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Abstract Background Autism and schizophrenia spectrum disorders (SSDs) both feature atypical social cognition. Despite evidence for comparable group-level performance in lower-level emotion processing and higher-level mentalizing, limited research has examined the neural basis of social cognition across these conditions. Our goal was to compare the neural correlates of social cognition in autism, SSDs, and typically developing controls (TDCs). Methods Data came from two harmonized studies in individuals diagnosed with autism or SSDs and TDCs (aged 16–35 years), including behavioral social cognitive metrics and two functional magnetic resonance imaging (fMRI) tasks: a social mirroring Imitate/Observe (ImObs) task and the Empathic Accuracy (EA) task. Group-level comparisons, and transdiagnostic analyses incorporating social cognitive performance, were run using FSL’s PALM for each task, covarying for age and sex (1000 permutations, thresholded at p

Abstract Purpose Although comprehensive and widespread guidelines on how to conduct systematic reviews of outcome measurement instruments (OMIs) exist, for example from the COSMIN (COnsensus-based Standards for the selection of health Measurement INstruments) initiative, key information is often missing in published reports. This article describes the development of an extension of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 guideline: PRISMA-COSMIN for OMIs 2024. Methods The development process followed the Enhancing the QUAlity and Transparency Of health Research (EQUATOR) guidelines and included a literature search, expert consultations, a Delphi study, a hybrid workgroup meeting, pilot testing, and an end-of-project meeting, with integrated patient/public involvement. Results From the literature and expert consultation, 49 potentially relevant reporting items were identified. Round 1 of the Delphi study was completed by 103 panelists, whereas round 2 and 3 were completed by 78 panelists. After 3 rounds, agreement (≥67%) on inclusion and wording was reached for 44 items. Eleven items without consensus for inclusion and/or wording were discussed at a workgroup meeting attended by 24 participants. Agreement was reached for the inclusion and wording of 10 items, and the deletion of 1 item. Pilot testing with 65 authors of OMI systematic reviews further improved the guideline through minor changes in wording and structure, finalized during the end-of-project meeting. The final checklist to facilitate the reporting of full systematic review reports contains 54 (sub)items addressing the review’s title, abstract, plain language summary, open science, introduction, methods, results, and discussion. Thirteen items pertaining to the title and abstract are also included in a separate abstract checklist, guiding authors in reporting for example conference abstracts. Conclusion PRISMA-COSMIN for OMIs 2024 consists of two checklists (full reports; abstracts), their corresponding explanation and elaboration documents detailing the rationale and examples for each item, and a data flow diagram. PRISMA-COSMIN for OMIs 2024 can improve the reporting of systematic reviews of OMIs, fostering their reproducibility and allowing end-users to appraise the quality of OMIs and select the most appropriate OMI for a specific application. Note In order to encourage its wide dissemination this article is freely accessible on the web sites of the journals: Health and Quality of Life Outcomes; Journal of Clinical Epidemiology; Journal of Patient-Reported Outcomes; Quality of Life Research.

Abstract Background A sizeable proportion of pathogenic genetic variants identified in young children tested for congenital differences are associated with neurodevelopmental psychiatric disorders (NPD). In this growing group, a genetic diagnosis often precedes the emergence of diagnosable developmental concerns. Here, we describe DAGSY (Developmental Assessment of Genetically Susceptible Youth), a novel interdisciplinary ‘genetic-diagnosis-first’ clinic integrating psychiatric, psychological and genetic expertise, and report our first observations and feedback from families and referring clinicians. Methods We retrieved data on referral sources and indications, genetic and NPD diagnoses and recommendations for children seen at DAGSY between 2018 and 2022. Through a survey, we obtained feedback from twenty families and eleven referring clinicians. Results 159 children (mean age 10.2 years, 57.2% males) completed an interdisciplinary (psychiatry, psychology, genetic counselling) DAGSY assessment during this period. Of these, 69.8% had a pathogenic microdeletion or microduplication, 21.5% a sequence-level variant, 4.4% a chromosomal disorder, and 4.4% a variant of unknown significance with emerging evidence of pathogenicity. One in four children did not have a prior NPD diagnosis, and referral to DAGSY was motivated by their genetic vulnerability alone. Following assessment, 76.7% received at least one new NPD diagnosis, most frequently intellectual disability (24.5%), anxiety (20.7%), autism spectrum (18.9%) and specific learning (16.4%) disorder. Both families and clinicians responding to our survey expressed satisfaction, but also highlighted some areas for potential improvement. Conclusions DAGSY addresses an unmet clinical need for children identified with genetic variants that confer increased vulnerability for NPD and provides a crucial platform for research in this area. DAGSY can serve as a model for interdisciplinary clinics integrating child psychiatry, psychology and genetics, addressing both clinical and research needs for this emerging population.

Abstract Introduction Our group developed an Integrated Care Pathway to facilitate the delivery of evidence-based care for adolescents experiencing depression called CARIBOU-2 (Care for Adolescents who Receive Information ‘Bout OUtcomes, 2nd iteration). The core pathway components are assessment, psychoeducation, psychotherapy options, medication options, caregiver support, measurement-based care team reviews and graduation. We aim to test the clinical and implementation effectiveness of the CARIBOU-2 pathway relative to treatment-as-usual (TAU) in community mental health settings. Methods and analysis We will use a Type 1 Hybrid Effectiveness-Implementation, Non-randomized Cluster Controlled Trial Design. Primary participants will be adolescents (planned n = 300, aged 13–18 years) with depressive symptoms, presenting to one of six community mental health agencies. All sites will begin in the TAU condition and transition to the CARIBOU-2 intervention after enrolling 25 adolescents. The primary clinical outcome is the rate of change of depressive symptoms from baseline to the 24-week endpoint using the Childhood Depression Rating Scale—Revised (CDRS-R). Generalized mixed effects modelling will be conducted to compare this outcome between intervention types. Our primary hypothesis is that there will be a greater rate of reduction in depressive symptoms in the group receiving the CARIBOU-2 intervention relative to TAU over 24 weeks as per the CDRS-R. Implementation outcomes will also be examined, including clinician fidelity to the pathway and its components, and cost-effectiveness. Ethics and dissemination Research ethics board approvals have been obtained. Should our results support our hypotheses, systematic implementation of the CARIBOU-2 intervention in other community mental health agencies would be indicated.

Abstract Background Previous research has demonstrated heterogeneous adaptive outcomes across the autism spectrum; however, the current literature remains limited in elucidating turning points and associated factors for longitudinal variability (chronogeneity). To address these empirical gaps, we aimed to provide a finer‐grained characterization of trajectories of adaptive functioning from early childhood to adolescence in autism. Methods Our sample (N = 406) was drawn from an inception cohort of children diagnosed Autistic at ages 2–5. Adaptive functioning was assessed with Vineland Adaptive Behavior Scales (VABS, 2nd Edition) across 6 visits from the time of diagnosis by age 18. Parallel‐process latent growth curve modeling were used to estimate domain‐level VABS trajectories, followed by latent class growth analysis to identify trajectory subgroups. Child characteristics at diagnosis, family demographics, and participation outcomes at adolescence were compared across subgroups. Results Piecewise latent growth models best described VABS trajectories with two turning points identified at around ages 5‐6 and 9–10, respectively reflecting transitions into school age and early adolescence. We parsed four VABS trajectory subgroups that vary by level of functioning and change rate for certain domains and periods. Around 16% of the sample exhibited overall adequate functioning (standard score >85) with notable early growth and social adaptation during adolescence. About 21% showed low adaptive functioning (standard score ≤70), with decreasing slopes by age 6 followed by improvements in communication and daily‐living skills by age 10. The other two subgroups (63% in total) were characterized by adaptive functioning between low and adequate levels, with relatively stable trajectories entering school age. These subgroups differed most in their cognitive ability at diagnosis, household income, and social participation in adolescence. Conclusions We identified key individual and family characteristics and time windows associated with distinct adaptive functioning trajectories, which have important implications for providing timely and tailored supports to Autistic people across developmental stages.

