Whole-genome sequencing in autism identifies hot spots for de novo germline mutation.

De novo mutation plays an important role in autism spectrum disorders (ASDs). Notably, pathogenic copy number variants (CNVs) are characterized by high mutation rates. We hypothesize that hypermutability is a property of ASD genes and may also include nucleotide-substitution hot spots. We investigated global patterns of germline mutation by whole-genome sequencing of monozygotic twins concordant for ASD and their parents. Mutation rates varied widely throughout the genome (by 100-fold) and could be explained by intrinsic characteristics of DNA sequence and chromatin structure. Dense clusters of mutations within individual genomes were attributable to compound mutation or gene conversion. Hypermutability was a characteristic of genes involved in ASD and other diseases. In addition, genes impacted by mutations in this study were associated with ASD in independent exome-sequencing data sets. Our findings suggest that regional hypermutation is a significant factor shaping patterns of genetic variation and disease risk in humans.

Fetal alcohol spectrum disorders and access to regional center services in San Diego County.

BACKGROUND: Fetal alcohol spectrum disorders (FASD) are developmental disabilities that are estimated to occur in 2-5% of elementary school children and that negatively impact a child's ability to function without support. Timely diagnosis-informed interventions are crucial to optimizing the developmental trajectory of children with FASD. The true prevalence of FASD among children receiving services for developmental disabilities is unknown. METHODS: An FASD prevalence study was carried out between 2011 and 2014 among a sample of 5- to 7-year-old children who were receiving services provided by the California State Regional Center for Developmental Disabilities in San Diego County. Children whose parent or caregiver consented were evaluated using the Collaboration on Fetal Alcohol Spectrum Disorders Prevalence study assessment protocol and classification criteria. RESULTS: Among 216 eligible caregiver-child dyads, 44 completed assessments that were sufficient to obtain a classification for FASD, including fetal alcohol syndrome (FAS), partial FAS, alcohol-related neurodevelopmental disorder, or no fetal alcohol spectrum disorder. Fifteen children were classified as meeting the criteria for an FASD. A minimum FASD prevalence rate of 69.4 per 1000 (6.9%) among all eligible children was estimated. None of the children classified as FASD were receiving services because of an FASD diagnosis, and none had previously been diagnosed with FASD. Autism was the most common qualifying diagnosis for which children classified as FASD were receiving services. CONCLUSIONS: The 6.9% prevalence estimate among Regional Center clients was higher than the prevalence estimate of 2.3% in the same community among 5- to 7-year-old children in the general population, though the estimate was based on only 20% of eligible dyads. All children in the sample were receiving Regional Center services for another diagnosis. Barriers to eligibility for services for children with FASD may lead to less than optimum care for these children. Study findings support the facilitation of access to developmental services for children with FASD.

Frequency and Complexity of De Novo Structural Mutation in Autism.

Genetic studies of autism spectrum disorder (ASD) have established that de novo duplications and deletions contribute to risk. However, ascertainment of structural variants (SVs) has been restricted by the coarse resolution of current approaches. By applying a custom pipeline for SV discovery, genotyping, and de novo assembly to genome sequencing of 235 subjects (71 affected individuals, 26 healthy siblings, and their parents), we compiled an atlas of 29,719 SV loci (5,213/genome), comprising 11 different classes. We found a high diversity of de novo mutations, the majority of which were undetectable by previous methods. In addition, we observed complex mutation clusters where combinations of de novo SVs, nucleotide substitutions, and indels occurred as a single event. We estimate a high rate of structural mutation in humans (20%) and propose that genetic risk for ASD is attributable to an elevated frequency of gene-disrupting de novo SVs, but not an elevated rate of genome rearrangement.

Fetal Alcohol Spectrum Disorders in a Pacific Southwest City: Maternal and Child Characteristics.

