A comparison of gender diversity in transgender young people with and without autistic traits from the Trans 20 cohort study.

Background: There is an elevated co-occurrence of autism in trans individuals, with recent meta-analyses suggesting that 11% of trans individuals are autistic. The presence of autism in trans young people can create clinical challenges by adding complexity to the presentation, assessment and management of those presenting to gender clinics. Although many trans young people display traits of autism, how these traits relate to the nature of their gender diversity is unclear. Methods: This study compared gender identity, gender expression and gender dysphoria (GD) in trans young people with and without autistic traits. Baseline data from a cohort study of trans children and adolescents who first attended the Royal Children's Hospital Gender Service (Victoria, Australia) between February 2017 and January 2020 were analysed cross-sectionally. Autistic traits were assessed via the Social Responsiveness Scale-2. Gender was assessed using tools that measure gender identity, social transition, GD, body dissatisfaction, voice dysphoria, and chest dysphoria. Findings: 522 participants were included, of whom 239 (45.8%) exhibited autistic traits (SRS total T-score ≥60). Those with and without autistic traits were similar in their age (mean (SD) age 14.0 (2.9) and 13.1 (3.6) years respectively) and gender identity: the majority (73.7% (n = 174) and 70.5% (n = 198) respectively) identified in a binary way. Higher rates of social transition (specifically, changing pronouns) were noted in those with autistic traits (Difference in proportion 11.7, 95% confidence interval [CI] 2.4-21.1, p = 0.014). GD was high in both groups with ∼95% displaying clinically relevant levels of GD. Chest dysphoria was similar between groups, while voice dysphoria was higher in those with autistic traits (standardised mean difference [SMD] = 0.3, 95% confidence interval [CI]: 0.1-0.5 p = 0.00087). Dissatisfaction with secondary gendered characteristics (SMD = 0.3, CI: 0.1-0.5 p = 0.0011) and hormonally unresponsive body characteristics (SMD = 0.2, CI: 0.1-0.4 p = 0.016) was higher in trans young people with autistic traits. Interpretation: The similarly high severity of GD in those with and without autistic traits reinforces the importance of trans young people with and without autistic traits being availed the same opportunities to access gender-affirming care. Subtle differences identified between the groups in other areas of gender diversity suggest trans young people with autistic traits may have distinct needs and that gender-affirming care may need to be tailored accordingly. Funding: The Royal Children's Hospital Foundation, Hugh D.T. Williamson Foundation; Australian National Health and Medical Research Council-Clinical Trials and Cohort Studies scheme (GNT 2006529).

Sensory Processing in Children and Adolescents with Neurofibromatosis Type 1.

Despite the evidence of elevated autistic behaviors and co-occurring neurodevelopmental difficulties in many children with neurofibromatosis type 1 (NF1), we have a limited understanding of the sensory processing challenges that may occur with the condition. This study examined the sensory profile of children and adolescents with NF1 and investigated the relationships between the sensory profiles and patient characteristics and neuropsychological functioning. The parent/caregivers of 152 children with NF1 and 96 typically developing children completed the Sensory Profile 2 (SP2), along with standardized questionnaires assessing autistic behaviors, ADHD symptoms, internalizing symptoms, adaptive functioning, and social skills. Intellectual functioning was also assessed. The SP2 data indicated elevated sensory processing problems in children with NF1 compared to typically developing children. Over 40% of children with NF1 displayed differences in sensory registration (missing sensory input) and were unusually sensitive to and unusually avoidant of sensory stimuli. Sixty percent of children with NF1 displayed difficulties in one or more sensory modalities. Elevated autistic behaviors and ADHD symptoms were associated with more severe sensory processing difficulties. This first detailed assessment of sensory processing, alongside other clinical features, in a relatively large cohort of children and adolescents with NF1 demonstrates the relationships between sensory processing differences and adaptive skills and behavior, as well as psychological well-being. Our characterization of the sensory profile within a genetic syndrome may help facilitate more targeted interventions to support overall functioning.