Abstract Background Due to limitations of categorical definitions of mental illness, there is a need for quantitative empirical investigations of the dimensional structure of psychopathology. Using exploratory bifactor methods, this study investigated a comprehensive and representative structure of psychopathology in children to better understand how psychotic‐like experiences (PLEs), autism spectrum disorder (ASD) symptoms, impulsivity, and sensitivity to reward and punishment, may be integrated into extant general factor models of psychopathology. Methods We used seven child‐report and three parent‐report instruments capturing diverse mental health symptoms in 11,185 children aged 9–10 from the Adolescent Brain Cognitive DevelopmentSM (ABCD) Study. We built on previous modeling frameworks by conducting both split sample and full sample factor analytic approaches that harnessed recent methodological advances in bifactor exploratory structural equation modeling (B‐ESEM) to examine a wide range of psychopathology measures not previously integrated into a single analysis. Validity of psychopathology dimensions was examined by investigating associations with sex, age, cognition, imaging measures, and medical service usage. Results All four factor analytic models showed excellent fit and similar structure within informant. PLEs loaded most highly onto a general psychopathology factor, suggesting that they may reflect non‐specific risk for mental illness. ASD symptoms loaded separately from attention/hyperactivity symptoms. Symptoms of impulsivity and sensitivity to reward and punishment loaded onto specific factors, distinct from externalizing and internalizing factors. All identified factors were associated with clinically relevant risk factors, providing preliminary evidence for their construct validity. Conclusion By integrating diverse child‐report and parent‐report psychopathology measures for children in the ABCD sample, we deliver data on the quantitative structure of psychopathology for an exceptionally large set of measurements and discuss implications for the field.

Abstract Background The economic shutdown and school closures associated with the COVID-19 pandemic have negatively influenced many young people’s educational and training opportunities, leading to an increase in youth not in education, employment, or training (NEET) globally and in Canada. NEET youth have a greater vulnerability to mental health and substance use problems, compared to their counterparts who are in school and/or employed. There is limited evidence on the association between COVID-19 and NEET youth. The objectives of this exploratory study included investigating: longitudinal associations between the COVID-19 pandemic and the mental health and substance use (MHSU) of NEET youth; and MHSU among subgroups of NEET and non-NEET youth. Methods 618 youth (14–28 years old) participated in this longitudinal, cohort study. Youth were recruited from four pre-existing studies at the Centre for Addiction and Mental Health. Data on MHSU were collected across 11 time points during the COVID-19 pandemic (April 2020-August 2022). MHSU were measured using the CoRonavIruS Health Impact Survey Youth Self-Report, the Global Appraisal of Individual Needs Short Screener, and the PTSD Checklist for DSM-5. Linear Mixed Models and Generalized Estimating Equations were used to analyze associations of NEET status and time on mental health and substance use. Exploratory analyses were conducted to investigate interactions between sociodemographic characteristics and NEET status and time. Results At baseline, NEET youth were significantly more likely to screen positive for an internalizing disorder compared to non-NEET youth (OR = 1.92; 95%CI=[1.26–2.91] p = 0.002). No significant differences were found between youth with, and without, NEET in MHSU symptoms across the study time frame. Youth who had significantly higher odds of screening positive for an internalizing disorder included younger youth (OR = 1.06, 95%CI=[1.00-1.11]); youth who identify as Trans, non-binary or gender diverse (OR = 8.33, 95%CI=[4.17–16.17]); and those living in urban areas (OR = 1.35, 95%CI=[1.03–1.76]), compared to their counterparts. Youth who identify as White had significantly higher odds of screening positive for substance use problems (OR = 2.38, 95%CI=[1.72–3.23]) compared to racialized youth. Conclusions Our findings indicate that sociodemographic factors such as age, gender identity, ethnicity and area of residence impacted youth MHSU symptoms over the course of the study and during the pandemic. Overall, NEET status was not consistently associated with MHSU symptoms over and above these factors. The study contributes to evidence on MHSU symptoms of NEET youth.

Summary: Background: Semi-structured diagnostic interviews and symptom checklists present similar internal reliability. We aim to investigate whether they differ in predicting poor life outcomes in the transition from childhood to young adulthood. Methods: For this longitudinal study, we used data from the Brazilian High Risk Cohort Study for Childhood Mental Health Conditions. Eligible participants were aged 6–14 years on the day of study enrolment (January to February, 2010) and were enrolled in public schools by a biological parent in Porto Alegre and São Paulo, Brazil. 2511 young people and their caregivers were assessed at baseline in 2010–11, and 1917 were assessed 8 years later (2018–19; 76·3% retention). Clinical thresholds were derived using semi-structured parent-report interview based on the Diagnostic and Statistical Manual of Mental Disorders, according to the Developmental and Well-being Assessment (DAWBA), and clinical scores as defined by the Child Behavior Checklist (CBCL; T-score ≥70 considered positive caseness). At 8 years, participants were assessed for a composite life-threatening outcome (a composite of death, suicide attempts, severe self-harm, psychiatric inpatient admission, or emergency department visits) and a composite poor life chances outcome (a composite of any criminal conviction, substance misuse, or school dropout). We evaluated the accuracy of DAWBA and CBCL to predict these outcomes. Logistic regression models were adjusted for age, sex, race or ethnicity, study site, and socioeconomic class. Findings: DAWBA and CBCL had similar sensitivity, specificity, predictive values, and test accuracy for both composite outcomes and their components. Any mental health problem, as classified by DAWBA and CBCL, was independently associated with the composite life-threatening outcome (DAWBA adjusted odds ratio 1·62, 95% CI 1·20–2·18; CBCL 1·66, 1·19–2·30), but only CBCL independently predicted poor life chances (1·56, 1·19–2·04). Participants classified by both approaches did not have higher odds of the life-threatening outcome when compared with participants classified by DAWBA or CBCL alone, nor for the poor life chances outcome when compared with those classified by CBCL alone. Interpretation: Classifying children and adolescents based on a semi-structured diagnostic interview was not statistically different to symptom checklist in terms of test accuracy and predictive validity for relevant life outcomes. Classification based on symptom checklist might be a valid alternative to costly and time-consuming methods to identify young people at risk for poor life outcomes. Funding: Conselho Nacional de Desenvolvimento Científico e Tecnológico; Fundação de Amparo à Pesquisa do Estado de São Paulo; and Medical Research Council, European Research Council. Translation: For the Portuguese translation of the abstract see Supplementary Materials section.

Abstract Background Adolescents with depression often experience relationship problems with their caregivers, which predict poorer treatment outcomes. Personalising interventions by targeting factors associated with poor treatment outcomes may enhance the effectiveness of interventions. We report the development and initial evaluation of an intervention designed to target caregiver‐adolescent relationship problems in the context of adolescent depression. Methods Following a literature search to identify established caregiver interventions, we developed a new group intervention for caregivers through an iterative process including six rounds of the group with n = 53 caregivers of adolescents age 13–18 in the context of an integrated care pathway for adolescent depression. Caregivers rated their family functioning at the beginning and end of the program and provided anonymous satisfaction ratings. Enrolment and attendance data were examined. Youth with lived experience of depression and their caregivers provided input that was incorporated in the final version of the intervention. Results The final intervention consists of 8 weekly, 1.5 h group sessions, delivered face‐to‐face, addressing: psychoeducation, the cognitive‐behavioural model and caregiving, positive caregiving, listening and validation, expressing emotions effectively, and problem solving. Reach (56%), attendance (M = 63%, SD = 31%), and satisfaction (M = 92%; SD = 7%) supported the feasibility of the program. Caregivers reported significant improvements in family functioning, t(21) = 2.68, p = .014, dz = 0.56 [95% CI 0.11–1.0]. Discussion A group intervention is acceptable to caregivers of adolescents with depression and may be associated with improved family functioning. Further research is needed, including a randomised controlled trial to test effects of the intervention on various dimensions of the caregiver‐youth relationship and on youth depression outcomes.

