Development of a long-term time-weighted exposure metric that accounts for missing data in the Seychelles Child Development Study.

In many studies of the health effects of toxicants, exposure is measured once even though exposure may be continuous. However, some studies collect repeated measurements on participants over an extended time with the goal of determining a long-term metric that captures the average or cumulative exposure. This can be challenging, especially when exposure is measured at irregular intervals and has some missing values. Here we describe a method for determining a measure of long-term exposure using data on postnatal mercury (Hg) from the Seychelles Child Development Study (SCDS) Main Cohort as a model. In this cohort (n = 779), we incorporate postnatal Hg values that were measured on most study participants at seven ages, three between 6 months and 5.5 years ("childhood"), and an additional four between 17 and 24 years ("early adulthood"). We develop time-weighted measures of average exposure during the childhood and the early adulthood periods and compare the strengths and weaknesses of our metric to two standard measures: overall average and cumulative exposure. We account for missing values through an imputation method that uses information about age- and sex-specific Hg means and the participant's Hg values at similar ages to estimate subject-specific missing Hg values. We compare our method to the implicit imputation assumed by these two standard methods, and to Fully Conditional Specification (FCS), an alternative method of imputing missing data. To determine the accuracy of our imputation method we use data from participants with no missing Hg values in the relevant time window. The imputed values from our proposed method are substantially closer to the observed values on average than the average or cumulative exposure, while also performing slightly better than FCS. In conclusion, time-weighted long-term exposure appears to offer advantages over cumulative exposure in longitudinal studies with repeated measures where the follow-up period for a toxicant is similar for all participants. Additionally, our method to impute missing values maximizes the number of participants for whom the overall exposure metric can be calculated and should provide a more accurate long-term exposure metric than standard methods when exposure has missing values. Our method is applicable to any study of long-term toxicant effects when longitudinal exposure measurements are available but have missing values.

Delivery Mode and Child Development at 20 Months of Age and 7 Years of Age in the Republic of Seychelles.

OBJECTIVE: To determine if cesarean delivery is adversely associated with child neurodevelopment as measured at 20 months and 7 years. METHODS: In a prospective cohort study (n = 1328) in the Republic of Seychelles, we examined the association between mode of delivery and 22 measures of child neurodevelopment spanning multiple domains: cognition, executive and psychomotor function, language development, behavior, scholastic achievement, and social communication. Using multivariable linear regression, we evaluated the relationship between delivery mode (Cesarean/vaginal delivery) and each developmental outcome, while controlling for relevant covariates including child sex and age, maternal age, maternal IQ, whether both parents lived with the child, and Hollingshead socioeconomic status. RESULTS: At 20 months, children born via cesarean delivery had slightly higher scores (ß = 0.11, 95% confidence interval: 0.00, 0.21) on the Infant Behavior Questionnaire-Revised Positive Affectivity/Surgency subtest, a measure of infant temperament, as compared to vaginal delivery. Delivery mode was not associated with any of the 7-year developmental outcomes. CONCLUSIONS FOR PRACTICE: Our study does not support the notion that cesarean delivery is associated with child neurodevelopmental outcomes.

Using Parent Target Problem Narratives to Evaluate Outcomes in Children with Autism Spectrum Disorder.

This paper examines the reliability and validity of parent target problems (PTPs) in a multi-site randomized controlled trial of parent training (PT) versus psychoeducation (PEP) in children (150 boys, 19 girls; mean age 4.7 ± 1.2 years) with autism spectrum disorder (ASD) and disruptive behavior. At baseline, treatment blind, independent evaluators asked parents to nominate the child's top two problems. Each problem was documented in a brief narrative. Narratives were reviewed and revised at follow-up visits during the six-month trial. When the trial was completed, five judges, blind to treatment condition, independently rated change from baseline on a 9-point scale (1 = normal; 2 = markedly improved; 3 = definitely improved; 4 = equivocally improved; 5 = no change; 6 = possibly worse; 7 = definitely worse; 8 = markedly worse; 9 = disastrously worse) at Weeks 8, 12, 16, and 24 (inter-rater intraclass correlation = 0.78). PTP scores for the two target problems were averaged across the five raters, yielding a mean score for each child at each time point. Mean PTP scores showed improvement in both treatment groups over the 24-week study. Compared to PEP, PTP ratings showed a steeper decline in PT based on significant interaction of group and time (t(df) = 2.14(155.9), p = 0.034; Week 24 effect size = 0.75). In categorical analysis, we compared cutoffs mean PTP scores of 3.0 (definitely improved), 3.25, and 3.5 with the positive response rate on the Clinical Global Impressions-Improvement scale from the original study. Sensitivities ranged from 52-78%. PTP narratives offer a systematic, reliable, and valid way to track child-specific outcomes in clinical trials and clinical practice.

