Background Chromosomal microarray analysis has emerged as a primary diagnostic tool for the evaluation of developmental delay and structural malformations in children. We aimed to evaluate the accuracy, efficacy, and incremental yield of chromosomal microarray analysis as compared with karyotyping for routine prenatal diagnosis. Methods Samples from women undergoing prenatal diagnosis at 29 centers were sent to a central karyotyping laboratory. Each sample was split in two; standard karyotyping was performed on one portion and the other was sent to one of four laboratories for chromosomal microarray. Results We enrolled a total of 4406 women. Indications for prenatal diagnosis were advanced maternal age (46.6%), abnormal result on Down’s syndrome screening (18.8%), structural anomalies on ultrasonography (25.2%), and other indications (9.4%). In 4340 (98.8%) of the fetal samples, microarray analysis was successful; 87.9% of samples could be used without tissue culture. Microarray analysis of the 4282 nonmosaic samples identified all the aneuploidies and unbalanced rearrangements identified on karyotyping but did not identify balanced translocations and fetal triploidy. In samples with a normal karyotype, microarray analysis revealed clinically relevant deletions or duplications in 6.0% with a structural anomaly and in 1.7% of those whose indications were advanced maternal age or positive screening results. Conclusions In the context of prenatal diagnostic testing, chromosomal microarray analysis identified additional, clinically significant cytogenetic information as compared with karyotyping and was equally efficacious in identifying aneuploidies and unbalanced rearrangements but did not identify balanced translocations and triploidies. (Funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development and others; ClinicalTrials.gov number, NCT01279733.)

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Chromosomal microarray versus karyotyping for prenatal diagnosis

Cowden syndrome (CS) and Bannayan-Riley-Ruvalcaba syndrome are allelic, defined by germline PTEN mutations, and collectively referred to as PTEN hamartoma tumor syndrome. To date, there are no existing criteria based on large prospective patient cohorts to select patients for PTEN mutation testing. To address these issues, we conducted a multicenter prospective study in which 3042 probands satisfying relaxed CS clinical criteria were accrued. PTEN mutation scanning, including promoter and large deletion analysis, was performed for all subjects. Pathogenic mutations were identified in 290 individuals (9.5%). To evaluate clinical phenotype and PTEN genotype against protein expression, we performed immunoblotting (PTEN, P-AKT1, P-MAPK1/2) for a patient subset (n = 423). In order to obtain an individualized estimation of pretest probability of germline PTEN mutation, we developed an optimized clinical practice model to identify adult and pediatric patients. For adults, a semiquantitative score—the Cleveland Clinic (CC) score—resulted in a well-calibrated estimation of pretest probability of PTEN status. Overall, decreased PTEN protein expression correlated with PTEN mutation status; decreasing PTEN protein expression correlated with increasing CC score (p < 0.001), but not with the National Comprehensive Cancer Network (NCCN) criteria (p = 0.11). For pediatric patients, we identified highly sensitive criteria to guide PTEN mutation testing, with phenotypic features distinct from the adult setting. Our model improved sensitivity and positive predictive value for germline PTEN mutation relative to the NCCN 2010 criteria in both cohorts. We present the first evidence-based clinical practice model to select patients for genetics referral and PTEN mutation testing, further supported biologically by protein correlation.

A Clinical Scoring System for Selection of Patients for PTEN Mutation Testing Is Proposed on the Basis of a Prospective Study of 3042 Probands

Parents and teachers of children with special needs face unique social-emotional challenges in carrying out their caregiving roles. Stress associated with these roles impacts parents' and special educators' health and well-being, as well as the quality of their parenting and teaching. No rigorous studies have assessed whether mindfulness training (MT) might be an effective strategy to reduce stress and cultivate well-being and positive caregiving in these adults. This randomized controlled study assessed the efficacy of a 5-week MT program for parents and educators of children with special needs. Participants receiving MT showed significant reductions in stress and anxiety and increased mindfulness, self-compassion, and personal growth at program completion and at 2 months follow-up in contrast to waiting-list controls. Relational competence also showed significant positive changes, with medium-to-large effect sizes noted on measures of empathic concern and forgiveness. MT significantly influenced caregiving competence specific to teaching. Mindfulness changes at program completion mediated outcomes at follow-up, suggesting its importance in maintaining emotional balance and facilitating well-being in parents and teachers of children with developmental challenges.

