Bloorview Research Institute

This review presents an analytical and comparative survey of upper limb prosthesis acceptance and abandonment as documented over the past 25 years, detailing areas of consumer dissatisfaction and ongoing technological advancements. English-language articles were identified in a search of Ovid, PubMed, and ISI Web of Science (1980 until February 2006) for key words upper limb and prosthesis. Articles focused on upper limb prostheses and addressing: (i) Factors associated with abandonment; (ii) Rejection rates; (iii) Functional analyses and patterns of wear; and (iv) Consumer satisfaction, were extracted with the exclusion of those detailing tools for outcome measurement, case studies, and medical procedures. Approximately 200 articles were included in the review process with 40 providing rates of prosthesis rejection. Quantitative measures of population characteristics, study methodology, and prostheses in use were extracted from each article. Mean rejection rates of 45% and 35% were observed in the literature for body-powered and electric prostheses respectively in pediatric populations. Significantly lower rates of rejection for both body-powered (26%) and electric (23%) devices were observed in adult populations while the average incidence of non-wear was similar for pediatric (16%) and adult (20%) populations. Documented rates of rejection exhibit a wide range of variance, possibly due to the heterogeneous samples involved and methodological differences between studies. Future research should comprise of controlled, multifactor studies adopting standardized outcome measures in order to promote comprehensive understanding of the factors affecting prosthesis use and abandonment. An enhanced understanding of these factors is needed to optimize prescription practices, guide design efforts, and satiate demand for evidence-based measures of intervention.

Rare copy-number variation (CNV) is an important source of risk for autism spectrum disorders (ASDs). We analyzed 2,446 ASD-affected families and confirmed an excess of genic deletions and duplications in affected versus control groups (1.41-fold, p = 1.0 × 10(-5)) and an increase in affected subjects carrying exonic pathogenic CNVs overlapping known loci associated with dominant or X-linked ASD and intellectual disability (odds ratio = 12.62, p = 2.7 × 10(-15), ∼3% of ASD subjects). Pathogenic CNVs, often showing variable expressivity, included rare de novo and inherited events at 36 loci, implicating ASD-associated genes (CHD2, HDAC4, and GDI1) previously linked to other neurodevelopmental disorders, as well as other genes such as SETD5, MIR137, and HDAC9. Consistent with hypothesized gender-specific modulators, females with ASD were more likely to have highly penetrant CNVs (p = 0.017) and were also overrepresented among subjects with fragile X syndrome protein targets (p = 0.02). Genes affected by de novo CNVs and/or loss-of-function single-nucleotide variants converged on networks related to neuronal signaling and development, synapse function, and chromatin regulation.

IMPORTANCE: Approximately one-third of children experiencing acute concussion experience ongoing somatic, cognitive, and psychological or behavioral symptoms, referred to as persistent postconcussion symptoms (PPCS). However, validated and pragmatic tools enabling clinicians to identify patients at risk for PPCS do not exist. OBJECTIVE: To derive and validate a clinical risk score for PPCS among children presenting to the emergency department. DESIGN, SETTING, AND PARTICIPANTS: Prospective, multicenter cohort study (Predicting and Preventing Postconcussive Problems in Pediatrics [5P]) enrolled young patients (aged 5-<18 years) who presented within 48 hours of an acute head injury at 1 of 9 pediatric emergency departments within the Pediatric Emergency Research Canada (PERC) network from August 2013 through September 2014 (derivation cohort) and from October 2014 through June 2015 (validation cohort). Participants completed follow-up 28 days after the injury. EXPOSURES: All eligible patients had concussions consistent with the Zurich consensus diagnostic criteria. MAIN OUTCOMES AND MEASURES: The primary outcome was PPCS risk score at 28 days, which was defined as 3 or more new or worsening symptoms using the patient-reported Postconcussion Symptom Inventory compared with recalled state of being prior to the injury. RESULTS: In total, 3063 patients (median age, 12.0 years [interquartile range, 9.2-14.6 years]; 1205 [39.3%] girls) were enrolled (n = 2006 in the derivation cohort; n = 1057 in the validation cohort) and 2584 of whom (n = 1701 [85%] in the derivation cohort; n = 883 [84%] in the validation cohort) completed follow-up at 28 days after the injury. Persistent postconcussion symptoms were present in 801 patients (31.0%) (n = 510 [30.0%] in the derivation cohort and n = 291 [33.0%] in the validation cohort). The 12-point PPCS risk score model for the derivation cohort included the variables of female sex, age of 13 years or older, physician-diagnosed migraine history, prior concussion with symptoms lasting longer than 1 week, headache, sensitivity to noise, fatigue, answering questions slowly, and 4 or more errors on the Balance Error Scoring System tandem stance. The area under the curve was 0.71 (95% CI, 0.69-0.74) for the derivation cohort and 0.68 (95% CI, 0.65-0.72) for the validation cohort. CONCLUSIONS AND RELEVANCE: A clinical risk score developed among children presenting to the emergency department with concussion and head injury within the previous 48 hours had modest discrimination to stratify PPCS risk at 28 days. Before this score is adopted in clinical practice, further research is needed for external validation, assessment of accuracy in an office setting, and determination of clinical utility.