Understanding nonliteral language abilities in children with neurofibromatosis type 1.

OBJECTIVE: Neurofibromatosis Type 1 (NF1) is a genetic syndrome that affects cognitive, behavioral, and social development. Nonliteral language (NLL) comprehension has not been examined in children with NF1. This study examined NLL comprehension in children with NF1 and associated neuropsychological correlates. METHOD: NLL comprehension was examined in children with NF1 (n = 49) and typically developing (TD) controls (n = 27) aged 4-12 years using a novel NLL task. The task assessed comprehension of sarcasm, metaphor, simile, and literal language. Cognitive (Wechsler Scales Composites or the Woodcock-Johnson Test of Cognitive Abilities Revised scaled scores) and behavioral (attention deficit hyperactivity disorder [ADHD] symptoms) correlates of NLL comprehension in children with NF1 were also examined. RESULTS: Children with NF1 demonstrated significantly poorer sarcasm comprehension than TD children and a vulnerability in metaphor comprehension. Simile and literal language comprehension were not significantly different between groups. Working memory difficulties and impulsive/hyperactive ADHD symptoms were associated with a reduced ability to identify sarcasm in NF1, while verbal comprehension, fluid reasoning, and inattentive ADHD symptoms were not. CONCLUSIONS: Results suggest children with NF1 experience challenges in understanding complex NLL comprehension, which are related to reduced working memory and increased impulsivity/hyperactivity. This study provides an initial insight into the figurative language abilities of children with NF1, which should be examined in relation to their social difficulties in future studies. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Delineating Visual Habituation Profiles in Preschoolers with Neurofibromatosis Type 1 and Autism Spectrum Disorder: A Cross-Syndrome Study.

Atypical habituation to repetitive information has been commonly reported in Autism Spectrum Disorder (ASD) but it is not yet clear whether similar abnormalities are present in Neurofibromatosis Type 1 (NF1). We employed a cross-syndrome design using a novel eye tracking paradigm to measure habituation in preschoolers with NF1, children with idiopathic ASD and typically developing (TD) children. Eye movements were recorded to examine fixation duration to simultaneously presented repeating and novel stimuli. Children with NF1 showed a bias for longer look durations to repeating stimuli at the expense of novel stimuli, and slower habituation in NF1 was associated with elevated ASD traits. These findings could indicate aberrant modulation of bottom-up attentional networks that interact with the emergence of ASD phenotypes.

Sex- and age-related differences in autistic behaviours in children with neurofibromatosis type 1.

This study investigated sex and age differences in autistic behaviours in children with neurofibromatosis type 1 (NF1) who scored within the clinical range on the Social Responsiveness Scale - Second Edition (T score ≥ 60). Thirty-four males and 28 females (3-16 years) were assessed with the Autism Diagnostic Observation Schedule - Second Edition and Autism Diagnostic Interview - Revised. Across both measures, males exhibited greater social communication deficits relative to females. Age-related abatement of social communication difficulties was observed for males but not females. Conversely, no sex differences were found for restricted/repetitive behaviours, which were stable over time for both males and females. The findings are discussed within the context of broader neurodevelopmental considerations that are common in NF1.

Early parenting behaviour is associated with complex attention outcomes in middle to late childhood in children born very preterm.

Attention deficits are common in children born very preterm (VP), especially for children with higher social risk. The aim of this study was to examine the association between parenting behavior and attention in children born VP, and whether this association is influenced by familial social risk. Two hundred and twenty-four children born <30 weeks' gestation and/or with a birth weight <1250 g were recruited at birth. At 2 years, social risk was calculated and parenting behaviors were observed during a parent-child interaction task, with children's attention skills assessed at 7 and 13 years using standardized assessments. Higher levels of sensitive parenting at 2 years were positively associated with divided attention at age 7 years, and higher levels of intrusive parenting were negatively associated with divided attention at 13 years. Children born VP with higher social risk were more positively influenced by sensitive parenting behavior for sustained attention at 7 years, selective attention at 13 years, and divided attention at 7 and 13 years than children born VP with lower social risk. Additionally, children born VP with higher social risk were more negatively influenced by intrusive parenting for sustained attention outcomes at 7 years than those with lower social risk. In summary, the evidence for a contribution of early parenting to attention outcomes in children born VP was stronger for more complex attention (divided attention) compared with basic attention domains. Our findings also suggest that early parenting behavior has a particular influence on children born VP from socially disadvantaged environments for attention outcomes.