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Mindfulness training effects for parents and educators of children with special needs.

We investigated whether minority children attending U.S. elementary and middle schools are disproportionately represented in special education. We did so using hazard modeling of multiyear longitudinal data and extensive covariate adjustment for potential child-, family-, and state-level confounds. Minority children were consistently less likely than otherwise similar White, English-speaking children to be identified as disabled and so to receive special education services. From kindergarten entry to the end of middle school, racial- and ethnic-minority children were less likely to be identified as having (a) learning disabilities, (b) speech or language impairments, (c) intellectual disabilities, (d) health impairments, or (e) emotional disturbances. Language-minority children were less likely to be identified as having (a) learning disabilities or (b) speech or language impairments.

Minorities Are Disproportionately Underrepresented in Special Education: Longitudinal Evidence Across Five Disability Conditions

BACKGROUND: Early identification of developmental delays is essential for optimal early intervention. An American Academy of Pediatrics (AAP) 2002 Periodic Survey of Fellows found OBJECTIVE: The goal of this study was to compare pediatricians9 use of standardized screening tools from 2002 to 2009. METHODS: A national, random sample of nonretired US AAP members were mailed Periodic Surveys (2002: N = 1617, response rate: 55%; 2009: N = 1620, response rate: 57%). χ2 analyses were used to examine responses across survey years; a multivariate logistic regression model was developed to compare differences in using ≥1 formal screening tools across survey years while controlling for various individual and practice characteristics. RESULTS: Pediatricians9 use of standardized screening tools increased significantly between 2002 and 2009. The percentage of those who self-reported always/almost always using ≥1 screening tools increased over time (23.0%–47.7%), as did use of specific instruments (eg, Ages & Stages Questionnaire, Parents9 Evaluation of Developmental Status). No differences were noted on the basis of physician or practice characteristics. CONCLUSIONS: The percentage of pediatricians who reported using ≥1 formal screening tools more than doubled between 2002 and 2009. Despite greater attention to consistent use of appropriate tools, the percentage remains less than half of respondents providing care to patients younger than 36 months. Given the critical importance of developmental screening in early identification, evaluation, and intervention, additional research is needed to identify barriers to greater use of standardized tools in practice.

Trends in the use of standardized tools for developmental screening in early childhood: 2002-2009.

OBJECTIVES. The objective of this study was to use a nationally representative longitudinal sample of children born in the United States in 2001 to estimate rates of eligibility for Part C early intervention, to estimate rates of access to services for developmental delays, and to examine factors that are associated with access to services. METHODS. Data for this study were collected as part of the Early Childhood Longitudinal Study, Birth Cohort, which obtained data from participants when children were 9 and 24 months of age. Descriptive analyses were used to generate national estimates of the prevalence of developmental delays that would make children eligible for Part C services and rates of participation in early intervention services. Logistic regression analyses were conducted to examine whether child developmental delay, race, insurance availability, and poverty status were associated with the probability of receiving services. RESULTS. Results indicated that ∼13% of children in the sample had developmental delays that would make them eligible for Part C early intervention. At 24 months, only 10% of children with delays received services. Children with developmental delays were more likely to receive services than those who do not have delays; black children were less likely to receive services than children from other ethnic and racial groups. CONCLUSIONS. The prevalence of developmental delays that make children eligible for Part C services is much higher than previously thought. Moreover, the majority of children who are eligible for Part C services are not receiving services for their developmental problems. Strategies need to be developed to monitor patterns of enrollment in early intervention services and reach out to more minority children, particularly black children.

Duan Zhang

Papers

Prevalence of Developmental Delays and Participation in Early Intervention Services for Young Children