The negative association between the caudate volume and ADHD symptoms was not moderated by a history of TBI. However, the relationship between ADHD symptoms and structure of the genu of the corpus callosum was negative in youths with TBI and positive in youths without TBI. Conclusions The identification of distinct ADHD etiology in youths with TBI provides neurobiological insight into the clinical heterogeneity in the disorder. Results indicate that genetic predisposition to ADHD does not increase the risk for ADHD symptoms associated with TBI. ADHD symptoms associated with TBI may be a result of a mechanical insult rather than neurodevelopmental factors.

Possible gender differences in manifestations of autism spectrum disorder (ASD) were examined using data on production of narratives. The Expression, Reception and Recall of Narrative Instrument (ERRNI; Bishop, Expression, Reception and Recall of Narrative Instrument, Harcourt assessment, London, 2004) was administered to a sample of matched 8-year-old intellectually able boys and girls with ASD (13M, 13F), who had been selected from a large, longitudinal study. In addition, transcripts of the narratives were analyzed in detail. Significant gender differences were found in narrative production. Girls included more salient story elements than boys. On detailed language analysis, girls were also shown to tell richer stories, including more descriptors of planning or intention. Overall, our findings suggest that subtle differences in social communication may exist between intellectually able boys and girls with ASD. If reliably identifiable in young children, such gender differences may contribute to differential diagnosis of ASD. In addition, such differences may pave the way for differential approaches to intervention when the target is effective communication in sophisticated discourse contexts.

Objective To evaluate the relationship between the timing of infant cereal introduction between 4 and 6 months of age and growth and dietary intake in later childhood. Study design A longitudinal cohort study was conducted among healthy children 0-10 years of age participating in The Applied Research Group for Kids cohort study between June 2008 and August 2019 in Toronto, Canada. Results Of 8943 children included, the mean (SD) age of infant cereal introduction was 5.7 (2.1) months. In the primary analysis, children who were introduced to infant cereal at 4 vs 6 months had 0.17 greater body mass index z score (95% CI 0.06-0.28; P = .002) and greater odds of obesity (OR 1.82; 95% CI 1.18-2.80; P = .006) at 10 years of age. In the secondary analysis, children who were introduced to infant cereal at 4 vs 6 months had 0.09 greater height-for-age z score (95% CI 0.04-0.15; P = .002) at 1 year of age, an association that was not observed at 5 or 10 years of age. Children who were introduced to infant cereal at 4 vs 6 months had greater nutrition risk which was primarily determined by a less-favorable eating behavior score at 18 months to 5 years of age (0.18 units higher; 95% CI 0.07-0.29; P = .001). Conclusions Introduction of infant cereal at 4 vs 6 months was associated with greater body mass index z score, greater odds of obesity, similar height-for-age z score, and less favorable eating behavior. These findings support recommendations for introducing solid food around 6 months of age.

BackgroundExternalizing and internalizing behaviors are common and contribute to impairment in children with neurodevelopmental disorders (NDDs). Associations between externalizing or internalizing behaviors and cortico-amygdalar connectivity have been found in children with and without clinically significant internalizing/externalizing behaviors. This study examined whether such associations are present across children with different NDDs.MethodsMulti-modal neuroimaging and behavioral data from the Province of Ontario Neurodevelopmental Disorders (POND) Network were used. POND participants aged 6-18 years with a primary diagnosis of autism spectrum disorder (ASD), attention-deficit/hyperactivity disorder (ADHD) or obsessive-compulsive disorder (OCD), as well as typically developing children (TDC) with T1-weighted, resting-state fMRI or diffusion weighted imaging and parent-report Child Behavioral Checklist (CBCL) data available, were analyzed (n range=157-346). Associations between externalizing or internalizing behavior and cortico-amygdalar structural and functional connectivity indices were examined using linear regressions, controlling for age, gender, and image-modality specific covariates. Behavior-by-diagnosis interaction effects were also examined.ResultsNo significant linear associations (or diagnosis-by-behavior interaction effects) were found between CBCL-measured externalizing or internalizing behaviors and any of the connectivity indices examined. Post-hoc bootstrapping analyses indicated stability and reliability of these null results.ConclusionsThe current study provides evidence in favour of the absence of a shared linear relationship between internalizing or externalizing behaviors and cortico-amygdalar connectivity properties across a transdiagnostic sample of children with various NDDs and TDC. Detecting shared brain-behavior relationships in children with NDDs may benefit from the use of different methodological approaches, including incorporation of multi-dimensional behavioral data (i.e. behavioral assessments, neurocognitive tasks, task-based fMRI) or clustering approaches to delineate whether subgroups of individuals with different brain-behavior profiles are present within heterogeneous cross-disorder samples.