BackgroundIntensive longitudinal data collection, including ecological momentary assessment (EMA), has the potential to reduce recall biases, collect more ecologically valid data, and increase our understanding of dynamic associations between variables. EMA is typically administered using an application that is downloaded on participants’ devices, which presents cost and privacy concerns that may limit its use. Research Electronic Data Capture (REDCap), a web-based survey application freely available to nonprofit organizations, may allow researchers to overcome these barriers; however, at present, little guidance is available to researchers regarding the setup of EMA in REDCap, especially for those who are new to using REDCap or lack advanced programming expertise. ObjectiveWe provide an example of a simplified EMA setup in REDCap. This study aims to demonstrate the feasibility of this approach. We provide information on survey completion and user behavior in a sample of parents and children recruited across Canada. MethodsWe recruited 66 parents and their children (aged 9-13 years old) from an existing longitudinal cohort study to participate in a study on risk and protective factors for children’s mental health. Parents received survey prompts (morning and evening) by email or SMS text message for 14 days, twice daily. Each survey prompt contained 2 sections, one for parents and one for children to complete. ResultsThe completion rates were good (mean 82%, SD 8%) and significantly higher on weekdays than weekends and in dyads with girls than dyads with boys. Children were available to respond to their own survey questions most of the time (in 1134/1498, 75.7% of surveys submitted). The number of assessments submitted was significantly higher, and response times were significantly faster among participants who selected SMS text message survey notifications compared to email survey notifications. The average response time was 47.0 minutes after the initial survey notification, and the use of reminder messages increased survey completion. ConclusionsOur results support the feasibility of using REDCap for EMA studies with parents and children. REDCap also has features that can accommodate EMA studies by recruiting participants across multiple time zones and providing different survey delivery methods. Offering the option of SMS text message survey notifications and reminders may be an important way to increase completion rates and the timeliness of responses. REDCap is a potentially useful tool for researchers wishing to implement EMA in settings in which cost or privacy are current barriers. Researchers should weigh these benefits with the potential limitations of REDCap and this design, including staff time to set up, monitor, and clean the data outputs of the project.

Introduction: Poor quality T1-weighted brain scans systematically affect the calculation of brain measures. Removing the influence of such scans requires identifying and excluding scans with noise and artefacts through a quality control (QC) procedure. While QC is critical for brain imaging analyses, it is not yet clear whether different QC approaches lead to the exclusion of the same participants. Further, the removal of poor-quality scans may unintentionally introduce a sampling bias by excluding the subset of participants who are younger and/or feature greater clinical impairment. This study had two aims: (1) examine whether different QC approaches applied to T1-weighted scans would exclude the same participants, and (2) examine how exclusion of poor-quality scans impacts specific demographic, clinical and brain measure characteristics between excluded and included participants in three large pediatric neuroimaging samples. Methods: We used T1-weighted, resting-state fMRI, demographic and clinical data from the Province of Ontario Neurodevelopmental Disorders network (Aim 1: n = 553, Aim 2: n = 465), the Healthy Brain Network (Aim 1: n = 1051, Aim 2: n = 558), and the Philadelphia Neurodevelopmental Cohort (Aim 1: n = 1087; Aim 2: n = 619). Four different QC approaches were applied to T1-weighted MRI (visual QC, metric QC, automated QC, fMRI-derived QC). We used tetrachoric correlation and inter-rater reliability analyses to examine whether different QC approaches excluded the same participants. We examined differences in age, mental health symptoms, everyday/adaptive functioning, IQ and structural MRI-derived brain indices between participants that were included versus excluded following each QC approach. Results: Dataset-specific findings revealed mixed results with respect to overlap of QC exclusion. However, in POND and HBN, we found a moderate level of overlap between visual and automated QC approaches (rtet=0.52–0.59). Implementation of QC excluded younger participants, and tended to exclude those with lower IQ, and lower everyday/adaptive functioning scores across several approaches in a dataset-specific manner. Across nearly all datasets and QC approaches examined, excluded participants had lower estimates of cortical thickness and subcortical volume, but this effect did not differ by QC approach. Conclusion: The results of this study provide insight into the influence of QC decisions on structural pediatric imaging analyses. While different QC approaches exclude different subsets of participants, the variation of influence of different QC approaches on clinical and brain metrics is minimal in large datasets. Overall, implementation of QC tends to exclude participants who are younger, and those who have more cognitive and functional impairment. Given that automated QC is standardized and can reduce between-study differences, the results of this study support the potential to use automated QC for large pediatric neuroimaging datasets.

Background: Autism is not always considered for girls and women until later along their clinical diagnostic pathways. Misdiagnosis or late diagnosis can pose significant disadvantages with respect to accessing timely health and autism-related services and supports. Understanding what contributes to roadblocks and detours along clinical pathways to an autism diagnosis can shed light on missed opportunities for earlier recognition. Objective: Our objective was to examine what contributed to roadblocks, detours, and missed opportunities for earlier recognition and clinical diagnosis of autism for girls and women. Design: We conducted a qualitative secondary analysis using data from a Canadian primary study that examined the health and healthcare experiences of autistic girls and women through interviews and focus groups. Methods: Transcript data of 22 girls and women clinically diagnosed with autism and 15 parents were analysed, drawing on reflexive thematic analysis procedures. Techniques included coding data both inductively based on descriptions of roadblocks and detours and deductively based on conceptualizations of sex and gender. Patterns of ideas were categorized into themes and the ‘story’ of each theme was refined through writing and discussing analytic memos, reflecting on sex and gender assumptions, and creating a visual map of clinical pathways. Results: Contributing factors to roadblocks, detours, and missed opportunities for earlier recognition and diagnosis were categorized as follows: (1) age of pre-diagnosis ‘red flags’ and ‘signals’; (2) ‘non-autism’ mental health diagnoses first; (3) narrow understandings of autism based on male stereotypes; and (4) unavailable and unaffordable diagnostic services. Conclusion: Professionals providing developmental, mental health, educational, and/or employment supports can be more attuned to nuanced autism presentations. Research in collaboration with autistic girls and women and their childhood caregivers can help to identify examples of nuanced autistic features and how context plays a role in how these are experienced and navigated.

ObjectiveThis systematic review examined the effectiveness of Emergency Department-based and initiated youth suicide prevention interventions for suicide attempts, suicidal ideation, hospitalization, family system functioning, and other mental health symptoms.MethodsWe searched five databases for randomized controlled trial (RCT) studies that examined Emergency Department-based and initiated suicide prevention interventions among youth aged 10 to 18 years old between May 2020 to June 2022. Using Cohen's d and 95% confidence interval as our standardised metrics, we followed the Preferred Reporting Items for Systematic Review and Meta-Analyses (PRISMA) and Synthesis Without Meta-Analysis in Systematic Reviews (SWiM) guidelines when synthesizing, interpreting, and reporting the findings of this review.ResultsFive studies were included in this review. Findings were first synthesized according to the targeted population of the study intervention and this review's outcomes. Two interventions were effective for decreasing depressive symptoms, hospitalization recidivism, and/or increasing family empowerment. There were no interventions that reduced subsequent suicide attempts. A meta-analysis was not conducted due to the heterogeneity of the data.ConclusionA need exists to develop and evaluate Emergency Department-based and initiated youth suicide prevention interventions that can be successfully and sustainably implemented in practice. Future research should focus on evaluating the components of interventions that effectively mitigate suicide risk among high-risk youth.

Abstract 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.