BACKGROUND: There are limited data on the characteristics of children with fetal alcohol spectrum disorders (FASD) and their mothers from the general population in the United States. METHODS: During the 2012 and 2013 academic years, first-grade children in a large urban Pacific Southwest city were invited to participate in a study to estimate the prevalence of FASD. Children who screened positive on weight, height, or head circumference ≤25th centile or on parental report of developmental concerns were selected for evaluation, along with a random sample of those who screened negative. These children were examined for dysmorphology and neurobehavior and their mothers or collateral sources were interviewed. Children were classified as fetal alcohol syndrome (FAS), partial fetal alcohol syndrome (pFAS), alcohol-related neurodevelopmental disorder (ARND), or No FASD. RESULTS: A total of 854 children were evaluated; 5 FAS, 44 pFAS, 44 ARND, and 761 No FASD. Children with FAS or pFAS were more likely to have dysmorphic features, and 32/49 (65.3%) of those met criteria for neurobehavioral impairment on cognitive measures with or without behavioral deficits. In contrast, 28/44 (63.6%) of children with ARND met criteria on behavioral measures alone. Mothers of FASD children were more likely to recognize pregnancy later, be unmarried, and report other substance use or psychiatric disorders, but did not differ on age, socioeconomic status, education, or parity. Mothers of FASD children reported more drinks/drinking day each trimester. The risk of FASD was elevated with increasing number of drinks/drinking day prior to pregnancy recognition, even at the level of 1 drink per day (adjusted odds ratio 3.802, 95% confidence interval 1.634, 8.374). CONCLUSIONS: Data from this general population sample in a large urban region in the United States demonstrate the variability of expression of FASD and point to risk and protective factors for mothers in this setting.

A Randomized Clinical Trial of Umbilical Cord Milking vs Delayed Cord Clamping in Preterm Infants: Neurodevelopmental Outcomes at 22-26 Months of Corrected Age.

OBJECTIVE: To compare the effect of umbilical cord milking vs delayed cord clamping (DCC) on neurodevelopmental and health outcomes in very preterm infants at 22-26 months of corrected age. STUDY DESIGN: Neurodevelopmental outcomes at 2 years of age were assessed using the Bayley Scales of Infant Development, third edition, and a standardized neurologic examination. Data regarding pulmonary morbidities, neurosensory impairments, and hospitalizations were obtained by parental interview. Intention-to-treat was used for primary analyses. RESULTS: Of the 197 infants enrolled in the original study there were 15 deaths, 5 in the umbilical cord milking group and 10 in DCC group. Of the remaining infants, 135 (74%) were assessed at 22-26 months of corrected age. Demographics in umbilical cord milking (n = 70) and DCC (n = 65) groups were similar. Infants randomized to umbilical cord milking at birth had significantly higher cognitive and language composite scores, and were less likely to have a cognitive composite score of <85 (4% vs 15%; P = .04). Motor function was similar in both groups. There were no differences in the incidences of mild or moderate to severe neurodevelopmental impairment, hearing or visual impairments, pulmonary morbidities, or rehospitalizations between the 2 groups. CONCLUSIONS: Infants randomized to umbilical cord milking had higher language and cognitive scores compared with those randomized to DCC. There was no difference in rates of mild or moderate to severe neurodevelopmental impairment. TRIAL REGISTRATION: clinicaltrials.gov: NCT01434732.

Prevalence of Fetal Alcohol Spectrum Disorders in 4 US Communities.

Importance: Fetal alcohol spectrum disorders are costly, life-long disabilities. Older data suggested the prevalence of the disorder in the United States was 10 per 1000 children; however, there are few current estimates based on larger, diverse US population samples. Objective: To estimate the prevalence of fetal alcohol spectrum disorders, including fetal alcohol syndrome, partial fetal alcohol syndrome, and alcohol-related neurodevelopmental disorder, in 4 regions of the United States. Design, Setting, and Participants: Active case ascertainment methods using a cross-sectional design were used to assess children for fetal alcohol spectrum disorders between 2010 and 2016. Children were systematically assessed in the 4 domains that contribute to the fetal alcohol spectrum disorder continuum: dysmorphic features, physical growth, neurobehavioral development, and prenatal alcohol exposure. The settings were 4 communities in the Rocky Mountain, Midwestern, Southeastern, and Pacific Southwestern regions of the United States. First-grade children and their parents or guardians were enrolled. Exposures: Alcohol consumption during pregnancy. Main Outcomes and Measures: Prevalence of fetal alcohol spectrum disorders in the 4 communities was the main outcome. Conservative estimates for the prevalence of the disorder and 95% CIs were calculated using the eligible first-grade population as the denominator. Weighted prevalences and 95% CIs were also estimated, accounting for the sampling schemes and using data restricted to children who received a full evaluation. Results: A total of 6639 children were selected for participation from a population of 13 146 first-graders (boys, 51.9%; mean age, 6.7 years [SD, 0.41] and white maternal race, 79.3%). A total of 222 cases of fetal alcohol spectrum disorders were identified. The conservative prevalence estimates for fetal alcohol spectrum disorders ranged from 11.3 (95% CI, 7.8-15.8) to 50.0 (95% CI, 39.9-61.7) per 1000 children. The weighted prevalence estimates for fetal alcohol spectrum disorders ranged from 31.1 (95% CI, 16.1-54.0) to 98.5 (95% CI, 57.5-139.5) per 1000 children. Conclusions and Relevance: Estimated prevalence of fetal alcohol spectrum disorders among first-graders in 4 US communities ranged from 1.1% to 5.0% using a conservative approach. These findings may represent more accurate US prevalence estimates than previous studies but may not be generalizable to all communities.