Prenatal methylmercury exposure and DNA methylation in seven-year-old children in the Seychelles Child Development Study.

BACKGROUND: Methylmercury (MeHg) is present in fish and is a neurotoxicant at sufficiently high levels. One potential mechanism of MeHg toxicity early in life is epigenetic dysregulation that may affect long-term neurodevelopment. Altered DNA methylation of nervous system-related genes has been associated with adult mental health outcomes. OBJECTIVE: To assess associations between prenatal MeHg exposure and DNA methylation (at the cytosine of CG dinucleotides, CpGs) in three nervous system-related genes, encoding brain-derived neurotropic factor (BDNF), glutamate receptor subunit NR2B (GRIN2B), and the glucocorticoid receptor (NR3C1), in children who were exposed to MeHg in utero. METHODS: We tested 406 seven-year-old Seychellois children participating in the Seychelles Child Development Study (Nutrition Cohort 2), who were prenatally exposed to MeHg from maternal fish consumption. Total mercury in maternal hair (prenatal MeHg exposure measure) collected during pregnancy was measured using atomic absorption spectroscopy. Methylation in DNA from the children's saliva was measured by pyrosequencing. To assess associations between prenatal MeHg exposure and CpG methylation at seven years of age, we used multivariable linear regression models adjusted for covariates. RESULTS: We identified associations with prenatal MeHg exposure for DNA methylation of one GRIN2B CpG and two NR3C1 CpGs out of 12 total CpG sites. Higher prenatal MeHg was associated with higher methylation for each CpG site. For example, NR3C1 CpG3 had an expected increase of 0.03-fold for each additional 1 ppm of prenatal MeHg (B = 0.030, 95% CI 0.001, 0.059; p = 0.047). Several CpG sites associated with MeHg are located in transcription factor binding sites and the observed methylation changes are predicted to lead to lower gene expression. CONCLUSIONS: In a population of people who consume large amounts of fish, we showed that higher prenatal MeHg exposure was associated with differential DNA methylation at seven years of age at specific CpG sites that may influence neurodevelopment and mental health.

A pilot investigation of an iOS-based app for toilet training children with autism spectrum disorder.

We developed an iOS-based app with a transmitter/disposable sensor and corresponding manualized intervention for children with autism spectrum disorder. The app signaled the onset of urination, time-stamped accidents for analysis, reminded parents to reinforce intervals of continence, provided a visual outlet for parents to communicate reinforcement, and afforded opportunity for timely feedback from clinicians. We compared this intervention with an intervention that uses standard behavioral treatment in a pilot randomized controlled trial of 33 children with autism spectrum disorder aged 3-6 years with urinary incontinence. Parents in both groups received initial training and four booster consultations over 3 months. Results support the feasibility of parent-mediated toilet training studies (e.g., 84% retention rate, 92% fidelity of parent-implemented intervention). Parents used the app and related technology with few difficulties or malfunctions. There were no statistically significant group differences for rate of urine accidents, toilet usage, or satisfaction at close of intervention or 3-month follow-up; however, the alarm group trended toward greater rate of skill acquisition with significantly less day-to-day intervention. Further development of alarm and related technology and future comparative studies with a greater number of participants are warranted.

Maternal Gestational Immune Response and Autism Spectrum Disorder Phenotypes at 7 Years of Age in the Seychelles Child Development Study.

Findings from observational and experimental studies suggest that maternal inflammation during pregnancy is associated with autism spectrum disorder (ASD). We report the first study in humans to examine this association in a large prospective birth cohort. We studied 788 mother-child pairs from the Seychelles Child Development Study Nutrition Cohort 2. Thirteen inflammatory markers were measured in mothers' serum at 28 weeks' gestation, along with the sum of T-helper 1 (Th1) and 2 (Th2) cytokines. The Social Communication Questionnaire (SCQ) and Social Responsiveness Scale (SRS) were administered at age 7 years to obtain information on ASD phenotype. We evaluated associations between maternal inflammatory markers and ASD phenotype using multivariable linear regression. For the SCQ, increased MCP-1 (a chemokine that is upregulated in response to pro-inflammatory cytokines) was associated with fewer ASD symptoms (B = - 0.40; 95% CI = - 0.72, - 0.09). Increased IL-4 (a cytokine that is typically associated with an enhanced anti-inflammatory response) was associated with more ASD symptoms (B = 2.10; 95% CI = 0.78, 3.43). For the SRS, higher concentrations of the anti-inflammatory cytokine IL-10 were associated with fewer ASD symptoms (B = - 0.18; 95% CI = - 0.35, - 0.01), but only after removal of outliers. No associations were observed for other markers. These findings suggest that a shift in the maternal immune balance during pregnancy may be associated with ASD symptomatology. While the use of well-established measures that capture ASD phenotypic variability is a strength of the study, measurement of peripheral immune markers only once during gestation is a limitation. Our results should be confirmed using maternal immune markers measured throughout gestation.