Altered excitatory and inhibitory neurotransmission has been implicated in autism spectrum disorder (ASD). Interventions using repetitive transcranial magnetic stimulation (rTMS) to enhance or inhibit cortical excitability are under study for various targets, though the mechanistic effects of rTMS have yet to be examined in ASD. Here, we examined whether an excitatory rTMS treatment course modulates glutamatergic (Glx) or γ-aminobutyric acid (GABA) metabolite levels in emerging adults with ASD. Twenty-eight participants with ASD and executive function impairment [23.3 ± 4.69 years; seven-female] underwent two magnetic resonance spectroscopy (MRS) scans of the left dorsolateral prefrontal cortex (DLPFC). MRS scans were acquired before and after participants with ASD were randomized to receive a 20-session course of active or sham rTMS to the DLPFC. Baseline MRS data was available for 19 typically developing controls [23.8 ± 4.47 years; six-female]. Metabolite levels for Glx and GABA+ were compared between ASD and control groups, at baseline, and metabolite level change, pre-to-post-rTMS treatment, was compared in ASD participants that underwent active vs. sham rTMS. Absolute change in Glx was greater in the active vs. sham-rTMS group [F(1,19) = 6.54, p = 0.02], though the absolute change in GABA+ did not differ between groups. We also examined how baseline metabolite levels related to pre/post-rTMS metabolite level change, in the active vs. sham groups. rTMS group moderated the relation between baseline Glx and pre-to-post-rTMS Glx change, such that baseline Glx predicted Glx change in the active-rTMS group only [b = 1.52, SE = 0.32, t(18) = 4.74, p < 0.001]; Glx levels increased when baseline levels were lower, and decreased when baseline levels were higher. Our results indicate that an interventional course of excitatory rTMS to the DLPFC may modulate local Glx levels in emerging adults with ASD, and align with prior reports of glutamatergic alterations following rTMS. Interventional studies that track glutamatergic markers may provide mechanistic insights into the therapeutic potential of rTMS in ASD.Clinical Trial Registration:Clinicaltrials.gov (ID: NCT02311751), https://clinicaltrials.gov/ct2/show/NCT02311751?term=ameis&rank=1; NCT02311751.

Background: Restricted and repetitive behaviors are one of the characteristic features of Autism Spectrum Disorder. This domain of symptoms includes a broad range of behaviors. There is a need to study each behavior individually to better understand the role they each have in the development of autistic children. Moreover, there are currently no longitudinal studies investigating change in these behaviors over development. Methods: The goal of the present study was to explore the association between age and non-verbal IQ (NVIQ) on 15 RRB symptoms included in the Autism Diagnostic Interview-Revised (ADI-R) over time. A total of 205 children with ASD were assessed using the ADI-R at time of diagnosis, at age 6 years, and at age 11 years, and with the addition of the Wechsler Intelligence Scales for Children – Fourth Edition (WISC-IV) at age 8 years.Results: The proportion of children showing each RRB tended to diminish with increasing age (p < 0.001), except for sensitivity to noise and circumscribed interests, where the proportion increased over time. Although there was no significant main effect of NVIQ (p = 0.101), there was a significant interaction between age and NVIQ (p < 0.01). This was mainly driven by Difficulties with change in routine, for which higher NVIQ was associated with the prevalence of the behavior remaining relatively stable with age, while lower NVIQ was associated with the behavior becoming more prevalent with age.Limitations: The study focused on the presence/absence of each RRB but did not account for potential changes in frequency or severity of the behaviors over development. Furthermore, some limitations are inherent to the measures used. The ADI-R relies on parent-report and hence has some level of subjectivity, while the Wechsler intelligence scales can underestimate the intellectual abilities of some autistic children.Conclusions: These results confirm that specific RRBs are differentially linked to age and NVIQ. Studying RRBs individually is a promising approach to better understand how RRBs change over the development of autistic children and are linked to other developmental domains.