Academic Difficulties in Children with Prenatal Alcohol Exposure: Presence, Profile, and Neural Correlates.

BACKGROUND: Academic achievement was evaluated in children with heavy prenatal alcohol exposure to determine potential strengths and weaknesses, evaluate the utility of different definitions for identifying low academic performance, and explore the neural correlates that may underlie academic performance. METHODS: Children (8 to 16 years) were assessed using the WIAT-II. Patterns of performance were examined in 2 subject groups: children with heavy prenatal alcohol exposure (n = 67) and controls (n = 61). A repeated-measures MANCOVA examining group differences on academic domain (reading, spelling, math) scores was conducted. Post hoc comparisons examined within-group profiles. Numbers and percentage of children with low achievement were calculated using several criteria. In a subsample (n = 42), neural correlates were analyzed using FreeSurfer v5.3 to examine relations between cortical structure (thickness and surface area) and performance. RESULTS: The alcohol-exposed group performed worse than controls on all domains and had a unique academic profile, supported by a significant group × academic domain interaction (p < 0.001). For the alcohol-exposed group, math reasoning was significantly lower than numerical operations, which was significantly lower than spelling and word reading. Over half of the alcohol-exposed group (58.2%) demonstrated low achievement on 1 or more academic domains. The number and percentage of children meeting criteria for low achievement varied based on the domain and definition used. The imaging analysis identified several surface area clusters that were differentially related to math (L superior parietal and R lateral/middle occipital) and spelling (bilateral inferior and medial temporal) performance by group, with no relations for the other academic domains. Generally, scores improved as surface area decreased in controls, whereas no relation or a positive relation was observed in the alcohol-exposed group. CONCLUSIONS: Alcohol-exposed children demonstrated deficits in academic performance across domains and definitions, with a relative weakness in math functioning. Atypical brain development may contribute to these impairments in academic achievement. Understanding academic difficulties can assist in advocating effectively for alcohol-exposed children.

Global Visual Motion Sensitivity: Associations with Parietal Area and Children's Mathematical Cognition.

Sensitivity to global visual motion has been proposed as a signature of brain development, related to the dorsal rather than ventral cortical stream. Thresholds for global motion have been found to be elevated more than for global static form in many developmental disorders, leading to the idea of "dorsal stream vulnerability." Here we explore the association of global motion thresholds with individual differences in children's brain development, in a group of typically developing 5- to 12-year-olds. Good performance was associated with a relative increase in parietal lobe surface area, most strongly around the intraparietal sulcus and decrease in occipital area. In line with the involvement of intraparietal sulcus, areas in visuospatial and numerical cognition, we also found that global motion performance was correlated with tests of visuomotor integration and numerical skills. Individual differences in global form detection showed none of these anatomical or cognitive correlations. This suggests that the correlations with motion sensitivity are unlikely to reflect general perceptual or attentional abilities required for both form and motion. We conclude that individual developmental variations in global motion processing are not linked to greater area in the extrastriate visual areas, which initially process such motion, but in the parietal systems that make decisions based on this information. The overlap with visuospatial and numerical abilities may indicate the anatomical substrate of the "dorsal stream vulnerability" proposed as characterizing neurodevelopmental disorders.

