A randomized double-blind controlled trial of everolimus in individuals with PTEN mutations: Study design and statistical considerations.

This randomized, double-blind controlled trial of everolimus in individuals with germline phosphatase and tensin homolog mutations (PTEN) was designed to evaluate the safety of everolimus compared with placebo and to evaluate the efficacy of everolimus on neurocognition and behavior compared to placebo as measured by standardized neurocognitive and motor measures as well as behavioral questionnaires. The safety profile of everolimus is characterized by manageable adverse events that are generally reversible and non-cumulative. The primary safety endpoint of this study was drop-out rate due to side effects, comparing everolimus versus placebo. We also sought to determine the frequency of adverse events by type and severity. The main efficacy endpoint was a neurocognitive composite computed in two ways: 1) an average for working memory, processing speed, and fine motor subtests; and 2) the same average as above except weighted 2/3, and an additional average based on all other available neurocognitive testing measures assessing the additional domains of nonverbal ability, visuomotor skills, verbal learning, and receptive and expressive language, weighted 1/3. Secondary efficacy endpoints examined the effect of everolimus on overall global clinical improvement, autism symptoms, behavioral problems, and adaptive abilities as measured by validated, standardized instruments. We predicted that the rate of adverse events would be no more than 10% higher in the everolimus group compared to placebo, and overall severity of side effects would be minimal. We also expected that individuals receiving everolimus would show more improvement, relative to those taking placebo, on the composite neurocognitive index.

The cognitive and behavioral phenotype of the 16p11.2 deletion in a clinically ascertained population.

BACKGROUND: Deletion of the recurrent ~600 kb BP4-BP5 chromosomal region 16p11.2 has been associated with a wide range of neurodevelopmental outcomes. METHODS: To clarify the phenotype of 16p11.2 deletion, we examined the psychiatric and developmental presentation of predominantly clinically referred individuals, with a particular emphasis on broader autism phenotype characteristics in individuals with recurrent ~600 kb chromosome 16p11.2 deletions. Using an extensive standardized assessment battery across three clinical sites, 85 individuals with the 16p11.2 deletion and 153 familial control subjects were evaluated for symptom presentation and clinical diagnosis. RESULTS: Individuals with the 16p11.2 deletion presented with a high frequency of psychiatric and developmental disorders (>90%). The most commonly diagnosed conditions were developmental coordination disorder, phonologic processing disorder, expressive and receptive language disorders (71% of individuals >3 years old with a speech and language-related disorder), and autism spectrum disorder. Individuals with the 16p11.2 deletion not meeting diagnostic criteria for autism spectrum disorder had a significantly higher prevalence of autism-related characteristics compared with the familial noncarrier control group. Individuals with the 16p11.2 deletion had a range of intellectual ability, but IQ scores were 26 points lower than noncarrier family members on average. CONCLUSIONS: Clinically referred individuals with the 16p11.2 deletion have high rates of psychiatric and developmental disorders and provide a genetically well-defined group to study the emergence of developmental difficulties, particularly associated with the broader autism phenotype.

A new approach to the measurement of adaptive behavior: development of the PEDI-CAT for children and youth with autism spectrum disorders.

The use of current adaptive behavior measures in practice and research is limited by their length and need for a professional interviewer. There is a need for alternative measures that more efficiently assess adaptive behavior in children and youth with autism spectrum disorders (ASDs). The Pediatric Evaluation of Disability Inventory-Computer Adaptive Test (PEDI-CAT) is a computer-based assessment of a child's ability to perform activities required for personal self-sufficiency and engagement in the community. This study evaluated the applicability, representativeness, and comprehensiveness of the Daily Activity, Social/Cognitive, and Responsibility domains for children and youth with an ASD. Twenty professionals and 18 parents provided feedback via in-person or virtual focus groups and cognitive interviews. Items were perceived to represent relevant functional activities within each domain. Child factors and assessment characteristics influenced parents' ratings. In response to feedback, 15 items and additional directions were added to ensure the PEDI-CAT is a meaningful measure when used with this population.

Practitioner's guide to assessment of autism spectrum disorders in infants and toddlers.

Recent advances in clinical research have made it possible to diagnosis autism spectrum disorders (ASD) as early as the second year of life. The diagnostic process early in development is often complex, and thus, familiarity with the most recent findings in clinical assessment instruments, early symptoms, and developmental trajectories of young children with autism is essential. This paper provides an empirically based practitioner's guide to issues and concerns related to early diagnosis of ASD in very young children, documentation of the course and patterns of ASD symptomatology in infants and toddlers, and current understanding in the field of diagnostic outcomes of children identified in the first and second year of life.

Comparing autism, PDD-NOS, and other developmental disabilities on parent-reported behavior problems: little evidence for ASD subtype validity.