INTRODUCTION The cerebral cortex underlies our complex cognitive capabilities. Variations in human cortical surface area and thickness are associated with neurological, psychological, and behavioral traits and can be measured in vivo by magnetic resonance imaging (MRI). Studies in model organisms have identified genes that influence cortical structure, but little is known about common genetic variants that affect human cortical structure. RATIONALE To identify genetic variants associated with human cortical structure at both global and regional levels, we conducted a genome-wide association meta-analysis of brain MRI data from 51,665 individuals across 60 cohorts. We analyzed the surface area and average thickness of the whole cortex and 34 cortical regions with known functional specializations. RESULTS We identified 369 nominally genome-wide significant loci ( P &lt; 5 × 10 −8 ) associated with cortical structure in a discovery sample of 33,992 participants of European ancestry. Of the 360 loci for which replication data were available, 241 loci influencing surface area and 66 influencing thickness remained significant after replication, with 237 loci passing multiple testing correction ( P &lt; 8.3 × 10 −10 ; 187 influencing surface area and 50 influencing thickness). Common genetic variants explained 34% (SE = 3%) of the variation in total surface area and 26% (SE = 2%) in average thickness; surface area and thickness showed a negative genetic correlation ( r G = −0.32, SE = 0.05, P = 6.5 × 10 −12 ), which suggests that genetic influences have opposing effects on surface area and thickness. Bioinformatic analyses showed that total surface area is influenced by genetic variants that alter gene regulatory activity in neural progenitor cells during fetal development. By contrast, average thickness is influenced by active regulatory elements in adult brain samples, which may reflect processes that occur after mid-fetal development, such as myelination, branching, or pruning. When considered together, these results support the radial unit hypothesis that different developmental mechanisms promote surface area expansion and increases in thickness. To identify specific genetic influences on individual cortical regions, we controlled for global measures (total surface area or average thickness) in the regional analyses. After multiple testing correction, we identified 175 loci that influence regional surface area and 46 that influence regional thickness. Loci that affect regional surface area cluster near genes involved in the Wnt signaling pathway, which is known to influence areal identity. We observed significant positive genetic correlations and evidence of bidirectional causation of total surface area with both general cognitive functioning and educational attainment. We found additional positive genetic correlations between total surface area and Parkinson’s disease but did not find evidence of causation. Negative genetic correlations were evident between total surface area and insomnia, attention deficit hyperactivity disorder, depressive symptoms, major depressive disorder, and neuroticism. CONCLUSION This large-scale collaborative work enhances our understanding of the genetic architecture of the human cerebral cortex and its regional patterning. The highly polygenic architecture of the cortex suggests that distinct genes are involved in the development of specific cortical areas. Moreover, we find evidence that brain structure is a key phenotype along the causal pathway that leads from genetic variation to differences in general cognitive function. Identifying genetic influences on human cortical structure. ( A ) Measurement of cortical surface area and thickness from MRI. ( B ) Genomic locations of common genetic variants that influence global and regional cortical structure. ( C ) Our results support the radial unit hypothesis that the expansion of cortical surface area is driven by proliferating neural progenitor cells. ( D ) Cortical surface area shows genetic correlation with psychiatric and cognitive traits. Error bars indicate SE. IMAGE CREDITS: (A) K. COURTNEY; (C) M. R. GLASS

