Faculty Bibliography

Sleep disturbances are prominent across neurodevelopmental disorders (NDDs) and may reflect specific abnormalities in brain development and function. Overnight polysomnography (PSG) allows for detailed investigation of sleep architecture, offering a unique window into neurocircuit function. Analysis of existing pediatric PSGs from clinical studies could enhance the availability of sleep studies in pediatric patients with NDDs towards a better understanding of mechanisms underlying abnormal development in NDDs. Here, we introduce and characterize a retrospective collection of 1527 clinical pediatric overnight PSGs across five different sites. We first developed an automated stager trained on independent pediatric sleep data, which yielded better performance compared to a generic stager trained primarily on adults. Using consistent staging across cohorts, we derived a panel of EEG micro-architectural features. This unbiased approach replicated broad trajectories previously described in typically developing sleep architecture. Further, we found sleep architecture disruptions in children with Down's Syndrome (DS) that were consistent across independent cohorts. Finally, we built and evaluated a model to predict age from sleep EEG metrics, which recapitulated our previous findings of younger predicted brain age in children with DS. Altogether, by creating a resource pooled from existing clinical data we expanded the available datasets and computational resources to study sleep in pediatric populations, specifically towards a better understanding of sleep in NDDs. This Retrospective Analysis of Sleep in Pediatric (RASP) cohorts dataset, including staging annotation derived from our automated stager, is deposited at https://sleepdata.org/datasets/rasp.

PURPOSE/OBJECTIVE:Our goals were to: 1) examine the occurrence of behavioral and emotional symptoms in children on the autism spectrum in a large national sample, stratifying by sex, and 2) evaluate whether children with increased autism-related social communication deficits also experience more behavioral and emotional problems. METHODS: Participants (n = 7,998) were from 37 cohorts from the Environmental influences on Child Health Outcomes (ECHO) Program. Cross-sectional information on demographic factors, parent-report of an ASD diagnosis by clinician, Social Responsiveness Scale (SRS) scores, and Child Behavior Checklist (CBCL) scores were obtained for children aged 2.5-18 years by surveys. We examined mean differences in CBCL Total Problems and DSM-oriented subscale scores by autism diagnosis and by child sex. Analyses using logistic regression were conducted to examine whether autism was associated with higher CBCL scores. We further examined if these relationships differed by child age category (< 6 years, 6-11 years, 12 + years). The relationships between SRS score and CBCL total and subscale scores were examined using quantile regression models, with analyses adjusted for child sex and age. RESULTS: In ECHO, 553 youth were reported by a parent to have a clinician diagnosis of autism spectrum disorder (ASD) (432 [78%] boys and 121 [22%] girls). Youth on the spectrum had higher mean CBCL raw scores on Total Problems and all DSM-oriented subscales compared to those not on the spectrum (all p < 0.0001). Analyses adjusted for sex and stratified by age group indicated that higher odds of autism diagnosis were associated with total, depression, anxiety, and attention-deficit/hyperactivity disorder (ADHD) scales in the top 30% of the CBCL score distribution. Autistic girls were more likely to have parent-reported depression and anxiety compared to autistic boys. In quantile regression analyses, we observed evidence of stronger associations between SRS and CBCL for those in higher quantiles of CBCL total problems scale score (beta representing 1-unit change in SRS associated with 1-unit increase in CBCL total problems scale score), among children in the 70-90th percentile (β = 1.60, p < 0.01), or top 10th percentile (β = 2.43, p < 0.01) of the CBCL total problems scale score distribution. Similar findings were seen for the DSM-oriented depression, anxiety, and ADHD subscales. CONCLUSION/CONCLUSIONS: Results from this large national sample suggest increased behavioral and emotional problems among autistic children compared to non-autistic children throughout early life. Among children on the spectrum this may warrant increased monitoring for co-occurring behavioral and emotional problems.

Adolescents living with HIV (ALHIV) have low adherence to antiretroviral therapy (ART). Poverty and mental health challenges remain major drivers of this poor ART adherence. We explored the mediators of the impact of an economic empowerment intervention on ART adherence among ALHIV and assessed the moderating effects of depression. We randomized 39 clinics (702 participants) into the control or intervention groups. Participants were aged 10-16, living with HIV and taking ART. The intervention comprising matched savings account, financial literacy training, and microenterprise workshops. We fitted a sequential structural equation model to examine how the three mediators-HIV stigma, barriers to medical care, and healthcare transition readiness-influenced ART adherence at year seven. Depression was included as a moderator. At baseline, the mean age was 12 years, and only 73.0% achieved good adherence (≥ 90%). The intervention directly improved ART adherence, β = 0.060 (95% CI: 0.038, 0.081), p < 0.001. Also, there was a significant indirect effect of the intervention on ART adherence, mediated through barriers to medical care, β =  - 0.036 (95% CI: - 0.041, - 0.032), p < 0.001, and HIV stigma, β =  - 0.011 (- 0.016, - 0.007), p < 0.001. Depression reduced the effect of the intervention on ART adherence β =  - 0.114 (- 0.123, - 0.104), p < 0.001. Our results showed that providing ALHIV with financial resources improved their ART adherence; however, this was affected by depression. Therefore, programs aimed at improving outcomes in ALHIV should consider incorporating interventions that address mental health challenges in addition to poverty.