Abstract Background Suicide is a leading cause of death in children and youth, with suicidal thoughts and suicide attempts (referred to as non-fatal suicidal behaviors (NFSB)) being among its strongest predictors. Positive parenting (e.g., warmth, responsiveness), negative parenting (e.g., control, hostility), and parent-child relationship quality (e.g., trust, communication) have been reported to be associated with differences in NFSB in this population. To date, no comprehensive systematic review has considered together the wide range of parenting factors studied in relation to NFSB, and no meta-analysis of existing findings has been conducted. The present study will critically appraise and synthesize the existing evidence from observational studies that examine the relationships between parenting factors and (i) suicidal ideation and (ii) suicide attempt in children and youth. Methods Studies will be retrieved from APA PsycInfo, MEDLINE, CINAHL, Embase, Scopus, and the Cochrane Library databases. Retrospective, cross-sectional, and longitudinal studies, conducted in clinical and population settings, among youth aged less than 25 years and published as articles and dissertations in English or French will be eligible. Two reviewers will select articles using the Covidence Software after title and abstract screening and full-text assessment, will extract information using double data entry, and will appraise studies’ quality using the Quality Assessment Tool for Observational Cohort and Cross-Sectional Studies. Any disagreements will be discussed with a third reviewer. Publication bias will be evaluated using funnel plots and Egger’s test. In addition to a narrative summary of results, meta-analyses will be conducted using results from at least three studies. Three-level random effect models will allow to derive pooled estimates from dependent effect sizes (from the same sample or study). In case of significant heterogeneity, moderation analyses will be performed considering participants’ characteristics and methodological aspects of studies. The results will be reported according to the PRISMA guidelines, and the certainty of evidence will be assessed using the GRADE approach. Discussion In highlighting parenting factors associated with NFSB and in estimating the overall strength of these associations in children and youth, our results will inform further intervention and prevention strategies designed for young people experiencing NFSB and their families. Systematic review registration PROSPERO CRD42020165345

Abstract Background Problem-solving training is a common ingredient of evidence-based therapies for youth depression and has shown effectiveness as a versatile stand-alone intervention in adults. This scoping review provided a first overview of the evidence supporting problem solving as a mechanism for treating depression in youth aged 14 to 24 years. Methods Five bibliographic databases (APA PsycINFO, CINAHL, Embase, MEDLINE, Web of Science) and the grey literature were systematically searched for controlled trials of stand-alone problem-solving therapy; secondary analyses of trial data exploring problem-solving-related concepts as predictors, moderators, or mediators of treatment response within broader therapies; and clinical practice guidelines for youth depression. Following the scoping review, an exploratory meta-analysis examined the overall effectiveness of stand-alone problem-solving therapy. Results Inclusion criteria were met by four randomized trials of problem-solving therapy (524 participants); four secondary analyses of problem-solving-related concepts as predictors, moderators, or mediators; and 23 practice guidelines. The only clinical trial rated as having a low risk of bias found problem-solving training helped youth solve personal problems but was not significantly more effective than the control at reducing emotional symptoms. An exploratory meta-analysis showed a small and non-significant effect on self-reported depression or emotional symptoms (Hedges’ g = − 0.34; 95% CI: − 0.92 to 0.23) with high heterogeneity. Removing one study at high risk of bias led to a decrease in effect size and heterogeneity (g = − 0.08; 95% CI: − 0.26 to 0.10). A GRADE appraisal suggested a low overall quality of the evidence. Tentative evidence from secondary analyses suggested problem-solving training might enhance outcomes in cognitive-behavioural therapy and family therapy, but dedicated dismantling studies are needed to corroborate these findings. Clinical practice guidelines did not recommend problem-solving training as a stand-alone treatment for youth depression, but five mentioned it as a treatment ingredient. Conclusions On its own, problem-solving training may be beneficial for helping youth solve personal challenges, but it may not measurably reduce depressive symptoms. Youth experiencing elevated depressive symptoms may require more comprehensive psychotherapeutic support alongside problem-solving training. High-quality studies are needed to examine the effectiveness of problem-solving training as a stand-alone approach and as a treatment ingredient.

Abstract Background A pediatric cancer diagnosis and its treatment can have a detrimental effect on the mental health of children and their families. Screening to identify psychosocial risk in families has been recognized as a standard of care in pediatric oncology, but there has been limited clinical application of this standard thus far. A significant impediment to the implementation of psychosocial screening is the dearth of information on how to translate psychosocial screening to clinical practice, and specifically, how to follow-up from screening results. This manuscript aims to describe a protocol of a new intervention examining the feasibility and acceptability of mapping via a Psychosocial Navigator (PSN) psychosocial screening results to specific recommendations of resources for families based on measured risk for psychosocial distress and mental health symptoms. Methods The pilot randomized control trial (RCT) consists of dyads of youth (10–17 years) newly diagnosed with cancer and their primary caregiver. This RCT includes two arms (intervention and control group), with each group completing measurements near diagnosis and 1 year later. After the initial assessment, dyads in the intervention group receive monthly screening results and recommendations from the study PSN that are tailored to these results. The patient’s primary healthcare team (nurse, social worker, oncologist) also receive the risk, distress, and mental health results as well as the recommendations from the PSN. Discussion This study addresses a significant barrier to the implementation of psychosocial screening in pediatric oncology: specifically, the limited knowledge of how to follow-up from screening results. Findings from this pilot will inform a future definitive RCT to test the effectiveness of the intervention on patient and family mental health outcomes. This project has implications for enhancing clinical care in pediatric oncology, as well as other pediatric populations. Strengths and limitations of this study This is the first study of screening and follow-up using a psychosocial navigator. This study involves both patient and caregiver report. The small sample size necessitates a future larger study to investigate the effects of intervention. Trial registration NCT04132856 , Registered 10 October 2019—retrospectively registered.

Abstract Background To co‐ordinate a multidisciplinary team in the delivery of guideline recommendations using a measurement‐based care framework, our group previously developed a care pathway for the treatment of depression in adolescents. Core components of the pathway were: assessment, education, cognitive‐behavioural therapy, a caregiver intervention group, a medication algorithm, and monthly measurement‐based care “team reviews” with the adolescent present. The aim of this study was to test the feasibility of conducting a controlled clinical trial of the pathway. Method We conducted a 20‐week pilot controlled clinical trial of the care pathway relative to treatment as usual. Participants were adolescents (age 14–18) with a primary diagnosis of Major Depressive Disorder recruited from one of two outpatient psychiatric clinics at academic hospitals. Site of presentation was the method of allocation. Thirty‐five youth were allocated to the pathway and 31 were allocated to treatment as usual. As this is a pilot study, trial feasibility outcomes were of primary interest, including clinician fidelity to the care pathway. Results Our target sample size was recruited over a 15‐month time interval. Clinician fidelity and adolescent engagement in the care pathway components on a priori checklists were high (95% and 80%, respectively). We collected baseline and 20‐week endpoint data for our primary outcome of the Children's Depression Rating Scale – Revised (CDRS‐R) for 83% of the sample. On linear mixed effects modelling, we observed a linear decrease in CDRS‐R across 4‐week intervals up to the 20‐week endpoint in both groups (β = −2.07; 95% CI −3.14 to −1.01). Conclusion A controlled clinical trial of a complex, multi‐component intervention for the treatment of depression in adolescents is feasible. Given the need to find optimal strategies to deliver effective care for adolescents with depression, a definitive randomized controlled trial of the pathway is warranted. Trial is registered at Clinicaltrials.gov: NCT03428555

Abstract Background Engaging youth and family members as active partners in research and service design offers great promise in improving projects. In youth mental health, recent research has highlighted the value of youth and family engagement. However, research on the experience and impacts of engagement is sparse. Objective This study explores the project team's experience of youth and family engagement in the design and development of the YouthCan IMPACT randomized controlled trial and clinical service pathway design. Design Qualitative data collected using semi‐structured interviews and a focus group as part of the YouthCan IMPACT clinical trial were analysed to understand the impacts of engagement. Twenty‐eight team members were interviewed, including youth and family members. A qualitative content analysis was conducted, with a member checking process. Results Team members reported facilitators, barriers and impacts of youth and family engagement. Facilitators included a safe environment and strong procedures conducive to inclusion in co‐design. Barriers included logistical, structural and institutional constraints. Overall, team members found youth and family engagement to be valuable and to positively impact the research and service design process. Discussion and Conclusions Youth and family engagement played a critical role in research and clinical service pathway design. The team found that their involvement improved the quality of the research and service pathway through sustained and multifaceted engagement. Facilitators and barriers to engagement may serve to guide future engagement initiatives. Future research should evaluate the long‐term impact of early engagement and further focus on family engagement. Patient/Public Contribution Youth and family members were engaged in the data analysis and interpretation process.