Fombonne's (2020) editorial is a thought-provoking appraisal of the literature on 'camouflaging', whereby some autistic people mask or compensate for their autistic characteristics as an attempt to fit in and to cope with disabilities under neurotypical social norms. Fombonne (2020) highlights three issues of contention: (a) construct validity and measurement of camouflaging; (b) camouflaging as a reason for late autism diagnosis in adolescence/adulthood; and (c) camouflaging as a feature of the 'female autism phenotype'. Here, we argue that (a) establishing construct validity and measurement of different aspects of camouflaging is warranted; (b) subjective experiences are important for the differential diagnosis of autism in adolescence/adulthood; and (c) camouflaging is not necessarily a feature of autism in female individuals - nevertheless, taking into account sex and gender influences in development is crucial to understand behavioural manifestations of autism. Future research and clinical directions should involve clarification of associated constructs and measurements, demography, mechanisms, impact (including harms and benefits) and tailored support.

Study Objectives: Up to 80% of children with autism spectrum disorder (ASD) experience sleep disturbance. Poor sleep impairs executive functioning (EF), a lifelong difficulty in ASD. Evidence suggests EF impairments in ASD is exacerbated by poor sleep. We examine whether early childhood sleep disturbances are associated with worsening EF trajectories in school-aged children with ASD. Methods: A subsample (n = 217) from the Pathways in ASD longitudinal study was analyzed. The Children’s Sleep Habits Questionnaire captured sleep duration, onset, and night awakenings before age 5 (Mean = 3.5 years). Metacognition (MI) and Behavioral Regulation (BRI) indices on the Teacher Behavior Rating Inventory of Executive Functioning measured EF difficulties at four time-points (7-11 years). We applied latent growth curve models to examine associations between sleep and EF, accounting for relevant covariates, including school-age sleep (Mean = 6.7 years). Results: Longer sleep onset at 3.5 years predicted a worsening BRI difficulties slope (b = 2.07, p < 0.04), but conversely predicted lower BRI difficulties at age 7.7 (b = -4.14, p = 0.04). A longer sleep onset at age 6.7 predicted higher BRI difficulties at age 7.7 (b = 7.78, p < 0.01). Longer sleep duration at age 6.7 predicted higher BRI difficulties at age 7.7 (b = 3.15, p = 0.01), but subscale analyses revealed shorter sleep duration at age 6.7 predicted a worsening inhibition slope (b = -0.597, p = 0.01). Conclusions: Different sleep phenotypes have different age-related impacts on selective behavioral regulation components, but not metacognition. Delayed sleep onset is a robust early predictor, whereas shorter sleep duration is a later predictor of worsening behavior regulation in school-aged children with ASD.

Background Sleep problems are more common and severe among children with autism spectrum disorder (ASD) compared to their typically developing peers. The goal of this study was to characterize sleep problems profiles and their clinical correlates, based on a five-factor model of the Children’s Sleep Habits Questionnaire (CSHQ) among preschool children with ASD. Objectives (1) To describe empirically-derived patterns (i.e., latent profiles) of sleep problems among young children with ASD; and (2) To examine relations between family cumulative risk and emotional-behavioral dysregulation symptoms and sleep profile membership. Design/Methods The study included 318 three-to-five year old children (M= 49.45 months; SD = 5.77). Latent profile analysis was used to identify and describe profiles of sleep problems. Sleep problems were assessed using a previously established CSHQ five-factor model: (1) Bedtime Routine; (2) Sleep Onset & Duration; (3) Night Waking; (4) Morning Waking; and (5) Sleep Disordered Breathing, with higher scores indicating greater problems. We assess whether profile membership was associated with dysregulation difficulties (CBCL 1.5-5) and family cumulative risk index (CRI; constructed based on socioeconomic status, maternal distress, family functioning, and other related factors) using a three-step method (Vermunt & Magidson, 2013). Results A five-profile model of children’s sleep problems showed the best fit (Figure 1). Profile 1, Nighttime Sleep Problems (28%), consisted of children with scores around the sample mean, except relatively lower scores on Morning Waking. Profile 2, Severe Sleep Problems (25%), consisted of children with relatively high scores across all sleep problems. Profile 3, Low Sleep Problems (18%), included children with the lowest levels of all sleep problems. Profile 4, Moderate Sleep Problems (17%), included children with all sleep problem levels near the sample mean. Profile 5, Morning Waking Problems (12%), consisted of children with low scores on Bedtime Routine problems but pronounced Morning Waking problems. Dysregulation difficulties (Wald = 13.90; p = .001) and family CRI (Wald = 13.27; p =.001) emerged as significant predictors of profile membership. Higher CRI was associated with higher odds of membership in Profile 2 (Severe Sleep Problems), and lower scores for dysregulation difficulties were associated with higher odds of membership in Profile 3 (Low Sleep Problems). Conclusion Children with ASD present distinct profiles of sleep problems that differ, not only by overall severity, but also by relative severity across types of sleep problems. Children’s dysregulation and family risk should be considered in examining children’s sleep.