The Pediatric Imaging, Neurocognition, and Genetics (PING) Data Repository.

The main objective of the multi-site Pediatric Imaging, Neurocognition, and Genetics (PING) study was to create a large repository of standardized measurements of behavioral and imaging phenotypes accompanied by whole genome genotyping acquired from typically-developing children varying widely in age (3 to 20 years). This cross-sectional study produced sharable data from 1493 children, and these data have been described in several publications focusing on brain and cognitive development. Researchers may gain access to these data by applying for an account on the PING portal and filing a data use agreement. Here we describe the recruiting and screening of the children and give a brief overview of the assessments performed, the imaging methods applied, the genetic data produced, and the numbers of cases for whom different data types are available. We also cite sources of more detailed information about the methods and data. Finally we describe the procedures for accessing the data and for using the PING data exploration portal.

Demographically Corrected Normative Standards for the Spanish Language Version of the NIH Toolbox Cognition Battery.

Hispanics are the fastest growing ethnicity in the United States, yet there are limited well-validated neuropsychological tools in Spanish, and an even greater paucity of normative standards representing this population. The Spanish NIH Toolbox Cognition Battery (NIHTB-CB) is a novel neurocognitive screener; however, the original norms were developed combining Spanish- and English-versions of the battery. We developed normative standards for the Spanish NIHTB-CB, fully adjusting for demographic variables and based entirely on a Spanish-speaking sample. A total of 408 Spanish-speaking neurologically healthy adults (ages 18-85 years) and 496 children (ages 3-7 years) completed the NIH Toolbox norming project. We developed three types of scores: uncorrected based on the entire Spanish-speaking cohort, age-corrected, and fully demographically corrected (age, education, sex) scores for each of the seven NIHTB-CB tests and three composites (Fluid, Crystallized, Total Composites). Corrected scores were developed using polynomial regression models. Demographic factors demonstrated medium-to-large effects on uncorrected NIHTB-CB scores in a pattern that differed from that observed on the English NIHTB-CB. For example, in Spanish-speaking adults, education was more strongly associated with Fluid scores, but showed the strongest association with Crystallized scores among English-speaking adults. Demographic factors were no longer associated with fully corrected scores. The original norms were not successful in eliminating demographic effects, overestimating children's performances, and underestimating adults' performances on the Spanish NIHTB-CB. The disparate pattern of demographic associations on the Spanish versus English NIHTB-CB supports the need for distinct normative standards developed separately for each population. Fully adjusted scores presented here will aid in more accurately characterizing acquired brain dysfunction among U.S. Spanish-speakers.

Jacobsen syndrome: Advances in our knowledge of phenotype and genotype.

In 1973, the Danish geneticist Petrea Jacobsen described a three-generation family in which the proband carried a presumed terminal deletion at the end of the long arm of chromosome 11 (11q). This patient had dysmorphic features, congenital heart disease, and intellectual disability. Since Dr. Jacobsen's initial report, over 200 patients with Jacobsen syndrome have been reported, suggesting that Jacobsen syndrome is a contiguous gene disorder. With the advent of high resolution deletion mapping and the completion of the human genome sequencing project, a comprehensive genotype/phenotype analysis for Jacobsen syndrome became possible. In this article, we review research describing individual causal genes in distal 11q that contribute to the overall Jacobsen syndrome clinical phenotype. Through a combination of human genetics and the use of genetically engineered animal models, causal genes have been identified for the clinical problems in JS that historically have caused the greatest morbidity and mortality: congenital heart disease, the Paris-Trousseau bleeding disorder, intellectual disability, autism, and immunodeficiency. Insights gained from these studies are being applied for future drug development and clinical trials, as well as for a potential strategy for the prevention of certain forms of congenital heart disease. The results of these studies will likely not only improve the prognostic and therapeutic approaches for patients with Jacobsen syndrome, but also for the general population afflicted with these problems.

Evidence for autism spectrum disorder in Jacobsen syndrome: identification of a candidate gene in distal 11q.