Children and youth flourish in environments that are predictable, safe, and structured. The COVID-19 pandemic has disrupted these protective factors making it difficult for children and youth to adapt and thrive. Pandemic-related school closures, family stress, and trauma have led to increases in mental health problems in some children and youth, an area of health that was already in crisis well before COVID-19 was declared a global pandemic. Because mental health problems early in life are associated with significant impairment across family, social, and academic domains, immediate measures are needed to mitigate the potential for long-term sequalae. Now more than ever, Canada needs a national mental health strategy that is delivered in the context in which children and youth are most easily accessible—schools. This strategy should provide coordinated care across sectors in a stepped care framework and across a full continuum of mental health supports spanning promotion, prevention, early intervention, and treatment. In parallel, we must invest in a comprehensive population-based follow-up of Statistics Canada’s Canadian Health Survey on Children and Youth so that accurate information about how the pandemic is affecting all Canadian children and youth can be obtained. It is time the Canadian government prioritizes the mental health of children and youth in its management of the pandemic and beyond.

Introduction An important consideration for determining the severity of mental health symptoms is their impact on youth’s daily lives. Those wishing to assess ‘life impact’ face several challenges: First, various measurement instruments are available, including of global functioning, health-related quality of life and well-being. Existing reviews have tended to focus on one of these domains; consequently, a comprehensive overview is lacking. Second, the extent to which such instruments truly capture distinct concepts is unclear. Third, many available scales conflate symptoms and their impact, thus undermining much needed analyses of associations between the two.Methods and analysis A scoping umbrella review will examine existing reviews of life impact measures for use with children and youth aged 6–24 years in the context of mental health and well-being research. We will systematically search six bibliographic databases (MEDLINE, Embase, APA PsycINFO, CINAHL, Web of Science, and the COSMIN database of systematic reviews of outcome measurement instruments), and conduct systematic record screening, data extraction and charting based on methodological guidance by the Joanna Briggs Institute. Data synthesis will involve the tabulation of scale characteristics, feasibility and measurement properties, and the use of summary statistics to synthesise how these instruments operationalise life impact. The protocol was registered prospectively with the Open Science Framework (osf.io/ers48).Ethics and dissemination This study will provide a comprehensive road map for researchers and clinicians seeking to assess life impact in youth mental health, providing guidance in navigating available measurement options. We will seek to publish the findings in a leading peer-reviewed journal in the field. Formal research ethics approval will not be required.

Abstract Background Although research on the relationship between parent and child mental health is growing, the impact of early parenting stress on preschool-aged children’s mental health remains unclear. The objective was to evaluate the association between parenting stress during infancy and mental health problems in 3-year-old children. Methods A prospective cohort study of healthy preschool-aged children recruited from 9 primary care practices in Toronto, Canada was conducted through the TARGet Kids! primary care practice-based research network. Parenting stress was measured when children were between 0 to 16 months of age, using the Parent Stress Index Short Form, PSI-SF. Parent-reported child mental health problems were measured at 36 to 47 months using the preschool Strengths and Difficulties Questionnaire, total difficulties score (TDS). Hierarchical linear regression analysis was used to investigate the association between standardized PSI-SF and TDS, adjusted for child age, sex, temperament, sleep duration and household income. To strengthen clinical interpretation, analysis was repeated using adjusted multivariable logistic regression (TDS dichotomized at top 20%). Results A total of 148 children (mean ± SD age, 37.2 ± 1.7 months, 49% male) were included in the analysis. Parenting stress during infancy (11.4 ± 3.1 months of age) was significantly associated with mental health problems in 3-year-old children (β = 0.35; 95% CI = 0.20–0.49, p

Abstract Background There is a growing recognition of sex and gender influences in autism. Increasingly, studies include comparisons between sexes or genders, but few have focused on clarifying the characteristics of autistic girls’/women’s physical health. Methods A scoping review was conducted to determine what is currently known about the physical health of autistic girls/women. We screened 1112 unique articles, with 40 studies meeting the inclusion criteria. We used a convergent iterative process to synthesize this content into broad thematic areas. Results Autistic girls/women experience more overall physical health challenges compared to non-autistic girls/women and to autistic boys/men. Emerging evidence suggests increased prevalence of epilepsy in autistic girls/women compared to non-autistic girls/women and to autistic boys/men. The literature also suggests increased endocrine and reproductive health conditions in autistic girls/women compared to non-autistic girls/women. Findings regarding gastrointestinal, metabolic, nutritional, and immune-related conditions are preliminary and inconsistent. Limitations The literature has substantial heterogeneity in how physical health conditions were assessed and reported. Further, our explicit focus on physical health may have constrained the ability to examine interactions between mental and physical health. The widely differing research aims and methodologies make it difficult to reach definitive conclusions. Nevertheless, in keeping with the goals of a scoping review, we were able to identify key themes to guide future research. Conclusions The emerging literature suggests that autistic girls/women have heightened rates of physical health challenges compared to non-autistic girls/women and to autistic boys/men. Clinicians should seek to provide holistic care that includes a focus on physical health and develop a women’s health lens when providing clinical care to autistic girls/women.

Abstract Background Emergency Departments (EDs) are a first point-of-contact for many youth with mental health and suicidality concerns and can serve as an effective recruitment source for randomized controlled trials (RCTs) of mental health interventions. However, recruitment in acute care settings is impeded by several challenges. This pilot RCT of a youth suicide prevention intervention recruited adolescents aged 12 to 17 years presenting to a pediatric hospital ED with suicide related behaviors. Methods Recruitment barriers were identified during the initial study recruitment period and included: the time of day of ED presentations, challenges inherent to study presentation, engagement and participation during an acute presentation, challenges approaching and enrolling acutely suicidal patients and families, ED environmental factors, and youth and parental concerns regarding the study. We calculated the average recruitment productivity for published trials of adolescent suicide prevention strategies which included the ED as a recruitment site in order to compare our recruitment productivity. Results In response to identified barriers, an enhanced ED-centered recruitment strategy was developed to address low recruitment rate, specifically (i) engaging a wider network of ED and outpatient psychiatry staff (ii) dissemination of study pamphlets across multiple areas of the ED and relevant outpatient clinics. Following implementation of the enhanced recruitment strategy, the pre-post recruitment productivity, a ratio of patients screened to patients randomized, was computed. A total of 120 patients were approached for participation, 89 (74.2%) were screened and 45 (37.5%) were consented for the study from March 2018 to April 2019. The screening to randomization ratio for the study period prior to the introduction of the enhanced recruitment strategies was 3:1, which decreased to 1.8:1 following the implementation of enhanced recruitment strategies. The ratio for the total recruitment period was 2.1:1. This was lower than the average ratio of 3.2:1 for published trials. Conclusions EDs are feasible sites for participant recruitment in RCTs examining new interventions for acute mental health problems, including suicidality. Engaging multi-disciplinary ED staff to support recruitment for such studies, proactively addressing anticipated concerns, and creating a robust recruitment pathway that includes approach at outpatient appointments can optimize recruitment. Trial registration ClinicalTrials.gov : NCT03488602 , retrospectively registered April 4, 2018.

Abstract Background Understanding the burden and determinants of suicide during adolescence is key to achieving global health goals. We examined the prevalence and determinants of self-reported suicidal ideation and attempts among younger (13–15 years) and older adolescents (16–17 years). Methods Pooled prevalence estimates with 95% confidence interval, were calculated for suicide ideation and attempts for 118 surveys from 90 countries that administered the Global School-based Student Health Survey (GSHS) to adolescents (13–17 years of age) from 2003 to 2017. Indicators (including individual and social factors) associated with suicidal ideation and attempts were determined from multivariable linear regressions on key outcomes. Results The prevalence of suicidal ideation representing 397,299 adolescents (51.3% female) was significantly higher among girls than boys whereas attempts did not differ by age or sex. Being bullied, or having no close friends was associated with suicidal ideation among girls 13–15 years and 16–17 years, respectively. Among all boys, being in a fight and having no close friends was associated with suicidal ideation with the addition of serious injury for boys 13–15 years. Common to all younger adolescents was an association of suicide attempt with being bullied and having had a serious injury. Among young boys, having no close friends was an additional indicator for suicide attempt. Having no close friends was associated with suicide attempt in older adolescents with the addition to being bullied in older girls and serious injury in older boys. Conclusions Building positive social relationships with peers and avoiding serious injury appear key to suicide prevention strategies for vulnerable adolescents. Targeted programs by age group and sex for such indicators could improve mental health during adolescence in low and middle-income countries, given the diverse risk profiles for suicidal ideation and attempts.

Abstract 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.