A randomized controlled trial of remote microphone listening devices to treat auditory deficits in children with neurofibromatosis type 1.

BACKGROUND: A high proportion of patients with neurofibromatosis type 1 (NF1) present with functional hearing deficiency as a result of neural abnormality in the late auditory brainstem. METHODS: In this randomized, two-period crossover study, we investigated the hypothesis that remote-microphone listening devices can ameliorate hearing and communication deficits in affected school-aged children (7-17 years). Speech perception ability in background noise was evaluated in device-active and inactive conditions using the CNC-word test. Participants were then randomized to one of two treatment sequences: (1) inactive device for two weeks (placebo), followed by active device use for two weeks, or (2) active device for 2 weeks, followed by inactive device for 2 weeks. Listening and communication ratings (LIFE-R Questionnaire) were obtained at baseline and at the end of each treatment phase. RESULTS: Each participant demonstrated functional hearing benefits with remote-microphone use. All showed a speech perception in noise increase when the device was activated with a mean phoneme-score difference of 16.4% (p < 0.001) and reported improved listening/communication abilities in the school classroom (mean difference: 23.4%; p = 0.017). DISCUSSION: Conventional hearing aids are typically ineffective as a treatment for auditory neural dysfunction, making sounds louder, but not clearer for affected individuals. In this study, we demonstrate that remote-microphone technologies are acceptable/tolerable in pediatric patients with NF1 and can ameliorate their hearing deficits. CONCLUSION: Remote-microphone listening systems offer a viable treatment option for children with auditory deficits associated with NF1.

Delineating the autistic phenotype in children with neurofibromatosis type 1.

BACKGROUND: Existing research has demonstrated elevated autistic behaviours in children with neurofibromatosis type 1 (NF1), but the autistic phenotype and its relationship to other neurodevelopmental manifestations of NF1 remains unclear. To address this gap, we performed detailed characterisation of autistic behaviours in children with NF1 and investigated their association with other common NF1 child characteristics. METHODS: Participants were drawn from a larger cross-sectional study examining autism in children with NF1. The population analysed in this study scored above threshold on the Social Responsiveness Scale-Second Edition (T-score ≥ 60; 51% larger cohort) and completed the Autism Diagnostic Interview-Revised (ADI-R) and/or the Autism Diagnostic Observation Schedule-Second Edition (ADOS-2). All participants underwent evaluation of their intellectual function, and behavioural data were collected via parent questionnaires. RESULTS: The study cohort comprised 68 children (3-15 years). Sixty-three per cent met the ADOS-2 'autism spectrum' cut-off, and 34% exceeded the more stringent threshold for 'autistic disorder' on the ADI-R. Social communication symptoms were common and wide-ranging, while restricted and repetitive behaviours (RRBs) were most commonly characterised by 'insistence on sameness' (IS) behaviours such as circumscribed interests and difficulties with minor changes. Autistic behaviours were weakly correlated with hyperactive/impulsive attention deficit hyperactivity disorder (ADHD) symptoms but not with inattentive ADHD or other behavioural characteristics. Language and verbal IQ were weakly related to social communication behaviours but not to RRBs. LIMITATIONS: Lack of genetic validation of NF1, no clinical diagnosis of autism, and a retrospective assessment of autistic behaviours in early childhood. CONCLUSIONS: Findings provide strong support for elevated autistic behaviours in children with NF1. While these behaviours were relatively independent of other NF1 comorbidities, the importance of taking broader child characteristics into consideration when interpreting data from autism-specific measures in this population is highlighted. Social communication deficits appear similar to those observed in idiopathic autism and are coupled with a unique RRB profile comprising prominent IS behaviours. This autistic phenotype and its relationship to common NF1 comorbidities such as anxiety and executive dysfunction will be important to examine in future research. Current findings have important implications for the early identification of autism in NF1 and clinical management.