BackgroundChildren with autism spectrum disorder (ASD) have increased susceptibility to anxiety disorders. Variation in a common ASD symptom, insistence on sameness behaviour, may predict future anxiety symptoms.AimsTo describe the joint heterogeneous longitudinal trajectories of insistence on sameness and anxiety in children with ASD and to characterise subgroups at higher risk for anxiety.MethodIn a longitudinal ASD cohort (n = 421), insistence on sameness behaviour was measured using the Autism Diagnostic Interview-Revised at approximately ages 3, 6 and 11 years. Anxiety was quantified at 8 time points between ages 3 and 11 years using the Child Behavior Checklist (CBCL) (parent report). Clusters of participants following similar trajectories were identified using group-based and joint trajectory modelling.ResultsThree insistence on sameness trajectories were identified: (a) ‘low-stable’ (41.7% of participants), (b) ‘moderate-increasing’ (52.0%) and (c) ‘high-peaking’ (i.e. increasing then stabilising/decreasing behaviour) (6.3%). Four anxiety trajectories were identified: (a) ‘low-increasing’ (51.0%), (b) ‘moderate-decreasing’ (16.2%), (c) ‘moderate-increasing’ (19.6%) and (d) ‘high-stable’ (13.1%). Of those assigned to the ‘high-peaking’ insistence on sameness trajectory, 95% jointly followed an anxiety trajectory that surpassed the threshold for clinical concern (T-score >65) by middle childhood (anxiety trajectories 3 or 4). Insistence on sameness and anxiety trajectories were similar in severity and direction for 64% of the sample; for 36%, incongruous patterns were seen (e.g. decreasing anxiety and increasing insistence on sameness).ConclusionsThe concurrent assessment of insistence on sameness behaviour and anxiety in ASD may help in understanding current symptom profiles and anticipating future trajectories. High preschool insistence on sameness in particular may be associated with elevated current or future anxiety symptoms.

Autism spectrum disorder (ASD), obsessive-compulsive disorder (OCD) and attention-deficit/hyperactivity disorder (ADHD) are clinically and biologically heterogeneous neurodevelopmental disorders (NDDs). The objective of the present study was to integrate brain imaging and behavioral measures to identify new brain-behavior subgroups cutting across these disorders. A subset of the data from the Province of Ontario Neurodevelopmental Disorder (POND) Network was used including participants with different NDDs (aged 6-16 years) that underwent cross-sectional T1-weighted and diffusion-weighted magnetic resonance imaging (MRI) scanning on the same 3T scanner, and behavioral/cognitive assessments. Similarity Network Fusion was applied to integrate cortical thickness, subcortical volume, white matter fractional anisotropy (FA), and behavioral measures in 176 children with ASD, ADHD or OCD with complete data that passed quality control. Normalized mutual information was used to determine top contributing model features. Bootstrapping, out-of-model outcome measures and supervised machine learning were each used to examine stability and evaluate the new groups. Cortical thickness in socio-emotional and attention/executive networks and inattention symptoms comprised the top ten features driving participant similarity and differences between four transdiagnostic groups. Subcortical volumes (pallidum, nucleus accumbens, thalamus) were also different among groups, although white matter FA showed limited differences. Features driving participant similarity remained stable across resampling, and the new groups showed significantly different scores on everyday adaptive functioning. Our findings open the possibility of studying new data-driven groups that represent children with NDDs more similar to each other than others within their own diagnostic group. Future work is needed to build on this early attempt through replication of the current findings in independent samples and testing longitudinally for prognostic value.