Researchers have designed training methods that can be used to improve mental health and to test the efficacy of education programs. However, few studies have demonstrated broad transfer from such training to performance on untrained cognitive activities. Here we report the effects of two interactive computerized training programs developed for preschool children: one for music and one for visual art. After only 20 days of training, only children in the music group exhibited enhanced performance on a measure of verbal intelligence, with 90% of the sample showing this improvement. These improvements in verbal intelligence were positively correlated with changes in functional brain plasticity during an executive-function task. Our findings demonstrate that transfer of a high-level cognitive skill is possible in early childhood.

OBJECTIVE: To investigate the roles of predisposing characteristics, established need, and enabling resources in upper-limb prosthesis use and abandonment. DESIGN: A self-administered, anonymous survey was designed to explore these factors. The questionnaire was available online and in paper format and was distributed through healthcare providers, community support groups, and one prosthesis manufacturer. Two hundred forty-two participants of all ages and levels of upper-limb absence completed the survey. RESULTS: Of participants, 20% had abandoned prosthesis use. Predisposing factors, namely, origin of limb absence, gender, bilateral limb absence, and, most importantly, level of limb absence, proved influential in the decision not to wear prostheses. Enabling resources such as the availability of health care, cost, and quality of training did not weigh heavily on prosthesis rejection, with the exception of the fitting time frame and the involvement of clients in the prosthesis selection. Conversely, the state of available technology was a highly censured factor in abandonment, specifically in the areas of comfort and function. Perceived need emerged as a predominant factor in prosthesis use. CONCLUSIONS: Future research should focus on continued development of more comfortable and functional prostheses, particularly for individuals with high-level or bilateral limb absence. Improved follow-up, repair, and information services, together with active involvement of clients in the selection of prostheses meeting their specific goals and needs, is recommended.

OBJECTIVES: To systematically review levels of metabolic expenditure and changes in activity patterns associated with active video game (AVG) play in children and to provide directions for future research efforts. DATA SOURCES: A review of the English-language literature (January 1, 1998, to January 1, 2010) via ISI Web of Knowledge, PubMed, and Scholars Portal using the following keywords: video game, exergame, physical activity, fitness, exercise, energy metabolism, energy expenditure, heart rate, disability, injury, musculoskeletal, enjoyment, adherence, and motivation. STUDY SELECTION: Only studies involving youth (< or = 21 years) and reporting measures of energy expenditure, activity patterns, physiological risks and benefits, and enjoyment and motivation associated with mainstream AVGs were included. Eighteen studies met the inclusion criteria. Articles were reviewed and data were extracted and synthesized by 2 independent reviewers. MAIN OUTCOME EXPOSURES: Energy expenditure during AVG play compared with rest (12 studies) and activity associated with AVG exposure (6 studies). MAIN OUTCOME MEASURES: Percentage increase in energy expenditure and heart rate (from rest). RESULTS: Activity levels during AVG play were highly variable, with mean (SD) percentage increases of 222% (100%) in energy expenditure and 64% (20%) in heart rate. Energy expenditure was significantly lower for games played primarily through upper body movements compared with those that engaged the lower body (difference, -148%; 95% confidence interval, -231% to -66%; P = .001). CONCLUSIONS: The AVGs enable light to moderate physical activity. Limited evidence is available to draw conclusions on the long-term efficacy of AVGs for physical activity promotion.