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 = ameis&rank = 1; 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.

Abstract Background Evidence-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. Methods RCTs 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. Results Eighteen 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. Conclusions Heterogeneous 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.

Abstract 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.

Abstract 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) .

Abstract Background Suicide is a leading cause of death among adolescents in North America. Youth who present to the Emergency Department (ED) with acute suicidality are at increased risk for eventual death by suicide, thereby presenting an opportunity for secondary prevention of suicide. The current study evaluates the effectiveness of a standardized individual and family-based suicidal behaviour risk reduction intervention targeting adolescents at high-risk for suicide. Methods A randomized controlled trial (RCT) will be conducted to evaluate the effectiveness of a manualized youth- and family- based suicide prevention strategy (SPS) as compared with case navigation (NAV) among adolescents aged 12 to 18 years of age who present to the ED with acute suicidal ideation (SI) or suicide risk behaviours (SRB). We will recruit 128 participants and compare psychiatric symptoms including SI/SRB, family communication, and functional impairment at baseline and follow-ups (post-intervention [6 weeks], 24 weeks). The primary outcome is change in suicidal ideation measured with the Suicide Ideation Questionnaire- Junior. SRBs are measured with the Suicide Behaviour Questionnaire. Secondary outcomes are change in depressive and anxious symptoms measured with semi-structured psychiatric interview and Screen for Child Anxiety Related Disorders; acute mental health crises measured by urgent medical (including ED) visits; family communication measured with Conflict Behaviour Questionnaire, functional impairment measured by Columbia Impairment Scale; cost effectiveness, and fidelity of implementation measured by audio recording and fidelity checklist. Discussion Results of this study will inform a larger multi-centre RCT that will include both community and academic hospitals in urban and rural settings. Study results will be shared at international psychiatry and emergency medicine meetings, in local rounds, and via publication in academic journals and clinician-oriented newsletters. If effective, the intervention may provide a brief, scalable, and transportable treatment program that may be implemented in a variety of settings, including those in which access to children’s mental health care services is challenging. Trial registration ClinicalTrials.gov: NCT03488602, retrospectively registered April 4, 2018.

Abstract 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.

There is a need for reliable and valid screening tools that assess depressive symptoms in adolescents in Pakistan. To address this need, the present study examined the psychometric properties and factor structure of a Sindhi-translated and adapted version of the child-report Mood and Feelings Questionnaire (MFQ-C) and the Short Mood and Feelings Questionnaire (SMFQ-C) in a community sample of adolescents living in Matiari, Pakistan. Questionnaires were translated into Sindhi and administered by study psychologists to 1350 participants (52.3% female) 9.0 to 15.9 years old. Measurement structure was examined using confirmatory factor analysis. Internal consistency was estimated, and convergent and divergent validity were explored using subscales from the Strengths and Difficulties Questionnaire and the Screen for Child Anxiety Related Emotional Disorders. The unidimensional structure of the MFQ-C was found to be adequate, but a four-factor structure comprising core mood, vegetative, cognitive and agitated distress symptoms best fit the data (CFI = 0.97, TLI = 0.97, RMSEA = 0.05). The original unidimensional structure of the SMFQ-C was supported (CFI = 0.97, TLI = 0.96, RMSEA = 0.07). The MFQ-C and the SMFQ-C respectively showed excellent (α = 0.92) and good internal consistency (α = 0.87) as well as satisfactory construct validity with some differences observed across the MFQ-C subscales. The SMFQ-C and the adapted MFQ-C appear to be reliable and valid measures of depressive symptoms among early adolescents living in rural Pakistan. Both total and subscale scores can be derived from the MFQ-C to assess general and specific dimensions of depressive symptoms in this population.

Background: Many phenotypic studies have estimated the degree of comorbidity between Autism Spectrum Disorder (ASD) and Attention Deficit Hyperactivity Disorder (ADHD), but few have examined the latent, or unobserved, structure of combined ASD and ADHD symptoms. This is an important perquisite toward better understanding the overlap between ASD and ADHD.Methods: We conducted a scoping review of studies that examined the factor or latent class structure of ASD and ADHD symptoms within the same clinical or general population sample.Results: Eight studies met final inclusion criteria. Four factor analysis studies found that ASD and ADHD domains loaded separately and one found that some ASD and ADHD domains loaded together. In the three latent class studies, there were evidence of profiles with high levels of co-occurring ASD and ADHD symptoms.Conclusions: Our scoping review provides some evidence of phenotypic overlap between ASD and ADHD at the latent, or unobserved, level, particularly when using a “person-centered” (latent class analysis) vs. a “variable-centered” (factor analysis) approach.

Background Current first-line treatments for paediatric depression demonstrate mild-to-moderate effectiveness. This has spurred a growing body of literature on lifestyle recommendations pertaining to nutrition, sleep and exercise for treating paediatric depression. Aims Paediatric depression clinical practice guidelines (CPGs) were reviewed for quality and to catalogue recommendations on nutrition, sleep and exercise made by higher-quality CPGs. Method Searches were conducted in Medline, EMBASE, PsycINFO, Web of Science and CINAHL, and grey literature CPGs databases for relevant CPGs. Eligible CPGs with a minimum or high-quality level, as determined by the Appraisal of Guidelines for Research and Evaluation, Second Edition instrument, were included if they were (a) paediatric; (b) CPGs, practice parameter or consensus or expert committee recommendations; (c) for depression; (d) the latest version and (e) lifestyle recommendations for nutrition, sleep or exercise. Key information extracted included author(s), language, year of publication, country, the institutional body issuing the CPG, target disorder, age group, lifestyle recommendation and the methods used to determine CPG lifestyle recommendations. Results Ten paediatric CPGs for depression with a minimum or high-quality level contained recommendations on nutrition, sleep or exercise. Lifestyle recommendations were predominately qualitative, with quantitative details only outlined in two CPGs for exercise. Most recommendations were brief general statements, with 50% lacking supporting evidence from the literature. Conclusions Interest in lifestyle interventions for treatment in child and youth depression is growing. However, current CPG lifestyle recommendations for nutrition, sleep or exercise are based on expert opinion rather than clinical trials.

Introduction Longitudinal trajectory methods, featuring outcome assessments at three or more time points, are increasingly being used as appropriate approaches to understand developmental pathways of people on the autism spectrum across the lifespan. Understanding the scope of this rapidly expanding body of research can help inform future trajectory studies and identify areas for potential meta-analysis as well as key evidence gaps. We present the protocol for a scoping review whose objective is to identify and summarise the scope of research that uses a longitudinal trajectory study design to examine development in children diagnosed with autism. Specifically, we will identify outcome domains and age intervals that have been well characterised, areas where further research is needed and the historical use of various longitudinal trajectory analytical approaches.Methods and analysis We outline the methods for the proposed scoping review according to the framework outlined by Arksey and O’Malley, with subsequent clarifications and enhancements by other authors. Using a search strategy developed by a medical librarian, we will search six databases for relevant publications. Titles and abstracts will be screened in duplicate, followed by full-text screening. Data extraction fields developed predominantly a priori from a set of guiding subquestions will be used to chart relevant data. The findings will include quantitative aggregate summaries, narrative summaries, and appraisal of trajectory studies according to our methodological subquestions. We will consult autistic self-advocate and parent–caregiver stakeholders to facilitate interpretation of the findings.Ethics and dissemination Research ethics approval is not required for this scoping review. The results will be presented to researcher, care professional, policy-maker and stakeholder audiences at local and international conferences, other dissemination activities and published in a peer-reviewed journal.

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.