PURPOSE: Jacobsen syndrome, also called the 11q terminal deletion disorder, is a contiguous gene disorder caused by the deletion of the end of the long arm of chromosome 11. Intellectual skills range from low average to severe/profound intellectual disability and usually correlate with deletion size. Comprehensive genotype/phenotype evaluations are limited, and little is known about specific behavioral characteristics associated with 11q terminal deletion disorder. METHODS: In this prospective study, 17 patients with 11q terminal deletion disorder underwent cognitive and behavioral assessments. Deletion sizes were determined by array comparative genomic hybridization. RESULTS: Deletion sizes ranged from 8.7 to 14.5 Mb across the patients. We found that 8 of 17 patients (47%) exhibited behavioral characteristics consistent with an autism spectrum disorder diagnosis. There was no correlation between deletion size and the presence of autism spectrum disorder, implicating at least one predisposing gene in the distal 8.7 Mb of 11q. The findings from three additional patients with autistic features and "atypical" distal 11q deletions led to the identification of an autism "critical region" in distal 11q containing four annotated genes including ARHGAP32 (also known as RICS), a gene encoding rho GTPase activating protein. CONCLUSION: Results from this study support early autism spectrum disorder screening for patients with 11q terminal deletion disorder and provide further molecular insights into the pathogenesis of autism spectrum disorder.

Demographically Corrected Normative Standards for the English Version of the NIH Toolbox Cognition Battery.

Demographic factors impact neuropsychological test performances and accounting for them may help to better elucidate current brain functioning. The NIH Toolbox Cognition Battery (NIHTB-CB) is a novel neuropsychological tool, yet the original norms developed for the battery did not adequately account for important demographic/cultural factors known to impact test performances. We developed norms fully adjusting for all demographic variables within each language group (English and Spanish) separately. The current study describes the standards for individuals tested in English. Neurologically healthy adults (n=1038) and children (n=2917) who completed the NIH Toolbox norming project in English were included. We created uncorrected scores weighted to the 2010 Census demographics, and applied polynomial regression models to develop age-corrected and fully demographically adjusted (age, education, sex, race/ethnicity) scores for each NIHTB-CB test and composite (i.e., Fluid, Crystallized, and Total Composites). On uncorrected NIHTB-CB scores, age and education demonstrated significant, medium-to-large associations, while sex showed smaller, but statistically significant effects. In terms of race/ethnicity, a significant stair-step effect on uncorrected NIHTB-CB scores was observed (African American

Long-term influence of normal variation in neonatal characteristics on human brain development.

It is now recognized that a number of cognitive, behavioral, and mental health outcomes across the lifespan can be traced to fetal development. Although the direct mediation is unknown, the substantial variance in fetal growth, most commonly indexed by birth weight, may affect lifespan brain development. We investigated effects of normal variance in birth weight on MRI-derived measures of brain development in 628 healthy children, adolescents, and young adults in the large-scale multicenter Pediatric Imaging, Neurocognition, and Genetics study. This heterogeneous sample was recruited through geographically dispersed sites in the United States. The influence of birth weight on cortical thickness, surface area, and striatal and total brain volumes was investigated, controlling for variance in age, sex, household income, and genetic ancestry factors. Birth weight was found to exert robust positive effects on regional cortical surface area in multiple regions as well as total brain and caudate volumes. These effects were continuous across birth weight ranges and ages and were not confined to subsets of the sample. The findings show that (i) aspects of later child and adolescent brain development are influenced at birth and (ii) relatively small differences in birth weight across groups and conditions typically compared in neuropsychiatric research (e.g., Attention Deficit Hyperactivity Disorder, schizophrenia, and personality disorders) may influence group differences observed in brain parameters of interest at a later stage in life. These findings should serve to increase our attention to early influences.

Multimodal imaging of the self-regulating developing brain.