OBJECTIVE: Neuroimaging studies show structural differences in both cortical and subcortical brain regions in children and adults with autism spectrum disorder (ASD) compared with healthy subjects. Findings are inconsistent, however, and it is unclear how differences develop across the lifespan. The authors investigated brain morphometry differences between individuals with ASD and healthy subjects, cross-sectionally across the lifespan, in a large multinational sample from the Enhancing Neuroimaging Genetics Through Meta-Analysis (ENIGMA) ASD working group. METHOD: The sample comprised 1,571 patients with ASD and 1,651 healthy control subjects (age range, 2-64 years) from 49 participating sites. MRI scans were preprocessed at individual sites with a harmonized protocol based on a validated automated-segmentation software program. Mega-analyses were used to test for case-control differences in subcortical volumes, cortical thickness, and surface area. Development of brain morphometry over the lifespan was modeled using a fractional polynomial approach. RESULTS: The case-control mega-analysis demonstrated that ASD was associated with smaller subcortical volumes of the pallidum, putamen, amygdala, and nucleus accumbens (effect sizes [Cohen's d], 0.13 to -0.13), as well as increased cortical thickness in the frontal cortex and decreased thickness in the temporal cortex (effect sizes, -0.21 to 0.20). Analyses of age effects indicate that the development of cortical thickness is altered in ASD, with the largest differences occurring around adolescence. No age-by-ASD interactions were observed in the subcortical partitions. CONCLUSIONS: The ENIGMA ASD working group provides the largest study of brain morphometry differences in ASD to date, using a well-established, validated, publicly available analysis pipeline. ASD patients showed altered morphometry in the cognitive and affective parts of the striatum, frontal cortex, and temporal cortex. Complex developmental trajectories were observed for the different regions, with a developmental peak around adolescence. These findings suggest an interplay in the abnormal development of the striatal, frontal, and temporal regions in ASD across the lifespan.

PURPOSE: To measure consumer satisfaction with upper limb prosthetics and provide an enumerated list of design priorities for future developments. METHODS: A self-administered, anonymous survey collected information on participant demographics, history of and goals for prosthesis use, satisfaction, and design priorities. The questionnaire was available online and in paper format and was distributed through healthcare providers, community support groups, and one prosthesis manufacturer; 242 participants of all ages and levels of upper limb absence completed the survey. RESULTS: Rates of rejection for myoelectric hands, passive hands, and body-powered hooks were 39%, 53%, and 50%, respectively. Prosthesis wearers were generally satisfied with their devices while prosthesis rejecters were dissatisfied. Reduced prosthesis weight emerged as the highest priority design concern of consumers. Lower cost ranked within the top five design priorities for adult wearers of all device types. Life-like appearance is a priority for passive/cosmetic prostheses, while improved harness comfort, wrist movement, grip control and strength are required for body-powered devices. Glove durability, lack of sensory feedback, and poor dexterity were also identified as design priorities for electric devices. CONCLUSIONS: Design priorities reflect consumer goals for prosthesis use and vary depending on the type of prosthesis used and age. Future design efforts should focus on the development of more light-weight, comfortable prostheses.

Autism Spectrum Disorder (ASD) demonstrates high heritability and familial clustering, yet the genetic causes remain only partially understood as a result of extensive clinical and genomic heterogeneity. Whole-genome sequencing (WGS) shows promise as a tool for identifying ASD risk genes as well as unreported mutations in known loci, but an assessment of its full utility in an ASD group has not been performed. We used WGS to examine 32 families with ASD to detect de novo or rare inherited genetic variants predicted to be deleterious (loss-of-function and damaging missense mutations). Among ASD probands, we identified deleterious de novo mutations in six of 32 (19%) families and X-linked or autosomal inherited alterations in ten of 32 (31%) families (some had combinations of mutations). The proportion of families identified with such putative mutations was larger than has been previously reported; this yield was in part due to the comprehensive and uniform coverage afforded by WGS. Deleterious variants were found in four unrecognized, nine known, and eight candidate ASD risk genes. Examples include CAPRIN1 and AFF2 (both linked to FMR1, which is involved in fragile X syndrome), VIP (involved in social-cognitive deficits), and other genes such as SCN2A and KCNQ2 (linked to epilepsy), NRXN1, and CHD7, which causes ASD-associated CHARGE syndrome. Taken together, these results suggest that WGS and thorough bioinformatic analyses for de novo and rare inherited mutations will improve the detection of genetic variants likely to be associated with ASD or its accompanying clinical symptoms.

