Copy Number Variant Risk Scores Associated With Cognition, Psychopathology, and Brain Structure in Youths in the Philadelphia Neurodevelopmental Cohort.

Importance: Psychiatric and cognitive phenotypes have been associated with a range of specific, rare copy number variants (CNVs). Moreover, IQ is strongly associated with CNV risk scores that model the predicted risk of CNVs across the genome. But the utility of CNV risk scores for psychiatric phenotypes has been sparsely examined. Objective: To determine how CNV risk scores, common genetic variation indexed by polygenic scores (PGSs), and environmental factors combine to associate with cognition and psychopathology in a community sample. Design, Setting, and Participants: The Philadelphia Neurodevelopmental Cohort is a community-based study examining genetics, psychopathology, neurocognition, and neuroimaging. Participants were recruited through the Children's Hospital of Philadelphia pediatric network. Participants with stable health and fluency in English underwent genotypic and phenotypic characterization from November 5, 2009, through December 30, 2011. Data were analyzed from January 1 through July 30, 2021. Exposures: The study examined (1) CNV risk scores derived from models of burden, predicted intolerance, and gene dosage sensitivity; (2) PGSs from genomewide association studies related to developmental outcomes; and (3) environmental factors, including trauma exposure and neighborhood socioeconomic status. Main Outcomes and Measures: The study examined (1) neurocognition, with the Penn Computerized Neurocognitive Battery; (2) psychopathology, with structured interviews based on the Schedule for Affective Disorders and Schizophrenia for School-Age Children; and (3) brain volume, with magnetic resonance imaging. Results: Participants included 9498 youths aged 8 to 21 years; 4906 (51.7%) were female, and the mean (SD) age was 14.2 (3.7) years. After quality control, 18 185 total CNVs greater than 50 kilobases (10 517 deletions and 7668 duplications) were identified in 7101 unrelated participants genotyped on Illumina arrays. In these participants, elevated CNV risk scores were associated with lower overall accuracy on cognitive tests (standardized ß = 0.12; 95% CI, 0.10-0.14; P = 7.41 × 10-26); lower accuracy across a range of cognitive subdomains; increased overall psychopathology; increased psychosis-spectrum symptoms; and higher deviation from a normative developmental model of brain volume. Statistical models of developmental outcomes were significantly improved when CNV risk scores were combined with PGSs and environmental factors. Conclusions and Relevance: In this study, elevated CNV risk scores were associated with lower cognitive ability, higher psychopathology including psychosis-spectrum symptoms, and greater deviations from normative magnetic resonance imaging models of brain development. Together, these results represent a step toward synthesizing rare genetic, common genetic, and environmental factors to understand clinically relevant outcomes in youth.

Engineering a mobile platform to promote sleep in the pediatric primary care setting.

STUDY OBJECTIVES: Pediatricians lack tools to support families at home for the promotion of childhood sleep. We are using the Multiphase Optimization Strategy (MOST) framework to guide the development of a mobile health platform for childhood sleep promotion. The objective of this study is to demonstrate feasibility of a mobile health platform towards treating children with insufficient sleep. METHODS: Children aged 10-12 years were enrolled (Study #1: N = 30; Study #2: N = 43). Participants wore a sleep tracker to measure sleep duration. Data were retrieved by a mobile health platform, programmed to send introductory messages during run-in (2 weeks) and goal achievement messages during intervention (7 weeks) periods. In study #1, participants were randomized to control, gain-framed incentive or loss-framed incentive arms. In study #2, participants were randomized to control, loss-framed incentive, normative feedback or loss-framed incentive plus normative feedback arms. RESULTS: In study #1, 1514 nights of data were captured (69%) and sleep duration during the intervention was higher by an average of 21 (95% CI: -8, 51) and 34 (95% CI: 7, 61) minutes per night for the gain-framed and loss-framed arms, respectively, compared to controls. In study #2, 2,689 nights of data were captured (81%), with no major differences in average sleep duration between the control and the loss-framed or normative feedback arms. CONCLUSIONS: We have developed and deployed a mobile health platform that can capture sleep data and remotely communicate with families. Promising candidate intervention components will be further investigated under the optimization phase of the MOST framework. CLINICAL TRIALS: Both studies included in this manuscript were registered at clinicaltrials.gov:-Study #1: NCT03263338-Study #2: NCT03426644.

Evaluation of Attention-Deficit/Hyperactivity Disorder Medications, Externalizing Symptoms, and Suicidality in Children.