Self-regulation refers to the ability to control behavior, cognition, and emotions, and self-regulation failure is related to a range of neuropsychiatric problems. It is poorly understood how structural maturation of the brain brings about the gradual improvement in self-regulation during childhood. In a large-scale multicenter effort, 735 children (4-21 y) underwent structural MRI for quantification of cortical thickness and surface area and diffusion tensor imaging for quantification of the quality of major fiber connections. Brain development was related to a standardized measure of cognitive control (the flanker task from the National Institutes of Health Toolbox), a critical component of self-regulation. Ability to inhibit responses and impose cognitive control increased rapidly during preteen years. Surface area of the anterior cingulate cortex accounted for a significant proportion of the variance in cognitive performance. This finding is intriguing, because characteristics of the anterior cingulum are shown to be related to impulse, attention, and executive problems in neurodevelopmental disorders, indicating a neural foundation for self-regulation abilities along a continuum from normality to pathology. The relationship was strongest in the younger children. Properties of large-fiber connections added to the picture by explaining additional variance in cognitive control. Although cognitive control was related to surface area of the anterior cingulate independently of basic processes of mental speed, the relationship between white matter quality and cognitive control could be fully accounted for by speed. The results underscore the need for integration of different aspects of brain maturation to understand the foundations of cognitive development.

Association of common genetic variants in GPCPD1 with scaling of visual cortical surface area in humans.

Visual cortical surface area varies two- to threefold between human individuals, is highly heritable, and has been correlated with visual acuity and visual perception. However, it is still largely unknown what specific genetic and environmental factors contribute to normal variation in the area of visual cortex. To identify SNPs associated with the proportional surface area of visual cortex, we performed a genome-wide association study followed by replication in two independent cohorts. We identified one SNP (rs6116869) that replicated in both cohorts and had genome-wide significant association (P(combined) = 3.2 × 10(-8)). Furthermore, a metaanalysis of imputed SNPs in this genomic region identified a more significantly associated SNP (rs238295; P = 6.5 × 10(-9)) that was in strong linkage disequilibrium with rs6116869. These SNPs are located within 4 kb of the 5' UTR of GPCPD1, glycerophosphocholine phosphodiesterase GDE1 homolog (Saccharomyces cerevisiae), which in humans, is more highly expressed in occipital cortex compared with the remainder of cortex than 99.9% of genes genome-wide. Based on these findings, we conclude that this common genetic variation contributes to the proportional area of human visual cortex. We suggest that identifying genes that contribute to normal cortical architecture provides a first step to understanding genetic mechanisms that underlie visual perception.

Reliability and validity of composite scores from the NIH Toolbox Cognition Battery in adults.

This study describes psychometric properties of the NIH Toolbox Cognition Battery (NIHTB-CB) Composite Scores in an adult sample. The NIHTB-CB was designed for use in epidemiologic studies and clinical trials for ages 3 to 85. A total of 268 self-described healthy adults were recruited at four university-based sites, using stratified sampling guidelines to target demographic variability for age (20-85 years), gender, education, and ethnicity. The NIHTB-CB contains seven computer-based instruments assessing five cognitive sub-domains: Language, Executive Function, Episodic Memory, Processing Speed, and Working Memory. Participants completed the NIHTB-CB, corresponding gold standard validation measures selected to tap the same cognitive abilities, and sociodemographic questionnaires. Three Composite Scores were derived for both the NIHTB-CB and gold standard batteries: "Crystallized Cognition Composite," "Fluid Cognition Composite," and "Total Cognition Composite" scores. NIHTB Composite Scores showed acceptable internal consistency (Cronbach's alphas=0.84 Crystallized, 0.83 Fluid, 0.77 Total), excellent test-retest reliability (r: 0.86-0.92), strong convergent (r: 0.78-0.90) and discriminant (r: 0.19-0.39) validities versus gold standard composites, and expected age effects (r=0.18 crystallized, r=-0.68 fluid, r=-0.26 total). Significant relationships with self-reported prior school difficulties and current health status, employment, and presence of a disability provided evidence of external validity. The NIH Toolbox Cognition Battery Composite Scores have excellent reliability and validity, suggesting they can be used effectively in epidemiologic and clinical studies.

Measurement of emerging neurocognitive and language skills in the HEALthy Brain and Child Development (HBCD) study.