Autism spectrum disorder (ASD), obsessive-compulsive disorder (OCD) and attention-deficit/hyperactivity disorder (ADHD) are clinically and biologically heterogeneous neurodevelopmental disorders (NDDs). The objective of the present study was to integrate brain imaging and behavioral measures to identify new brain-behavior subgroups cutting across these disorders. A subset of the data from the Province of Ontario Neurodevelopmental Disorder (POND) Network including participants with different NDDs (aged 6-16 years) that underwent cross-sectional T1-weighted and diffusion-weighted magnetic resonance imaging (MRI) scanning on the same 3T scanner, and behavioral/cognitive assessments was used. Similarity Network Fusion was applied to integrate cortical thickness, subcortical volume, white matter fractional anisotropy (FA), and behavioral measures in 176 children with ASD, ADHD or OCD with complete data that passed quality control. Normalized mutual information (NMI) was used to determine top contributing model features. Bootstrapping, out-of-model outcome measures and supervised machine learning were each used to examine stability and evaluate the new groups. Cortical thickness in socio-emotional and attention/executive networks and inattention symptoms comprised the top ten features driving participant similarity and differences between four transdiagnostic groups. Subcortical volumes (pallidum, nucleus accumbens, thalamus) were also different among groups, although white matter FA showed limited differences. Features driving participant similarity remained stable across resampling, and the new groups showed significantly different scores on everyday adaptive functioning. Our findings open the possibility of studying new data-driven groups that represent children with NDDs more similar to each other than others within their own diagnostic group. Such new groups can be evaluated longitudinally for prognostic utility and could be stratified for clinical trials targeted toward each group’s unique brain and behavioral profiles.

An update of the chapter on Mental, Behavioral and Neurodevelopmental Disorders in the International Classification of Diseases and Related Health Problems (ICD) is of great interest around the world. The recent approval of the 11th Revision of the ICD (ICD-11) by the World Health Organization (WHO) raises broad questions about the status of nosology of mental disorders as a whole as well as more focused questions regarding changes to the diagnostic guidelines for specific conditions and the implications of these changes for practice and research. This Forum brings together a broad range of experts to reflect on key changes and controversies in the ICD-11 classification of mental disorders. Taken together, there is consensus that the WHO’s focus on global applicability and clinical utility in developing the diagnostic guidelines for this chapter will maximize the likelihood that it will be adopted by mental health professionals and administrators. This focus is also expected to enhance the application of the guidelines in non-specialist settings and their usefulness for scaling up evidence-based interventions. The new mental disorders classification in ICD-11 and its accompanying diagnostic guidelines therefore represent an important, albeit iterative, advance for the field.

International audience; Autism spectrum disorder (ASD) is often grouped with other brain-related phenotypes into a broader category of neurodevelopmental disorders (NDDs). In clinical practice, providers need to decide which genes to test in individuals with ASD phenotypes, which requires an understanding of the level of evidence for individual NDD genes that supports an association with ASD. Consensus is currently lacking about which NDD genes have sufficient evidence to support a relationship to ASD. Estimates of the number of genes relevant to ASD differ greatly among research groups and clinical sequencing panels, varying from a few to several hundred. This Roadmap discusses important considerations necessary to provide an evidence-based framework for the curation of NDD genes based on the level of information supporting a clinically relevant relationship between a given gene and ASD.

Copy number variations (CNVs) are implicated across many neurodevelopmental disorders (NDDs) and contribute to their shared genetic etiology. Multiple studies have attempted to identify shared etiology among NDDs, but this is the first genome-wide CNV analysis across autism spectrum disorder (ASD), attention deficit hyperactivity disorder (ADHD), schizophrenia (SCZ), and obsessive-compulsive disorder (OCD) at once. Using microarray (Affymetrix CytoScan HD), we genotyped 2,691 subjects diagnosed with an NDD (204 SCZ, 1,838 ASD, 427 ADHD and 222 OCD) and 1,769 family members, mainly parents. We identified rare CNVs, defined as those found in NRXN1, SEH1L, LDLRAD4, GNAL, GNG13, MKRN1, DCTN2, KNDC1, PCMTD2, KIF5A, SYNM, and long non-coding RNAs: AK127244 and PTCHD1-AS. We demonstrated that CNVs impacting the same genes could potentially contribute to the etiology of multiple NDDs. The CNVs identified will serve as a useful resource for both research and diagnostic laboratories for prioritization of variants.