The mediating role of ADHD symptoms between executive function and social skills in children with neurofibromatosis type 1.

Children with neurofibromatosis type 1 (NF1) often experience executive dysfunction, attention deficit/hyperactivity disorder (ADHD) symptoms and poor social skills, however, the nature of the relationships between these domains in children with NF1 is unclear. This study investigated these relationships using primary caregiver ratings of executive functions, ADHD symptoms and social skills in children with NF1. Participants were 136 children with NF1 and 93 typically developing (TD) controls aged 3-15 years recruited from 3 multidisciplinary neurofibromatosis clinics in Melbourne and Sydney, Australia, and Washington DC, USA. Mediation analysis was performed on primary outcome variables: parent ratings of executive functions (Behavior Rating Inventory of Executive Function, Metacognition Index), ADHD symptoms (Conners-3/Conners ADHD Diagnostic and Statistical Manual for Mental Disorders Scales) and social skills (Social Skills Improvement System-Rating Scale), adjusting for potential confounders (full scale IQ, sex, and social risk). Results revealed significantly poorer executive functions, elevated ADHD symptoms and reduced social skills in children with NF1 compared to controls. Poorer executive functions significantly predicted elevated ADHD symptoms and poorer social skills. Elevated ADHD symptoms significantly mediated the relationship between executive functions and social skills problems although did not fully account for social dysfunction. This study provides evidence for the importance of targeting ADHD symptoms as part of future interventions aimed at promoting prosocial behaviors in children with NF1.

Auditory Dysfunction Among Individuals With Neurofibromatosis Type 1.

Importance: Neurofibromatosis type 1 (NF1) affects hearing through disruption of central auditory processing. The mechanisms, functional severity, and management implications are unclear. Objective: To investigate auditory neural dysfunction and its perceptual consequences in individuals with NF1. Design, Setting, and Participants: This case-control study included children and adults with NF1 and control participants matched on age, sex, and hearing level. Patients were recruited through specialist neurofibromatosis and neurogenetic outpatient clinics between April and September 2019. An evaluation of auditory neural activity, monaural/binaural processing, and functional hearing was conducted. Diffusion-weighted magnetic resonance imaging (MRI) data were collected from a subset of participants (10 children with NF1 and 10 matched control participants) and evaluated using a fixel-based analysis of apparent fiber density. Main Outcomes and Measures: Type and severity of auditory dysfunction evaluated via laboratory testing and questionnaire data. Results: A total of 44 participants (18 [41%] female individuals) with NF1 with a mean (SD) age of 16.9 (10.7) years and 44 control participants (18 [41%] female individuals) with a mean (SD) age of 17.2 (10.2) years were included in the study. Overall, 11 participants (25%) with NF1 presented with evidence of auditory neural dysfunction, including absent, delayed, or low amplitude electrophysiological responses from the auditory nerve and/or brainstem, compared with 1 participant (2%) in the control group (odds ratio [OR], 13.03; 95% CI, 1.59-106.95). Furthermore, 14 participants (32%) with NF1 showed clinically abnormal speech perception in background noise compared with 1 participant (2%) in the control group (OR, 20.07; 95% CI, 2.50-160.89). Analysis of diffusion-weighted MRI data of participants with NF1 showed significantly lower apparent fiber density within the ascending auditory brainstem pathways. The regions identified corresponded to the neural dysfunction measured using electrophysiological assessment. Conclusions and Relevance: The findings of this case-control study could represent new neurobiological and clinical features of NF1. Auditory dysfunction severe enough to impede developmental progress in children and restrict communication in older participants is a common neurobiological feature of the disorder.