IMPORTANCE: The use of genome-wide tests to provide molecular diagnosis for individuals with autism spectrum disorder (ASD) requires more study. OBJECTIVE: To perform chromosomal microarray analysis (CMA) and whole-exome sequencing (WES) in a heterogeneous group of children with ASD to determine the molecular diagnostic yield of these tests in a sample typical of a developmental pediatric clinic. DESIGN, SETTING, AND PARTICIPANTS: The sample consisted of 258 consecutively ascertained unrelated children with ASD who underwent detailed assessments to define morphology scores based on the presence of major congenital abnormalities and minor physical anomalies. The children were recruited between 2008 and 2013 in Newfoundland and Labrador, Canada. The probands were stratified into 3 groups of increasing morphological severity: essential, equivocal, and complex (scores of 0-3, 4-5, and ≥6). EXPOSURES: All probands underwent CMA, with WES performed for 95 proband-parent trios. MAIN OUTCOMES AND MEASURES: The overall molecular diagnostic yield for CMA and WES in a population-based ASD sample stratified in 3 phenotypic groups. RESULTS: Of 258 probands, 24 (9.3%, 95%CI, 6.1%-13.5%) received a molecular diagnosis from CMA and 8 of 95 (8.4%, 95%CI, 3.7%-15.9%) from WES. The yields were statistically different between the morphological groups. Among the children who underwent both CMA and WES testing, the estimated proportion with an identifiable genetic etiology was 15.8% (95%CI, 9.1%-24.7%; 15/95 children). This included 2 children who received molecular diagnoses from both tests. The combined yield was significantly higher in the complex group when compared with the essential group (pairwise comparison, P = .002). [table: see text]. CONCLUSIONS AND RELEVANCE: Among a heterogeneous sample of children with ASD, the molecular diagnostic yields of CMA and WES were comparable, and the combined molecular diagnostic yield was higher in children with more complex morphological phenotypes in comparison with the children in the essential category. If replicated in additional populations, these findings may inform appropriate selection of molecular diagnostic testing for children affected by ASD.

BACKGROUND: The diagnosis of autism spectrum disorder (ASD) made before age 3 has been found to be remarkably stable in clinic- and community-ascertained samples. The stability of an ASD diagnosis in prospectively ascertained samples of infants at risk for ASD due to familial factors has not yet been studied, however. The American Academy of Pediatrics recommends intensive surveillance and screening for this high-risk group, which may afford earlier identification. Therefore, it is critical to understand the stability of an ASD diagnosis made before age 3 in young children at familial risk. METHODS: Data were pooled across seven sites of the Baby Siblings Research Consortium. Evaluations of 418 later-born siblings of children with ASD were conducted at 18, 24, and 36 months of age and a clinical diagnosis of ASD or Not ASD was made at each age. RESULTS: The stability of an ASD diagnosis at 18 months was 93% and at 24 months was 82%. There were relatively few children diagnosed with ASD at 18 or 24 months whose diagnosis was not confirmed at 36 months. There were, however, many children with ASD outcomes at 36 months who had not yet been diagnosed at 18 months (63%) or 24 months (41%). CONCLUSIONS: The stability of an ASD diagnosis in this familial-risk sample was high at both 18 and 24 months of age and comparable with previous data from clinic- and community-ascertained samples. However, almost half of the children with ASD outcomes were not identified as being on the spectrum at 24 months and did not receive an ASD diagnosis until 36 months. Thus, longitudinal follow-up is critical for children with early signs of social-communication difficulties, even if they do not meet diagnostic criteria at initial assessment. A public health implication of these data is that screening for ASD may need to be repeated multiple times in the first years of life. These data also suggest that there is a period of early development in which ASD features unfold and emerge but have not yet reached levels supportive of a diagnosis.