AIM The Modified Checklist for Autism in Toddlers (M-CHAT) could be appropriate for universal screening for autism spectrum disorder (ASD) at 18 months and 24 months. Validation studies, however, reported differences in psychometric properties across sample populations. This meta-analysis summarized its accuracy measures and quantified their change in relation to patient and study characteristics. METHOD Four electronic databases (MEDLINE, PsycINFO, CINAHL, and Embase) were searched to identify articles published between January 2001 and May 2016. Bayesian regression models pooled study-specific measures. Meta-regressions covariates were age at screening, study design, and proportion of males. RESULTS On the basis of the 13 studies included, the pooled sensitivity was 0.83 (95% credible interval [CI] 0.75-0.90), specificity was 0.51 (95% CI 0.41-0.61), and positive predictive value was 0.53 (95% CI 0.43-0.63) in high-risk children and 0.06 (95% CI

BACKGROUND: Early diagnosis of autism spectrum disorder (ASD) is essential in most Canadian jurisdictions to access interventions that improve long-term child outcomes. Our main objective was to identify factors associated with timing of ASD diagnosis in five provinces across Canada. METHODS: Factors influencing age of diagnosis were assessed in the analyses of an inception cohort of children diagnosed with ASD between ages 2 and 5 years. We examined bivariate associations and using a series of multiple variable regression models, evaluated the unique contributions of developmental functioning, ASD symptoms and demographic variables. Children with known genetic abnormalities, or severe sensory or motor impairments interfering with assessment were excluded. RESULTS: Participants were 421 children (84.6% boys). The mean age of diagnosis was 38.2 months (SD=8.7), an average of 19 months after parents identified initial concerns. Factors associated with later diagnosis included more advanced language and cognitive skills, and higher levels of restricted repetitive behaviour symptoms. Child sex and family demographics were not associated with age of diagnosis. In regression analyses, language and cognitive skills accounted for 6.8% of variance in age of diagnosis and ASD symptoms contributed an additional 5.5%. Provincial site accounted for 4.0% of variance in age of diagnosis, independent of developmental skills and ASD symptoms. INTERPRETATION: Diagnosis of ASD occurred, on average, 19 months after parents’ initial concerns. Language and cognitive skills, symptom severity and provincial site accounted for variation in age of ASD diagnosis in this Canadian cohort. Variable presentation across the developmental continuum must be considered in planning assessment services to ensure timely ASD diagnosis so that outcomes can be improved. Policy and practice leadership is also needed to reduce interprovincial variability.

Objective Outdoor free play is important for preschoolers' physical activity, health, and development. Certain temperamental characteristics are associated with obesity, nutrition, and sedentary behaviors in preschoolers, but the relationship between temperament and outdoor play has not been examined. This study examined whether there is an association between temperament and outdoor play in young children. Methods Healthy children aged 1 to 5 years recruited to The Applied Research Group for Kids (TARGet Kids!), a community-based primary care research network, from July 2008 to September 2013 were included. Parent-reported child temperament was assessed using the Childhood Behavior Questionnaire. Outdoor free play and other potential confounding variables were assessed through validated questionnaires. Multivariable linear regression was used to determine the association between temperament and outdoor play, adjusted for potential confounders. Results There were 3393 children with data on outdoor play. The association between negative affectivity and outdoor play was moderated by sex; in boys, for every 1-point increase in negative affectivity score, mean outdoor play decreased by 4.7 minutes per day. There was no significant association in girls. Surgency was associated with outdoor play; for every 1-point increase in surgency/extraversion, outdoor play increased by 4.6 minutes per day. Conclusions Young children's temperamental characteristics were associated with their participation in outdoor free play. Consideration of temperament could enhance interventions and strategies to increase outdoor play in young children. Longitudinal studies are needed to elucidate the relationship between children's early temperament and physical activity.

The American Academy of Pediatrics recommends universal screening for autism spectrum disorder at 18 and 24 months. This study compared the cost-effectiveness of universal or high-risk screening to surveillance monitoring. Simulation models estimated the costs and outcomes from birth to age 6 years. The incremental cost per child diagnosed by 36 months was $41,651.6 for high-risk screening and $757,116.9 for universal screening from the societal perspective. Universal screening may not be a cost-effective approach to increase earlier treatment initiation, as most children initiated treatment after age 60 months. Eliminating wait times resulted in more children initiated treatment by 48 months, but at a high initial cost that may be offset by future cost-savings related to better outcomes.