Behavioral Intervention for Social Challenges in Children and Adolescents: A Systematic Review and Meta-analysis.

Importance: Social deficits are a common and disabling feature of many pediatric disorders; however, whether behavioral interventions are associated with benefits for children and adolescents with social deficits is poorly understood. Objective: To assess whether behavioral interventions in children and adolescents with neurodevelopmental or mental health disorders are associated with improvements in social function and social cognition, and whether patient, intervention, and methodological characteristics moderate the association. Data Sources: For this systematic review and meta-analysis, the PsycINFO, MEDLINE, and PubMed electronic databases were searched in December 2020 for randomized clinical trials published from database inception to December 1, 2020, including terms related to neurodevelopmental or mental health disorders, social behavior, randomized clinical trials, and children and adolescents. Data were analyzed in January 2021. Study Selection: Randomized clinical trials that enrolled participants aged 4 to 17 years with social deficits and examined the efficacy of a clinician-administered behavioral intervention targeting social functioning or social cognition were included. A total of 9314 records were identified, 78 full texts were assessed for eligibility, and 33 articles were included in the study; 31 of these reported social function outcomes and 12 reported social cognition outcomes. Data Extraction and Synthesis: Articles were reviewed using the Cochrane Risk of Bias Assessment for randomized clinical trials. Data were independently extracted and pooled using a weighted random-effects model. Main Outcomes and Measures: The main outcome was the association of behavioral intervention with social function and social cognition. Hedges g was used to measure the standardized mean difference between intervention and control groups. Standardized effect sizes were calculated for the intervention group vs the comparison group for each trial. Results: A total of 31 trials including 2131 participants (1711 [80%] male; 420 [20%] female; mean [SD] age, 10.8 [2.2] years) with neurodevelopmental or mental health disorders (autism spectrum disorder [ASD] [n = 23], attention-deficit/hyperactivity disorder [n = 4], other conditions associated with social deficits [n = 4]) were analyzed to examine differences in social function between the intervention and control groups. Significantly greater gains in social function were found among participants who received an intervention than among the control groups (Hedges g, 0.61; 95% CI, 0.40-0.83; P < .001). The type of control condition (wait list vs active control vs treatment as usual) was a significant moderator of effect size (Q2, 7.11; P = .03). Twelve studies including 487 individuals with ASD (48 [10%] female; 439 [90%] male; mean [SD] age, 10.4 [1.7] years) were analyzed to examine differences in social cognition between intervention and control groups. The overall mean weighted effect was significant (Hedges g, 0.67; 95% CI, 0.39-0.96; P < .001), indicating the treatment groups had better performance on social cognitive tasks. Conclusions and Relevance: In this systematic review and meta-analysis, significantly greater gains in social function and social cognition were reported among children and adolescents who received behavioral interventions for social deficits compared with participants receiving the control conditions. These findings suggest that children and adolescents with social deficits might benefit from social skills training regardless of their specific neurodevelopmental or mental health diagnosis.

Recommendations for Social Skills End Points for Clinical Trials in Neurofibromatosis Type 1.

OBJECTIVE: To review parent-report social skills measures to identify and recommend consensus outcomes for use in clinical trials of social deficit in children and adolescents (ages 6-18 years) with neurofibromatosis type 1 (NF1). METHODS: Searches were conducted via PubMed and ClinicalTrials.gov to identity social skills outcome measures with English language versions used in clinical trials in the past 5 years with populations with known social skills deficits, including attention-deficit/hyperactivity disorder and autism spectrum disorder (ASD). Measures were rated by the Response Evaluation in Neurofibromatosis and Schwannomatosis (REiNS) Neurocognitive Committee on patient characteristics, use in published studies, domains assessed, availability of standard scores, psychometric properties, and feasibility to determine their appropriateness for use in NF1 clinical trials. RESULTS: Two measures were ultimately recommended by the committee: the Social Responsiveness Scale-2 (SRS-2) and the Social Skills Improvement System-Rating Scale (SSIS-RS). CONCLUSIONS: Each of the 2 measures assesses different aspects of social functioning. The SSIS-RS is appropriate for studies focused on broader social functioning; the SRS-2 is best for studies targeting problematic social behaviors associated with ASD. Researchers will need to consider the goals of their study when choosing a measure, and specific recommendations for their use are provided.