Introduction Transition from child and adolescent mental health services (CAMHS) to community or adult mental health services (AMHS) is a highly problematic health systems hurdle, especially for transition-aged youth. A planned and purposeful transition process is often non-existent or experienced negatively by youth and their caregivers. Stakeholders, including youth and their caregivers, have demanded interventions to support more effective transitions, such a transition navigator. The transition navigator model uses a navigator to facilitate complex transitions from acute care CAMHS to community or AMHS. However, despite the widespread implementation of this model, there has been no evaluation of the programme, hindering its scalability. This paper describes the study protocol of the Navigator Evaluation Advancing Transitions study that aims to collaborate with patients, caregivers and clinicians in the evaluation of the navigator model.Methods and analysis A pre and post mixed-method study will be conducted, using the Triple Aim Framework, to evaluate the navigator model. We will recruit participants from one large tertiary and two community hospitals in Toronto, Canada. For the quantitative portion of the study, we will recruit a sample of 45 youth (15 at each site), aged 16–18, and their caregivers at baseline (referral to navigator) (T1) and 6 months (T2). Youth and caregiver participants will complete a set of standardised measures to assess mental health, service utilisation, and satisfaction outcomes. For the qualitative portion of the study, semistructured interviews will be conducted at 6 months (T2) with youth, their caregivers and clinicians to better understand their experience and satisfaction with the model.Ethics and dissemination Research Ethics Board (REB) approval has been obtained from the lead research sites, the University of Toronto and the Hospital for Sick Children. The results of the study will be reported in peer-reviewed publications, webinars and conferences and to all relevant stakeholders.

Abstract Background Community-based, integrated youth service hubs have the potential to address some of the longstanding issues with mental health services for youth, including problems with access and system fragmentation. Better understanding of these approaches, particularly efforts to create a single point of entry to comprehensive, evidence-based services through youth service hubs, is needed to help guide future implementation and evaluation. This scoping review identifies the key principles and characteristics of these models of care, as well as the state of the literature, particularly with regard to implementation and replicability. Method Electronic databases and grey literature sources were searched for material from 2001 to 2019, with diverse search terms capturing the concept of “integrated” or “one-stop shop” youth mental health services. Title/abstract and full text review were conducted, as well as additional focused searching. After screening 4891 texts at the title/abstract level and 496 at the full-text level, 110 documents were included for data extraction. Results Several integrated care hub models for youth mental health services and related frameworks were identified internationally, largely in high-income countries. Common principles included an emphasis on rapid access to care and early intervention, youth and family engagement, youth-friendly settings and services, evidence-informed approaches, and partnerships and collaboration. Program characteristics also revealed similarities (e.g., providing evidence-informed or evidence-based services in youth-friendly spaces), with some differences (e.g., care coordination methods, types of service providers), potentially attributable to lack of available information about key ingredients. Outcome research was limited, with few rigorous evaluations of youth outcomes. Moreover, sufficient information for replication, community evaluation of feasibility or actual implementation was rarely provided. Conclusion Internationally, integrated youth service hubs were found to share common key principles, while providing comprehensive services to youth with mental health difficulties. There is a great need for common language and measurement framework to facilitate replication, rigorous evaluation of outcomes, knowledge exchange, and dissemination of findings.

Abstract Background Inadequate and poor quality outcome reporting in clinical trials is a well-documented problem that impedes the ability of researchers to evaluate, replicate, synthesize, and build upon study findings and impacts evidence-based decision-making by patients, clinicians, and policy-makers. To facilitate harmonized and transparent reporting of outcomes in trial protocols and published reports, the Instrument for reporting Planned Endpoints in Clinical Trials (InsPECT) is being developed. The final product will provide unique InsPECT extensions to the SPIRIT (Standard Protocol Items: Recommendations for Interventional Trials) and CONSORT (Consolidated Standards of Reporting Trials) reporting guidelines. Methods The InsPECT SPIRIT and CONSORT extensions will be developed in accordance with the methodological framework created by the EQUATOR (Enhancing the Quality and Transparency of Health Research Quality) Network for reporting guideline development. Development will consist of (1) the creation of an initial list of candidate outcome reporting items synthesized from expert consultations and a scoping review of existing guidance for reporting outcomes in trial protocols and reports; (2) a three-round international Delphi study to identify additional candidate items and assess candidate item importance on a 9-point Likert scale, completed by stakeholders such as trial report and protocol authors, systematic review authors, biostatisticians and epidemiologists, reporting guideline developers, clinicians, journal editors, and research ethics board representatives; and (3) an in-person expert consensus meeting to finalize the set of essential outcome reporting items for trial protocols and reports, respectively. The consensus meeting discussions will be independently facilitated and informed by the empirical evidence identified in the primary literature and through the opinions (aggregate rankings and comments) collected via the Delphi study. An integrated knowledge translation approach will be used throughout InsPECT development to facilitate implementation and dissemination, in addition to standard post-development activities. Discussion InsPECT will provide evidence-informed and consensus-based standards focused on outcome reporting in clinical trials that can be applied across diverse disease areas, study populations, and outcomes. InsPECT will support the standardization of trial outcome reporting, which will maximize trial usability, reduce bias, foster trial replication, improve trial design and execution, and ultimately reduce research waste and help improve patient outcomes.

Parents of children with autism assume substantial responsibility for navigating intervention to address autism-related concerns, including involvement in therapy. Little is known, from the perspective of these parents, regarding how to best engage and support them in this navigating process as it evolves over the child’s development. In this article, we present findings from a large qualitative study that investigated how parents of children with autism navigate intervention, to construct an in-depth theoretical account of how this group comes to be engaged in individual-level care. Using grounded theory methods and a symbolic interactionist framework, we analyzed select documents and 45 intensive interviews conducted with 32 mothers and 9 expert professionals from urban and rural regions of Ontario, Canada. Parent-defined concerns are the central impetus for the core process of navigating intervention, labeled using parents’ language making your own way. We describe how this process is analogous to engaging in care. Four meaning-making processes – defining concerns, informing the self, seeing what is involved, and adapting emotionally – all interacting in an ongoing fashion, together account for parents’ evolving readiness and motivation for taking action to navigate intervention. We illustrate how parents’ readiness and motivation for navigating intervention (and thus for engagement) evolves over a generalized trajectory, according to three highly overlapping processes experienced by most parents: coming to understand their child has autism, going into high gear, and easing off. These findings indicate multiple empirical conditions and factors affecting engagement that service planners and professionals will likely want to consider when seeking parent involvement as a means to improve outcomes in autism. Additionally, theoretical aspects are relevant to the developing understanding of how healthcare consumers in general become engaged in individual care, with implications for patient-centered care.

Suicidality is increased in autism spectrum disorder (ASD), yet effective interventions are lacking. Developing biologically based approaches for preventing and treating suicidality in ASD hinges on the identification of biomarkers of suicidal ideation (SI). Here, we assessed magnetic resonance spectroscopy (MRS) markers of glutamatergic neurotransmission in ASD youth and young adults. Twenty-eight ASD participants (16–33 years) underwent 1H-MRS, and metabolites were quantified using LCModel. N-acetylaspartate (NAA), glutamate (Glu), and the NAA/Glu ratio from the left dorsolateral prefrontal cortex were compared between ASD SI+ (n = 13) and ASD SI− (n = 15) participants. We found that ASD SI+ participants had a higher NAA/Glu ratio compared ASD SI- participants. The NAA/Glu ratio also predicted SI and significantly discriminated between ASD SI+/SI− participants. All analyses including NAA and Glu alone were non-significant. Here, we provide preliminary evidence for the importance of NAA/Glu in ASD with SI, with implications for biomarker discovery. Further mechanistic research into risk and interventional approaches to address SI in ASD are needed.

Background/Objectives: The child and adolescent psychiatry (CAP) subspecialty training program at the University of Toronto was among the first fully accredited CAP programs in Canada. As one of Canada's largest CAP subspecialty programs, we attract many excellent applicants annually. While objectivity and transparency in the selection of candidates have been valued, it was unclear which applicant attributes should be prioritized. This quality improvement project was undertaken to identify the key applicant attributes that should be prioritized for admission to the program.Materials/Methods: An initial list of attributes was compiled by project team members and feedback solicited. Through iterative design, this list was categorized into “end products,” “branding attributes” and “generic attributes.” The “end products” were removed as these represented outputs of training rather than attributes on which applicant selection should be based. Subsequent steps involved only the “branding” and “generic” attributes. A consensus-building exercise led to the creation of two short-lists of five attributes within each category. Finally, a paired-comparison forced choice methodology was used to determine the ranking of these attributes in order of importance when assessing applicants.Results: The final lists of “generic” and “branding” attributes developed through a consensus-building exercise are presented in rank order based on the paired-comparison methodology. The overall response rate for the forced choice electronic survey was 49% of faculty and learners.Conclusions/Discussion: This project used an iterative process of consensus building & pairwise comparison to prioritize key attributes for assessing trainee selection to the program. Going forward, these attributes will be incorporated into the file review and interview portions of our admissions process. In addition to emphasizing these priority attributes in admissions, there are implications for other aspects of the program including curriculum and faculty development, as well as guiding the overall mission and vision for the Division. A similar process could be undertaken by other training programs seeking to identify priority attributes for admission to their programs.