At least 3 million Americans sustain a mild traumatic brain injury (mTBI) each year, and 1 in 5 have symptoms that persist beyond 1 month. Standards of mTBI care have evolved rapidly, with numerous expert consensus statements and clinical practice guidelines published in the last 5 years. This Special Communication synthesizes recent expert consensus statements and evidenced-based clinical practice guidelines for civilians, athletes, military, and pediatric populations for clinicians practicing outside of specialty mTBI clinics, including primary care providers. The article offers guidance on key clinical decisions in mTBI care and highlights priority interventions that can be initiated in primary care to prevent chronicity.

BACKGROUND: There are no effective medications for the treatment of social cognition/function deficits in autism spectrum disorder (ASD), and adult intervention literature in this area is sparse. Emerging data from animal models and genetic association studies as well as early, single-dose intervention studies suggest that the oxytocin system may be a potential therapeutic target for social cognition/function deficits in ASD. The primary aim of this study was to examine the safety/therapeutic effects of intranasal oxytocin versus placebo in adults with ASD, with respect to the two core symptom domains of social cognition/functioning and repetitive behaviors. METHODS: This was a pilot, randomized, double-blind, placebo-controlled, parallel design trial of intranasal oxytocin versus placebo in 19 adults with ASD (16 males; 33.20 ± 13.29 years). Subjects were randomized to 24 IU intranasal oxytocin or placebo in the morning and afternoon for 6 weeks. Measures of social function/cognition (the Diagnostic Analysis of Nonverbal Accuracy) and repetitive behaviors (Repetitive Behavior Scale Revised) were administered. Secondary measures included the Social Responsiveness Scale, Reading-the-Mind-in-the-Eyes Test and the Yale Brown Obsessive Compulsive Scale - compulsion subscale and quality of life (World Health Organization Quality of Life Questionnaire - emotional/social subscales). Full-information maximum-likelihood parameter estimates were obtained and tested using mixed-effects regression analyses. RESULTS: Although no significant changes were detected in the primary outcome measures after correcting for baseline differences, results suggested improvements after 6 weeks in measures of social cognition (Reading-the-Mind-in-the-Eyes Test, p = 0.002, d = 1.2), and quality of life (World Health Organization Quality of Life Questionnaire - emotion, p = 0.031, d = 0.84), both secondary measures. Oxytocin was well tolerated and no serious adverse effects were reported. CONCLUSIONS: This pilot study suggests that there is therapeutic potential to daily administration of intranasal oxytocin in adults with ASD and that larger and longer studies are warranted. TRIAL REGISTRATION: NCT00490802.

Autism spectrum disorder (ASD) is a developmental disorder involving abnormal communication, repetitive and restrictive interests, and impaired social functioning. ASD can have a profound impact on family life, including the roles and responsibilities that parents assume. In this metasynthesis, we explore the experiences of parents who care for a child with ASD. We undertook a thematic synthesis to integrate qualitative evidence, searching 10 electronic databases and reviewing 4,148 abstracts. We selected 31 articles for inclusion (involving 160 fathers and 425 mothers) and examined the articles using a constant comparative approach. We identified six themes: prediagnosis, diagnosis, family life adjustment, navigating the system, parental empowerment, and moving forward. Our findings can inform the development of programs and services for families, provide insight for health care workers who advocate on behalf of parents, and provide valuable information to parents, particularly those of children newly diagnosed with ASD.