Cognition, ADHD Symptoms, and Functional Impairment in Children and Adolescents With Neurofibromatosis Type 1.

Objective: We examined the contribution of attention and executive cognitive processes to ADHD symptomatology in NF1, as well as the relationships between cognition and ADHD symptoms with functional outcomes. Methods: The study sample consisted of 141 children and adolescents with NF1. Children were administered neuropsychological tests that assessed attention and executive function, from which latent cognitive variables were derived. ADHD symptomatology, adaptive skills, and quality of life (QoL) were assessed using parent-rated questionnaires. Path analyses were conducted to test relationships among cognitive functioning, ADHD symptomatology, and functional outcomes. Results: Significant deficits were observed on all outcome variables. Cognitive variables did not predict ADHD symptomatology. Neither did they predict functional outcomes. However, elevated ADHD symptomatology significantly predicted functional outcomes. Conclusion: Irrespective of cognitive deficits, elevated ADHD symptoms in children with NF1 negatively impact daily functioning and emphasize the importance of interventions aimed at minimizing ADHD symptoms in NF1.

Generation of four iPSC lines from Neurofibromatosis Type 1 patients.

We describe the generation and characterisation of four human induced pluripotent stem cell (iPSC) lines from peripheral blood mononuclear cells (PBMC) from individuals with neurofibromatosis type (NF1). PBMC reprogramming was performed using a non-integrative Sendai virus containing the reprogramming factors OCT4, SOX2, MYC and KLF4. All iPSC lines exhibited a normal karyotype, and pluripotency was validated by flow cytometry (EPCAM, TRA-1-81, SSEA1 and CD9) and immunofluorescence (OCT4 and Nanog). Differentiation of the cells into the three embryonic germ layers was confirmed using immunofluorescence. These iPSC lines are a valuable pre-clinical resource to study the molecular mechanisms underlying NF1.

Social skills and autism spectrum disorder symptoms in children with neurofibromatosis type 1: evidence for clinical trial outcomes.

AIM: We examined key features of two outcome measures for social dysfunction and autism spectrum disorder traits, the Social Responsiveness Scale, Second Edition (SRS-2) and the Social Skills Improvement System - Rating Scales (SSIS-RS), in children with neurofibromatosis type 1 (NF1). The aim of the study was to provide objective evidence as to which behavioural endpoint should be used in clinical trials. METHOD: Cross-sectional behavioural and demographic data were pooled from four paediatric NF1 tertiary referral centres in Australia and the United States (N=122; 65 males, 57 females; mean age [SD] 9y 2mo [3y], range 3-15y). RESULTS: Distributions of SRS-2 and SSIS-RS scores were unimodal and both yielded deficits, with a higher proportion of severely impaired scores on the SRS-2 (16.4%) compared to the SSIS-RS (8.2%). Pearson's product-moment correlations revealed that both questionnaires were highly related to each other (r=-0.72, p<0.001) and to measures of adaptive social functioning (both p<0.001). Both questionnaires were significantly related to attention-deficit/hyperactivity disorder symptoms, but only very weakly associated with intelligence. INTERPRETATION: The SRS-2 and SSIS-RS capture social dysfunction associated with NF1, suggesting both may be suitable choices for assessing social outcomes in this population in a clinical trial. However, careful thought needs to be given to the nature of the intervention when selecting either as a primary endpoint. WHAT THIS PAPER ADDS: The Social Responsiveness Scale, Second Edition yielded a large deficit relative to population norms. The Social Skills Improvement System - Rating Scales yielded a moderate deficit relative to population norms. Both scales were highly correlated, suggesting that they are measuring a unitary construct.