Objectives This study aimed to evaluate the association between maternal ethnicity and iron deficiency (ID) in early childhood, and to evaluate whether infant feeding practices linked to ID differ between maternal ethnic groups.Methods This was a cross-sectional study of healthy children 1–3 years of age. Adjusted multivariable logistic regression analyses were used to evaluate the association between maternal ethnicity and ID (serum ferritin 2 cups; meat consumption).Results Of 1851 children included, 12.2% had ID. Compared with the European referent group, we found higher odds of ID among children of South Asian and West Asian/North African maternal ethnicities, and lower odds of ID among children of East Asian maternal ethnicity. Statistically significant covariates associated with higher odds of ID included longer breastfeeding duration and daily cow’s milk intake >2 cups. Current infant formula use was associated with lower odds of ID. Children of South Asian maternal ethnicity had higher odds of bottle use beyond 15 months of age and lower odds of meat consumption.Conclusions We found increased odds of ID among children of South Asian and West Asian/Northern African maternal ethnicities. We found a higher odds of feeding practices linked to ID in children of South Asian maternal ethnicity, but not in children of West Asian/North African maternal ethnicity. Culturally tailored approaches to providing guidance to parents on healthy infant feeding practices may be important to prevent ID in early childhood.Trial registration number NCT01869530.

Introduction Among randomised controlled trials for depressed adolescents, the extent of variation in how depressive symptom outcomes are defined is unknown. The variability in which potential predictors of these outcomes are tested is also unclear. This paper is a protocol describing the methods of a planned scoping review. The scoping review will examine and summarise how change in depressive symptoms have been described in RCT treatment studies to date. This review will report the measures used to describe change in depressive symptoms and whether the measure was used as a continuous or binary outcome or both. This review will describe how dichotomous outcome terms are defined to describe change in depression severity. This review will also examine predictors, moderators and mediators of change in depressive symptoms within RCTs.Methods and analysis In this paper, we describe the protocol for our scoping review. Following the format outlined by the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for scoping reviews, a research librarian will develop an operationalised search strategy, which we will apply to the MEDLINE, Embase, PsycINFO and Cumulative Index to Nursing and Allied Health Literature databases. We will search for papers from inception to 6 February 2020. A hand search for key citations will also be conducted. Investigator-raters will screen articles, first via the titles and abstracts and then through full-text reviews. We will include articles with randomised control design which assess the treatment of adolescents with major depressive disorder. We will systematically extract and synthesise prespecified data which includes: definition of depression used for participant inclusion, measures used to evaluate changes in depression, type of outcome used (continuous, binary or both), definitions of dichotomous terms to denote change in depression (eg, response, remission, recovery, etc) and reported predictors/moderators/mediators of change.Ethics and dissemination Ethics approval is not required. Findings will be presented in journal publications and at conferences.

Background: Individuals with autism spectrum disorder (ASD) often present with executive functioning (EF) deficits, including spatial working memory (SWM) impairment, which impedes real-world functioning. The present study examined task-related brain activity, connectivity and individual variability in fMRI-measured neural response during an SWM task in older youth and young adults with autism and clinically significant EF impairment. Methods: Neuroimaging was analyzed in 29 individuals with ASD without intellectual disability who had clinically significant EF impairment on the Behavior Rating Inventory of Executive Function, and 20 typically developing controls (participant age range=16-34). An SWM N-Back task was performed during fMRI. SWM activity (2-Back vs. 0-Back) and task-related dorsolateral prefrontal cortex (DLPFC) connectivity was examined within and between groups. Variability of neural response during SWM was also examined. Results: During SWM performance both groups activated the expected networks, and no group differences in network activation or task-related DLPFC-connectivity were found. However, greater individual variability in the pattern of SWM activity was found in the ASD versus the typically developing control group. Conclusions: While there were no group differences in SWM task-evoked activity or connectivity, fronto-parietal network engagement was found to be more variable/idiosyncratic in ASD. Our results suggest that the fronto-parietal network may be shifted or sub-optimally engaged during SWM performance in participants with ASD with clinically significant EF impairment, with implications for developing targeted interventions for this subgroup.

Abstract Background Although several genetic variants for autism spectrum disorder (ASD) have now been identified, these largely occur sporadically or are de novo. Much less progress has been made in identifying inherited variants, even though the disorder itself is familial in the majority of cases. The objective of this study was to identify chromosomal regions that harbor inherited variants increasing the risk for ASD using an approach that examined both ASD and the broad autism phenotype (BAP) among a unique sample of extended pedigrees. Methods ASD and BAP were assessed using standardized tools in 28 pedigrees from Canada and the USA, each with at least three ASD-diagnosed individuals from two nuclear families. Genome-wide linkage analysis was performed using the posterior probability of linkage (PPL) statistic, a quasi-Bayesian method that provides strength of evidence for or against linkage in an essentially model-free manner, with outcomes on the probability scale. Results The results confirm appreciable interfamilial heterogeneity as well as a high level of intrafamilial heterogeneity. Both ASD and combined ASD/BAP specific loci are apparent. Conclusions Inclusion of subclinical phenotypes such as BAP should be more widely employed in genetic studies of ASD as a way of identifying inherited genetic variants for the disorder. Moreover, the results underscore the need for approaches to identifying genetic risk factors in extended pedigrees that are robust to high levels of inter/intrafamilial locus and allelic heterogeneity.

Researchers increasingly employ longitudinal trajectory methods to understand developmental pathways of people on the autism spectrum across the lifespan. By assessing developmental or health-related outcome domains at three or more timepoints, trajectory studies can characterize their shape and varying rates of change over time. The purpose of this scoping review was to identify and summarize the published breadth of research that uses a trajectory study design to examine development in children (to age 18 years) diagnosed with autism. Using a systematic search and screening procedure, 103 studies were included. This review summarizes methodological characteristics across studies including the varying statistical approaches used. A series of figures maps where published research is available across 10 outcome domains and the ages over which children have been followed. Evidence gaps, informed by the perspectives of the autistic and caregiver stakeholders that were engaged in this review, are discussed. We recommend that future trajectory research addresses the absence of studies from low- and middle-income countries, considers longitudinal assessment of outcome domains that caregivers and autistic people consider meaningful, and plans follow-up periods with assessment timepoints that cover the gaps in ages where more outcome-specific data are needed.

Abstract Background Autism spectrum disorder (ASD), a developmental disorder of early childhood onset, affects males four times more frequently than females, suggesting a role for the sex chromosomes. In this study, we describe a family with ASD in which a predicted pathogenic nonsense mutation in the X-chromosome gene RAB39B segregates with ASD phenotype. Methods Clinical phenotyping, microarray, and whole genome sequencing (WGS) were performed on the five members of this family. Maternal and female sibling X inactivation ratio was calculated, and phase was investigated. Mutant-induced pluripotent stem cells engineered for an exon 2 nonsense mutation were generated and differentiated into cortical neurons for expression and pathway analyses. Results Two males with an inherited RAB39B mutation both presented with macrocephaly, intellectual disability (ID), and ASD. Their female sibling with the same mutation presented with ID and a broad autism phenotype. In contrast, their transmitting mother has no neurodevelopmental diagnosis. Our investigation of phase indicated maternal preferential inactivation of the mutated allele, with no such bias observed in the female sibling. We offer the explanation that this bias in X inactivation may explain the absence of a neurocognitive phenotype in the mother. Our cellular knockout model of RAB39B revealed an impact on expression in differentiated neurons for several genes implicated in brain development and function, supported by our pathway enrichment analysis. Conclusions Penetrance for ASD is high among males but more variable among females with RAB39B mutations. A critical role for this gene in brain development and function is demonstrated.