Autism spectrum disorder (ASD) refers to a syndrome of social communication deficits and repetitive behaviors or restrictive interests. It remains a behaviorally defined syndrome with no reliable biological markers. The goal of this review is to summarize the available neuroimaging data and examine their implication for our understanding of the neurobiology of ASD.Although there is variability in the literature on structural magnetic resonance literature (MRI), there is evidence of volume abnormalities in both grey and white matter, with a suggestion of some region-specific differences. Early brain overgrowth is probably the most replicated finding in a subgroup of people with ASD, and new techniques, such as cortical-thickness measurements and surface morphometry have begun to elucidate in more detail the patterns of abnormalities as they evolve with age, and are implicating specific neuroanatomical or neurodevelopmental processes. Functional MRI and diffusion tensor imaging techniques suggest that such volume abnormalities are associated with atypical functional and structural connectivity in the brain, and researchers have begun to use magnetic resonance spectroscopy (MRS) techniques to explore the neurochemical substrate of such abnormalities. The data from multiple imaging methods suggests that ASD is associated with an atypically connected brain. We now need to further clarify such atypicalities, and start interpreting them in the context of what we already know about typical neurodevelopmental processes including migration and organization of the cortex. Such an approach will allow us to relate imaging findings not only to behavior, but also to genes and their expression, which may be related to such processes, and to further our understanding of the nature of neurobiologic abnormalities in ASD.

Altered structural brain asymmetry in autism spectrum disorder (ASD) has been reported. However, findings have been inconsistent, likely due to limited sample sizes. Here we investigated 1,774 individuals with ASD and 1,809 controls, from 54 independent data sets of the ENIGMA consortium. ASD was significantly associated with alterations of cortical thickness asymmetry in mostly medial frontal, orbitofrontal, cingulate and inferior temporal areas, and also with asymmetry of orbitofrontal surface area. These differences generally involved reduced asymmetry in individuals with ASD compared to controls. Furthermore, putamen volume asymmetry was significantly increased in ASD. The largest case-control effect size was Cohen's d = -0.13, for asymmetry of superior frontal cortical thickness. Most effects did not depend on age, sex, IQ, severity or medication use. Altered lateralized neurodevelopment may therefore be a feature of ASD, affecting widespread brain regions with diverse functions. Large-scale analysis was necessary to quantify subtle alterations of brain structural asymmetry in ASD.

Short-term test-retest reliability of the 10-metre fast walk test (10mFWT) and 6-minute walk test (6MWT) was evaluated in 31 ambulatory children with cerebral palsy (CP), with subgroup analyses in Gross Motor Function Classification System (GMFCS) Levels I (n=9), II (n=8), and III (n=14). Sixteen females and 15 males participated, mean age 9 years 5 months (SD 3y 7mo, range 4y 3mo-18y 2mo). Twenty had spastic diplegia, while the others had another form of CP. Retest interval varied from 1 to 4 weeks (mean 10.6d [SD 6.4]). Intraclass correlation coefficients (ICCs) estimated reliability. The 10mFWT ICC was 0.81 (95% confidence interval [CI] 0.65-0.90) across participants, and >0.59 in GMFCS subgroups (95% CI lower bound >0.01). The 6MWT ICC was 0.98, and >0.90 in GMFCS subgroups (95% CI lower bound >0.64). Bland-Altman plots indicated bias towards higher 6MWT retest distances in GMFCS Level I. Minimum detectable change (95% CI) was 61.9, 64.0, and 47.4m for the 6MWT within GMFCS Levels I, II, and III respectively. The conclusion is that while the 10mFWT showed inadequate test-retest reliability given its wide 95% CI, the 6MWT demonstrated good to excellent reliability. Investigation of the need for a practice walk when administering the 6MWT with children in GMFCS Level I is recommended to establish their fastest pace.