Neonatal brain abnormalities and brain volumes associated with goal setting outcomes in very preterm 13-year-olds.

Executive dysfunction including impaired goal setting (i.e., planning, organization skills, strategic reasoning) is documented in children born very preterm (VP; <30 weeks/<1250 g), however the neurological basis for this impairment is unknown. This study sought to examine the relationship between brain abnormalities and brain volumes on neonatal magnetic resonance imaging (MRI) and goal setting abilities of VP 13-year-olds. Participants were 159 children born VP in a prospective longitudinal study. Qualitative brain abnormality scores and quantitative brain volumes were derived from neonatal MRI brain scans (40 weeks' gestational age ± 2 weeks). Goal setting at 13 years was assessed using the Delis-Kaplan Executive Function Systems Tower Test, the Rey Complex Figure, and the Behavioural Assessment of the Dysexecutive System for Children Zoo Map and Six Part Test. A composite score was generated denoting overall performance on these goal setting measures. Separate regression models examined the association of neonatal brain abnormality scores and brain volumes with goal setting performance. There was evidence that higher neonatal white matter, deep grey matter and cerebellum abnormality scores were associated with poorer goal setting scores at 13 years. There was also evidence of positive associations between total brain volume, cerebellum, thalamic and cortical grey matter volumes and goal setting performance. Evidence for the associations largely persisted after controlling for potential confounders. Neonatal brain abnormality and brain volumes are associated with goal setting outcome in VP 13-year-olds. Used in conjunction with other clinical indicators, neonatal MRI may help to identify VP children at risk for later executive dysfunction.

Reproducibility of cognitive endpoints in clinical trials: lessons from neurofibromatosis type 1.

OBJECTIVE: Rapid developments in understanding the molecular mechanisms underlying cognitive deficits in neurodevelopmental disorders have increased expectations for targeted, mechanism-based treatments. However, translation from preclinical models to human clinical trials has proven challenging. Poor reproducibility of cognitive endpoints may provide one explanation for this finding. We examined the suitability of cognitive outcomes for clinical trials in children with neurofibromatosis type 1 (NF1) by examining test-retest reliability of the measures and the application of data reduction techniques to improve reproducibility. METHODS: Data were analyzed from the STARS clinical trial (n = 146), a multi-center double-blind placebo-controlled phase II trial of lovastatin, conducted by the NF Clinical Trials Consortium. Intra-class correlation coefficients were generated between pre- and post-performances (16-week interval) on neuropsychological endpoints in the placebo group to determine test-retest reliabilities. Confirmatory factor analysis was used to reduce data into cognitive domains and account for measurement error. RESULTS: Test-retest reliabilities were highly variable, with most endpoints demonstrating unacceptably low reproducibility. Data reduction confirmed four distinct neuropsychological domains: executive functioning/attention, visuospatial ability, memory, and behavior. Test-retest reliabilities of latent factors improved to acceptable levels for clinical trials. Applicability and utility of our model was demonstrated by homogeneous effect sizes in the reanalyzed efficacy data. INTERPRETATION: These data demonstrate that single observed endpoints are not appropriate to determine efficacy, partly accounting for the poor test-retest reliability of cognitive outcomes in clinical trials in neurodevelopmental disorders. Recommendations to improve reproducibility are outlined to guide future trial design.

Understanding autism spectrum disorder and social functioning in children with neurofibromatosis type 1: protocol for a cross-sectional multimodal study.