The HEALthy Brain and Child Development (HBCD) study, a multi-site prospective longitudinal cohort study, will examine human brain, cognitive, behavioral, social, and emotional development beginning prenatally and planned through early childhood. The study plans enrolling over 7000 families across 27 sites. This manuscript presents the measures from the Neurocognition and Language Workgroup. Constructs were selected for their importance in normative development, evidence for altered trajectories associated with environmental influences, and predictive validity for child outcomes. Evaluation of measures considered psychometric properties, brevity, and developmental and cultural appropriateness. Both performance measures and caregiver report were used wherever possible. A balance of norm-referenced global measures of development (e.g., Bayley Scales of Infant Development-4) and more specific laboratory measures (e.g., deferred imitation) are included in the HBCD study battery. Domains of assessment include sensory processing, visual-spatial reasoning, expressive and receptive language, executive function, memory, numeracy, adaptive behavior, and neuromotor. Strategies for staff training and quality control procedures, as well as anticipated measures to be added as the cohort ages, are reviewed. The HBCD study presents a unique opportunity to examine early brain and neurodevelopment in young children through a lens that accounts for prenatal exposures, health and socio-economic disparities.

Capturing the complexity of child behavior and caregiver-child interactions in the HEALthy Brain and Child Development (HBCD) Study using a rigorous and equitable approach.

The HEALthy Brain and Child Development (HBCD) Study, a multi-site prospective longitudinal cohort study, will examine human brain, cognitive, behavioral, social, and emotional development beginning prenatally and planned through early childhood. This article outlines methodological considerations and the decision-making process for measurement selection for child behavior, parenting/caregiver-child interactions, and the family/home environment for HBCD. The decision-making process is detailed, including formation of a national workgroup (WG-BEH) that focused on developmentally appropriate measures that take a rigorous and equitable approach and aligned with HBCD objectives. Multi-level-observational and caregiver-report measures were deemed necessary for capturing the desired constructs across multiple contexts while balancing the nuance of observational data with pragmatic considerations. WG-BEH prioritized developmentally sensitive, validated assessments with psychometrics supporting use in diverse populations and focused on mechanistic linkages and prediction of desired constructs. Other considerations included participant burden and retention, staff training needs, and cultural sensitivity. Innovation was permitted when it was grounded in evidence and filled key gaps. Finally, this article describes the rationale for the selected constructs (e.g., temperament, social-emotional development, parenting behaviors, family organization) and corresponding measures chosen for HBCD visits from early infancy through 17 months of age.

Diagnosis of autism spectrum disorders in 2-year-olds: a study of community practice.

BACKGROUND: Longitudinal research studies have demonstrated that experienced clinicians using standardized assessment measures can make a reliable diagnosis of autism spectrum disorders (ASDs) in children under age 3. Limited data are available regarding the sensitivity and specificity of these measures in community settings. The aims of this study were to determine how well a standardized diagnostic observational measure (Autism Diagnostic Observation Schedule - ADOS) functions alone, and with a brief parent measure within a community setting when administered by community clinicians. METHODS: Clinical records for 138 children between the ages of 24 and 36 months of age who were evaluated for possible ASD or social/language concerns at a hospital-based developmental evaluation clinic were examined. Evaluations were conducted by community-based clinical psychologists. Classification results obtained from standardized diagnostic measures were compared with case reviewer diagnosis, by reviewers blind to scores on diagnostic measures, using The Records-based Methodology for ASD Case Definition that was developed by the Metropolitan Atlanta Developmental Disabilities Surveillance Program. RESULTS: When compared with case review diagnosis, the ADOS demonstrated strong sensitivity and specificity for both Autism versus Not Autism and ASD versus Nonspectrum (NS) diagnoses in this young sample. The Social Communication Questionnaire (SCQ), using the lower cutoff of ≥12, had adequate sensitivity when differentiating Autism from Not Autism, but weak sensitivity when differentiating ASD from NS, missing about 80% of the children with pervasive developmental disorder - not otherwise specified. Using either the Modified Checklist for Autism in Toddlers or the SCQ in combination with the ADOS did not result in improved specificity over the ADOS alone and led to a drop in sensitivity when differentiating ASD from NS disorders. CONCLUSIONS: These results demonstrate that following best practice guidelines, the ADOS can be successfully incorporated into clinical practice with relatively good sensitivity and specificity, and worked well with a referred sample of 2-year-olds. A parent questionnaire did not lead to any improvement in diagnostic classification above the ADOS used in isolation.