Use of urine alarms in toilet training children with intellectual and developmental disabilities: A review.

The purpose of this review is to describe and evaluate the existing research on the use of urine alarms in the daytime toilet training of children with intellectual and developmental disabilities (IDD). A systematic literature search yielded 12 studies, many of which were published over a decade ago. The findings suggest that interventions that incorporate the use of urine alarms are promising in the treatment of daytime enuresis for children with IDD; however, more carefully controlled research is needed to confirm these findings and elucidate the precise role urine alarms may play in toileting interventions. Methodological strengths and limitations of the body of research are discussed.

Atomoxetine, Parent Training, and Their Combination in Children With Autism Spectrum Disorder and Attention-Deficit/Hyperactivity Disorder.

OBJECTIVE: Impairments associated with attention-deficit/hyperactivity disorder (ADHD) and noncompliance are prevalent in children with autism spectrum disorder (ASD). However, ADHD response to stimulants is well below rates in typically developing children, with frequent side effects. Group studies of treatments for noncompliance are rare in ASD. We examined individual and combined-effectiveness of atomoxetine (ATX) and parent training (PT) for ADHD symptoms and noncompliance. METHOD: In a 3-site, 10-week, double-blind, 2 × 2 trial of ATX and PT, 128 children (ages 5-14 years) with ASD and ADHD symptoms were randomized to ATX, ATX+PT, placebo+PT, or placebo. ATX was adjusted to optimal dose (capped at 1.8 mg/kg/day) over 6 weeks and maintained for 4 additional weeks. Nine PT sessions were provided. Primary outcome measures were the parent-rated DSM ADHD symptoms on the Swanson, Nolan and Pelham (SNAP) scale and Home Situations Questionnaire (HSQ). RESULTS: On the SNAP, ATX, ATX+PT and placebo+PT were each superior to placebo (effect sizes 0.57-0.98; p values of .0005, .0004, and .025, respectively). For noncompliance, ATX and ATX+PT were superior to placebo (effect sizes 0.47-0.64; p values .03 and .0028, respectively). ATX was associated with decreased appetite but was otherwise well tolerated. CONCLUSION: Both ATX and PT resulted in significant improvement on ADHD symptoms, whereas ATX (both alone and combined with PT) was associated with significant decreases on measures of noncompliance. ATX appears to have a better side effects profile than psychostimulants in the population with ASD. CLINICAL TRIAL REGISTRATION INFORMATION: Atomoxetine, Placebo and Parent Management Training in Autism; http://clinicaltrials.gov/; NCT00844753.

Effect of parent training vs parent education on behavioral problems in children with autism spectrum disorder: a randomized clinical trial.

IMPORTANCE: Disruptive behavior is common in children with autism spectrum disorder. Behavioral interventions are used to treat disruptive behavior but have not been evaluated in large-scale randomized trials. OBJECTIVE: To evaluate the efficacy of parent training for children with autism spectrum disorder and disruptive behavior. DESIGN, SETTING, AND PARTICIPANTS: This 24-week randomized trial compared parent training (n = 89) to parent education (n = 91) at 6 centers (Emory University, Indiana University, Ohio State University, University of Pittsburgh, University of Rochester, Yale University). We screened 267 children; 180 children (aged 3-7 years) with autism spectrum disorder and disruptive behaviors were randomly assigned (86% white, 88% male) between September 2010 and February 2014. INTERVENTIONS: Parent training (11 core, 2 optional sessions; 2 telephone boosters; 2 home visits) provided specific strategies to manage disruptive behavior. Parent education (12 core sessions, 1 home visit) provided information about autism but no behavior management strategies. MAIN OUTCOMES AND MEASURES: Parents rated disruptive behavior and noncompliance on co-primary outcomes: the Aberrant Behavior Checklist-Irritability subscale (range, 0-45) and the Home Situations Questionnaire-Autism Spectrum Disorder (range, 0-9). On both measures, higher scores indicate greater severity and a 25% reduction indicates clinical improvement. A clinician blind to treatment assignment rated the Improvement scale of the Clinical Global Impression (range, 1-7), a secondary outcome, with a positive response less than 3. RESULTS: At week 24, the Aberrant Behavior Checklist-Irritability subscale declined 47.7% in parent training (from 23.7 to 12.4) compared with 31.8% for parent education (23.9 to 16.3) (treatment effect, -3.9; 95% CI, -6.2 to -1.7; P < .001, standardized effect size = 0.62). The Home Situations Questionnaire-Autism Spectrum Disorder declined 55% (from 4.0 to 1.8) compared with 34.2% in parent education (3.8 to 2.5) (treatment effect, -0.7; 95% CI, -1.1 to -0.3; P < .001, standardized effect size = 0.45). Neither measure met the prespecified minimal clinically important difference. The proportions with a positive response on the Clinical Global Impression-Improvement scale were 68.5% for parent training vs 39.6% for parent education (P < .001). CONCLUSIONS AND RELEVANCE: For children with autism spectrum disorder, a 24-week parent training program was superior to parent education for reducing disruptive behavior on parent-reported outcomes, although the clinical significance of the improvement is unclear. The rate of positive response judged by a blinded clinician was greater for parent training vs parent education. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01233414.