BACKGROUND: Autism spectrum disorder (ASD) is characterized by notable phenotypic heterogeneity, which is often viewed as an obstacle to the study of its etiology, diagnosis, treatment, and prognosis. On the basis of empirical evidence, instead of three binary categories, the upcoming edition of the DSM 5 will use two dimensions - social communication deficits (SCD) and fixated interests and repetitive behaviors (FIRB) - for the ASD diagnostic criteria. Building on this proposed DSM 5 model, it would be useful to consider whether empirical data on the SCD and FIRB dimensions can be used within the novel methodological framework of Factor Mixture Modeling (FMM) to stratify children with ASD into more homogeneous subgroups. METHODS: The study sample consisted of 391 newly diagnosed children (mean age 38.3 months; 330 males) with ASD. To derive subgroups, data from the Autism Diagnostic Interview-Revised indexing SCD and FIRB were used in FMM; FMM allows the examination of continuous dimensions and latent classes (i.e., categories) using both factor analysis (FA) and latent class analysis (LCA) as part of a single analytic framework. RESULTS: Competing LCA, FA, and FMM models were fit to the data. On the basis of a set of goodness-of-fit criteria, a 'two-factor/three-class' factor mixture model provided the overall best fit to the data. This model describes ASD using three subgroups/classes (Class 1: 34%, Class 2: 10%, Class 3: 56% of the sample) based on differential severity gradients on the SCD and FIRB symptom dimensions. In addition to having different symptom severity levels, children from these subgroups were diagnosed at different ages and were functioning at different adaptive, language, and cognitive levels. CONCLUSIONS: Study findings suggest that the two symptom dimensions of SCD and FIRB proposed for the DSM 5 can be used in FMM to stratify children with ASD empirically into three relatively homogeneous subgroups.

IMPORTANCE: Large-scale neuroimaging studies have revealed group differences in cortical thickness across many psychiatric disorders. The underlying neurobiology behind these differences is not well understood. OBJECTIVE: To determine neurobiologic correlates of group differences in cortical thickness between cases and controls in 6 disorders: attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorder (ASD), bipolar disorder (BD), major depressive disorder (MDD), obsessive-compulsive disorder (OCD), and schizophrenia. DESIGN, SETTING, AND PARTICIPANTS: Profiles of group differences in cortical thickness between cases and controls were generated using T1-weighted magnetic resonance images. Similarity between interregional profiles of cell-specific gene expression and those in the group differences in cortical thickness were investigated in each disorder. Next, principal component analysis was used to reveal a shared profile of group difference in thickness across the disorders. Analysis for gene coexpression, clustering, and enrichment for genes associated with these disorders were conducted. Data analysis was conducted between June and December 2019. The analysis included 145 cohorts across 6 psychiatric disorders drawn from the ENIGMA consortium. The numbers of cases and controls in each of the 6 disorders were as follows: ADHD: 1814 and 1602; ASD: 1748 and 1770; BD: 1547 and 3405; MDD: 2658 and 3572; OCD: 2266 and 2007; and schizophrenia: 2688 and 3244. MAIN OUTCOMES AND MEASURES: Interregional profiles of group difference in cortical thickness between cases and controls. RESULTS: A total of 12 721 cases and 15 600 controls, ranging from ages 2 to 89 years, were included in this study. Interregional profiles of group differences in cortical thickness for each of the 6 psychiatric disorders were associated with profiles of gene expression specific to pyramidal (CA1) cells, astrocytes (except for BD), and microglia (except for OCD); collectively, gene-expression profiles of the 3 cell types explain between 25% and 54% of variance in interregional profiles of group differences in cortical thickness. Principal component analysis revealed a shared profile of difference in cortical thickness across the 6 disorders (48% variance explained); interregional profile of this principal component 1 was associated with that of the pyramidal-cell gene expression (explaining 56% of interregional variation). Coexpression analyses of these genes revealed 2 clusters: (1) a prenatal cluster enriched with genes involved in neurodevelopmental (axon guidance) processes and (2) a postnatal cluster enriched with genes involved in synaptic activity and plasticity-related processes. These clusters were enriched with genes associated with all 6 psychiatric disorders. CONCLUSIONS AND RELEVANCE: In this study, shared neurobiologic processes were associated with differences in cortical thickness across multiple psychiatric disorders. These processes implicate a common role of prenatal development and postnatal functioning of the cerebral cortex in these disorders.