INTRODUCTION: Children with the single-gene disorder neurofibromatosis type 1 (NF1) appear to be at an increased risk for autism spectrum disorder (ASD) and exhibit a unique social-cognitive phenotype compared with children with idiopathic ASD. A complete framework is required to better understand autism in NF1, from neurobiological levels through to behavioural and functional outcomes. The primary aims of this study are to establish the frequency of ASD in children with NF1, examine the social cognitive phenotype, investigate the neuropsychological processes contributing to ASD symptoms and poor social functioning in children with NF1, and to investigate novel structural and functional neurobiological markers of ASD and social dysfunction in NF1. The secondary aim of this study is to compare the neuropsychological and neurobiological features of ASD in children with NF1 to a matched group of patients with idiopathic ASD. METHODS AND ANALYSIS: This is an international, multisite, prospective, cross-sectional cohort study of children with NF1, idiopathic ASD and typically developing (TD) controls. Participants will be 200 children with NF1 (3-15 years of age), 70 TD participants (3-15 years) and 35 children with idiopathic ASD (7-15 years). Idiopathic ASD and NF1 cases will be matched on age, sex and intelligence. All participants will complete cognitive testing and parents will rate their child's behaviour on standardised questionnaires. Neuroimaging will be completed by a subset of participants aged 7 years and older. Children with NF1 that screen at risk for ASD on the parent-rated Social Responsiveness Scale 2nd Edition will be invited back to complete the Autism Diagnostic Observation Scale 2nd Edition and Autism Diagnostic Interview-Revised to determine whether they fulfil ASD diagnostic criteria. ETHICS AND DISSEMINATION: This study has hospital ethics approval and the results will be disseminated through peer-reviewed publications and international conferences.

Language Trajectories of Children Born Very Preterm and Full Term from Early to Late Childhood.

OBJECTIVE: To identify distinct language trajectories of children born very preterm and full term from 2 to 13 years of age and examine predictors for the identified trajectories. STUDY DESIGN: A cohort of 224 children born very preterm and 77 full term controls recruited at birth were followed up at ages 2, 5, 7, and 13 years. The number of distinct language trajectories was examined using latent growth mixture modeling allowing for linear and quadratic time trends. Potential predictors in the neonatal period (eg, birth group, sex, and medical risk) and at 2 years (ie, social risk and use of allied health services) for the language trajectories were tested using multinomial logistic regression. RESULTS: Five distinct language trajectories were identified across childhood: stable normal (32% of study cohort), resilient development showing catch-up (36%), precocious language skills (7%), stable low (17%), and high-risk (5%) development. The very preterm group was 8 times more likely to have a language trajectory that represented poorer language development compared with full term controls (very preterm, 40%; full term, 6%). Greater social risk and use of allied health services were associated with poorer language development. CONCLUSIONS: Variable language trajectories were observed, with a substantial proportion of children born very preterm exhibiting adverse language development. These findings highlight the need for monitoring language skills in children born very preterm before school entry and across middle childhood.

Goal Setting Deficits at 13 Years in Very Preterm Born Children.

OBJECTIVES: Preterm children demonstrate deficits in executive functions including inhibition, working memory, and cognitive flexibility; however, their goal setting abilities (planning, organization, strategic reasoning) remain unclear. This study compared goal setting abilities between very preterm (VP: <30 weeks/<1250 grams) and term born controls during late childhood. Additionally, early risk factors (neonatal brain abnormalities, medical complications, and sex) were examined in relationship to goal setting outcomes within the VP group. METHODS: Participants included 177 VP and 61 full-term born control children aged 13 years. Goal setting was assessed using several measures of planning, organization, and strategic reasoning. Parents also completed the Behavior Rating Inventory of Executive Function. Regression models were performed to compare groups, with secondary analyses adjusting for potential confounders (sex and social risk), and excluding children with major neurosensory impairment and/or IQ<70. Within the VP group, regression models were performed to examine the relationship between brain abnormalities, medical complications, and sex, on goal setting scores. RESULTS: The VP group demonstrated a clear pattern of impairment and inefficiency across goal setting measures, consistent with parental report, compared with their full-term born peers. Within the VP group, moderate/severe brain abnormalities on neonatal MRI predicted adverse goal setting outcomes at 13. CONCLUSIONS: Goal setting difficulties are a significant area of concern in VP children during late childhood. These difficulties are associated with neonatal brain abnormalities, and are likely to have functional consequences academically, socially and vocationally. (JINS, 2018, 24, 372-381).