Predicting Outcome of Community-Based Early Intensive Behavioral Intervention for Children with Autism.

We examined predictors of outcome (IQ, adaptive behavior, and ASD severity) after 12 and 24 months of early intensive behavioral intervention (EIBI) in 71, 20-59 months old children with autism spectrum disorder (ASD) who were enrolled in publicly-funded, community-based agencies. Predictors included social engagement (combining variables loading onto a single factor: social approach, joint attention, and imitation) and sensorimotor rituals. Younger age and higher IQ at intake predicted favorable outcomes at both 12 and 24 months. Adjusting for age, IQ, baseline predictor scores, EIBI hours, treatment site, and sensorimotor rituals, social engagement predicted superior later IQ and adaptive behavior. In contrast, sensorimotor rituals did not predict outcome. Although limited by the absence of a control group, the study indicates social engagement predicts some EIBI outcomes.

A review of atomoxetine effects in young people with developmental disabilities.

UNLABELLED: This review summarizes the pharmacokinetic characteristics, pharmacodynamic properties, common side effects, and clinical advantages and disadvantages associated with atomoxetine (ATX) treatment in typically developing children and adults with ADHD. Then the clinical research to date in developmental disabilities (DD), including autism spectrum disorders (ASD), is summarized and reviewed. Of the 11 relevant reports available, only two were placebo-controlled randomized clinical trials, and both focused on a single DD population (ASD). All trials but one indicated clinical improvement in ADHD symptoms with ATX, although it was difficult to judge the magnitude and validity of reported improvement in the absence of placebo controls. Effects of ATX on co-occurring behavioral and cognitive symptoms were much less consistent. Appetite decrease, nausea, and irritability were the most common adverse events reported among children with DD; clinicians should be aware that, as with stimulants, irritability appears to occur much more commonly in persons with DD than in typically developing individuals. Splitting the dose initially, starting below the recommended starting dose, and titrating slowly may prevent or ameliorate side effects. Patience is needed for the slow build-up of benefit. CONCLUSIONS: ATX holds promise for managing ADHD symptoms in DD, but properly controlled, randomized clinical trials of atomoxetine in intellectual disability and ASD are sorely needed. Clinicians and researchers should be vigilant for the emergence of irritability with ATX treatment. Effects of ATX on cognition in DD are virtually unstudied.

Disparities in diagnosis and access to health services for children with autism: data from the National Survey of Children's Health.

OBJECTIVE: Earlier assessment of autism improves outcomes. In addition, children with autism have significant need for medical care. Therefore, identification of factors associated with delays in the early diagnosis of autism and with decreased access to care has the potential to lead to interventions that will improve health and well-being. The aim of this study was to determine whether differences occur in the age-specific prevalence of autism or in access to health care in children of traditionally underserved populations. METHOD: Data from the National Survey of Children's Health of 2003/2004 were used. Diagnosis of autism and its severity were based on parental report. RESULTS: The prevalence of autism was lower for Latinos (26/10,000) than for non-Latinos (51/10,000). Whites and blacks had comparable rates. The lowest preschool rate of autism (16/10,000) occurred in poor children. Latinos and poor families rated their children's autism as more severe. Being black, Latino, or poor was associated with decreased access to services, while having Medicaid or State Children's Health Insurance Program was linked with better access to some services. CONCLUSIONS: Disparities in the prevalence and parent-reported severity of autism and in access to health care were found for children with autism. Programs for children in general (e.g., universal screening for autism) and programs that target traditionally underserved groups of children, their families, and their health care providers should be tested and implemented to optimize case finding of children with autism and to eliminate disparities in access to care and to early intervention.