Studies on the distinction between Autistic Disorder (AD) and Pervasive Developmental Disorder Not Otherwise Specified (PDD-NOS) have been inconclusive. This study examined the validity of PDD-NOS by comparing it to AD and other developmental disorders (DD) on parent-reported behavior problems. Fifty-four children with PDD-NOS were individually matched on age and non-verbal IQ to 54 children with AD and 54 children with DD. Groups were compared on select subscales of the Child Behavior Checklist. High rates of psychopathology were observed in both ASD groups. The only difference between PDD-NOS and AD groups was higher scores in the PDD-NOS group on two items measuring Anxiety/Depression. Cognitive functioning may be a more salient variable than subtype when studying psychopathology in individuals with ASDs.

The structure of the Autism Diagnostic Interview-Revised: diagnostic and phenotypic implications.

BACKGROUND: Multivariate statistics can assist in refining the nosology and diagnosis of pervasive developmental disorders (PDD) and also contribute important information for genetic studies. The Autism Diagnostic Interview-Revised (ADI-R) is one of the most widely used assessment instruments in the field of PDD. The current study investigated its factor structure and convergence with measures of adaptive, language, and intellectual functioning. METHODS: Analyses were conducted on 1,861 individuals with PDD between the ages of 4 and 18 years (mean = 8.3, SD = 3.2). ADI-R scores were submitted to confirmatory factor analysis (CFA) and exploratory factor analysis (EFA). Analyses were conducted according to verbal status (n = 1,329 verbal, n = 532 nonverbal) and separately for algorithm items only and for all items. ADI-R scores were correlated with scores on measures of adaptive, language, and intellectual functioning. RESULTS: Several factor solutions were examined and compared. CFAs suggested that two- and three-factor solutions were similar, and slightly superior to a one-factor solution. EFAs and measures of internal consistency provided some support for a two-factor solution consisting of social and communication behaviors and restricted and repetitive behaviors. Measures of functioning were not associated with ADI-R domain scores in nonverbal children, but negatively correlated in verbal children. CONCLUSIONS: Overall, data suggested that autism symptomatology can be explained statistically with a two-domain model. It also pointed to different symptoms susceptible to be helpful in linkage analyses. Implications of a two-factor model are discussed.

Sensitivity and specificity of the Modified Checklist for Autism in Toddlers and the Social Communication Questionnaire in preschoolers suspected of having pervasive developmental disorders.

This study assessed the psychometric properties of the Modified Checklist for Autism in Toddlers (M-CHAT) and the Social Communication Questionnaire (SCQ) in a sample of preschool children referred for possible pervasive developmental disorders (PDDs). The sample consisted of 82 children between the ages of 18 and 70 months (54 with a PDD diagnosis and 28 with non-PDD diagnoses). M-CHAT scores were analyzed for 56 children aged 18-48 months old and SCQ scores were analyzed for 65 children aged 30-70 months old. Optimal sensitivity and specificity were achieved using the cutoff score of any three items on the M-CHAT and lowering the cutoff score of the SCQ. The diagnostic agreement of both instruments was also compared in an overlapping subsample of 39 children aged 30-48 months. Overall, the M-CHAT and SCQ appear to more accurately classify children with PDDs who have lower intellectual and adaptive functioning.

Reelin signaling is impaired in autism.

BACKGROUND: Autism is a severe neurodevelopmental disorder with genetic and environmental etiologies. Recent genetic linkage studies implicate Reelin glycoprotein in causation of autism. To further investigate these studies, brain levels of Reelin protein and mRNA and mRNAs for VLDLR, Dab-1, and GSK3 were investigated. METHODS: Postmortem superior frontal, parietal, and cerebellar cortices of age, gender, and postmortem interval-matched autistic and control subjects were subjected to SDS-PAGE and Western blotting of Reelin protein. Quantitative reverse transcriptase polymerase chain reaction analysis of Reelin, VLDL-R, Dab-1, and GSK3 mRNA species in superior frontal and cerebellar cortices of autistic and control subjects were also performed. RESULTS: Reelin 410, 330, and 180 kDa/beta-actin values were reduced significantly in frontal and cerebellar, and nonsignificantly in parietal, areas of autistic brains versus control subjects, respectively. The mRNAs for Reln and Dab-1 were reduced significantly whereas the mRNA for Reln receptor VLDLR was elevated significantly in superior frontal and cerebellar areas of autistic brains versus control brains, respectively. CONCLUSIONS: Reductions in Reelin protein and mRNA and Dab 1 mRNA and elevations in Reln receptor VLDLR mRNA demonstrate impairments in the Reelin signaling system in autism, accounting for some of the brain structural and cognitive deficits observed in the disorder.