Importance: Childhood suicidality (ie, suicidal ideation or attempts) rates are increasing, and attention-deficit/hyperactivity disorder (ADHD) and externalizing symptoms are common risk factors associated with suicidality. More data are needed to describe associations of ADHD pharmacotherapy with childhood suicidality. Objective: To investigate the associations of ADHD pharmacotherapy with externalizing symptoms and childhood suicidality. Design, Setting, and Participants: In this cohort study, cross-sectional and 1-year-longitudinal associations were examined using data (collected during 2016-2019) from the Adolescent Brain Cognitive Development (ABCD) Study, a large, diverse US sample of children aged 9 to 11 years. Data analysis was performed from November to December 2020. Exposures: Main and interaction associations of externalizing symptoms (hyperactivity ADHD symptoms, oppositional defiant, and conduct disorder symptoms) and ADHD medication treatment (methylphenidate and amphetamine derivatives, α-2-agonists, and atomoxetine) at baseline assessment. Main Outcomes and Measures: Child-reported suicidality (past and present at baseline; current at longitudinal assessment). Covariates were age, sex, race/ethnicity, parents' education, marital status, and concomitant child psychiatric pharmacotherapy (antidepressants and antipsychotics). Results: Among 11 878 children at baseline assessment (mean [SD] age, 9.9 [0.6] years; 6196 boys [52.2%]; 8805 White [74.1%]), 1006 (8.5%) were treated with ADHD medication and 1040 (8.8%) reported past or current suicidality. Externalizing symptoms (median [range], 1 [0-29] symptom count) were associated with suicidality (for a change of 1 SD in symptoms, odds ratio [OR], 1.34; 95% CI, 1.26-1.42; P < .001), as was ADHD medication treatment (OR, 1.32; 95% CI, 1.06-1.64; P = .01). ADHD medication use was associated with less suicidality in children with more externalizing symptoms (significant symptom-by-medication interaction, B = -0.250; SE = 0.086; P = .004), such that for children who were not receiving ADHD medications, there was an association between more externalizing symptoms and suicidality (for a change of 1 SD in symptoms, OR, 1.42; 95% CI, 1.33-1.52; P < .001); however, for children who were receiving ADHD medication, there was no such association (OR, 1.15; 95% CI, 0.97-1.35; P = .10). The association with medication remained even when covarying for multiple confounders, including risk and protective factors for suicidality in ABCD, and was replicated in 1-year longitudinal follow-up. Sensitivity analyses matching participants with high numbers of externalizing symptoms taking and not taking ADHD medication treatment confirmed its association with less suicidality. Conclusions and Relevance: These findings suggest that ADHD medication treatment is associated with less suicidality in children with substantial externalizing symptoms and may be used to inform childhood suicide prevention strategies.

Changes in Sleep Duration and Timing During the Middle-to-High School Transition.

PURPOSE: The purpose of the study was to quantify changes in sleep during the middle-to-high school transition and determine if changes in sleep differ by sociodemographic characteristics. METHODS: Adolescents were enrolled in eighth grade and followed into ninth grade (N = 110; 2,470 nights observed). The outcomes were actigraphy-estimated sleep duration, sleep onset, sleep offset, and sleep sufficiency (≥8 hours of sleep). The exposures were school grade (eighth or ninth), school night status (school or nonschool), sex (female or male), and race (white, black, or other). RESULTS: On school nights, sleep duration declined by 25.8 minutes per night (p < .001) from eighth to ninth grade. There was no change in sleep duration on nonschool nights. Timing of sleep onset was 22.2 minutes later on school nights (p < .001) and 17.4 minutes later on nonschool nights (p < .001) in ninth grade. Timing of sleep offset did not change on school mornings but was 22.2 minutes later on nonschool mornings (p < .001) in ninth grade. The proportion of school nights (and nonschool nights) with sleep duration ≥8 hours was 9.4% (38.3%) in eighth grade and 5.7% (35.9%) in ninth grade. The odds of sleeping ≥8 hours per night was 42% lower in ninth grade, compared toeighth grade (odds ratio = .58; 95% confidence interval: .37, .91). Males were 59% less likely to sleep ≥8 hours per night. Black adolescents were 51% less likely to sleep ≥8 hours per night. CONCLUSIONS: Insufficient sleep is highly prevalent, especially on school nights and among male and black adolescents, and this problem worsens with the transition to high school.

Engineering a Mobile Platform to Promote Sleep in the Pediatric Primary Care Setting.

Background: Pediatricians lack tools to support families at home for the promotion of childhood sleep. We are using the Multiphase Optimization Strategy (MOST) framework to guide the development of a mobile health platform for childhood sleep promotion. Purpose: Under the preparation phase of the MOST framework, to demonstrate feasibility of a mobile health platform towards treating children with insufficient sleep. Methods: Children aged 10-12y were enrolled (Study #1: N=30; Study #2: N=43). Participants wore a sleep tracker to measure sleep duration. Data were retrieved by a mobile health platform, programmed to send introductory messages during run-in (2 weeks) and goal achievement messages during intervention (7 weeks) periods. In study #1, participants were randomized to control, gain-framed incentive or loss-framed incentive arms. In study #2, participants were randomized to control, loss-framed incentive, normative feedback or loss-framed incentive plus normative feedback arms. Results: In study #1, 1,514 nights of data were captured (69%) and sleep duration during the intervention was higher by an average of 21 (95% CI: -8, 51) and 34 (95% CI: 7, 61) minutes per night for the gain-framed and loss-framed arms, respectively, compared to controls. In study #2, 2,689 nights of data were captured (81%), with no major differences in average sleep duration between the control and the loss-framed or normative feedback arms. Conclusion: We have developed and deployed a mobile health platform that can capture sleep data and remotely communicate with families. Promising candidate intervention components will be further investigated under the optimization phase of the MOST framework.