One in six people are aged 10-19 years. Adolescence is a unique and formative time. Physical, emotional, and social changes, including exposure to poverty, abuse, or violence, can make adolescents vulnerable to mental health problems. Protecting adolescents from adversity, promoting socio-emotional learning and psychological well-being, and ensuring access to mental healthcare are critical for their health and well-being during adolescence and adulthood. Globally, it is estimated that 1 in 7 (14%) 10-19 year-olds experience mental health conditions (1), yet these remain largely unrecognized and untreated. Adolescents with mental health conditions are particularly vulnerable to social exclusion, discrimination, stigma (affecting readiness to seek help), educational difficulties, risk-taking behaviors, physical ill-health, and human rights violations.

OBJECTIVES/OBJECTIVE:Adolescents living with HIV (ALHIV) have low viral suppression levels, with 1 in 3 ALHIV experiencing virologic failure, calling for more efforts to reverse these trends. We developed and validated a model that predicts the risk of virologic failure (VF) among ALHIV. STUDY DESIGN/METHODS:Cross-sectional study. METHODS:We used baseline data from 702 ALHIV enrolled in the Suubi + Adherence cluster-randomized clinical trial. Participants were aged 10-16 years, living with HIV and aware of their HIV status, and are living with a family. We developed a risk-prediction model for VF (viral load of ≥200 copies/mL) using sociodemographic, behavioral, psychological, economic, and treatment-related factors. LASSO logistic regression using 10-fold cross-validation with bootstrapping was used to select the predictors for the final model. Model performance was assessed by determining the discrimination using the area under the curve and calibration by drawing a calibration plot. RESULTS:Using a lambda value of 0.007, the final model had 24 predictors (and interaction terms). The predictors included the participants' age, sex, work status, stigma, depressive symptoms, adherence self-efficacy, HIV knowledge, duration with HIV, time spent on ART, communication with the caregiver, family cohesion, social support, orphanhood status, number of people in the household, HIV disclosure, years spent at the current residence, and household asset ownership. The model predicted VF with AUC of 73.8 (95 % CI: 68.3-78.0) and calibration slope of 0.985. CONCLUSIONS:We developed and validated a model to predict the risk of virologic failure among ALHIV in Uganda, demonstrating its potential utility in identifying individuals at elevated risk for VF. Future models could be refined by incorporating clinical characteristics such as CD4 count to further improve predictive accuracy.

While studies have documented neural correlates of language delay in toddlers with developmental conditions, those at genetic risk for language delay, and those born premature, no studies have examined neural correlates in toddlers exhibiting early language delay without known etiology. This study examines brain morphometry in toddlers with and without early language delay. To do so, we collected magnetic resonance imaging on toddlers with language delay (LD; n=7, M_age=19.67 months, 3 female, 2 Hispanic, 4 non-caucasian) and a typically developing (TD; n=17, M_age=22.73 months, 8 female, 2 Hispanic, 3 non-caucasian) comparison group. Exploratory analyses examined group differences in total brain volume, cortical thickness, and cortical surface area using both a whole-brain and region of interest (Broca's and Wernicke's areas) approach. Results showed no gross brain anatomical differences between groups. However, there were group differences in cortical surface area in the temporal cortex (including Wernicke's area and left middle temporal gyrus, hedges' g= -.35) and Broca's area thickness. Results are reported using multiple analytic methods, age matching, and exclusion of children later diagnosed with autism. While this exploratory study has a limited sample size, it provides novel findings that can be utilized to guide hypothesis-driven imaging studies on toddler language delay.

OBJECTIVE/UNASSIGNED:We used resting-state functional magnetic resonance imaging to identify changes in brain functional connectivity (FC) associated with Organizational Skills Training (OST). METHOD/UNASSIGNED:In an open, waitlist-controlled, randomized clinical trial (NCT04108273), 51 children aged 8-12 years with deficient organizational skills were assigned to immediate tele-health OST treatment (twice weekly, 10 weeks) or waitlist. We obtained Children's Organizational Skills Scale-Parent version (COSS-P) scores and examined FC changes between dorsal anterior cingulate cortex (dACC) and preregistered subcortical anterior ventral striatum (aVS) regions-of-interest. RESULTS/UNASSIGNED: < 0.05). Analyses were then performed with two additional analytic pipelines, neither of which detected any significant effects. CONCLUSION/UNASSIGNED:Although improvements in organizational deficits were associated with increased FC within a circuit linking dACC and the default mode network region of the aVS in one analysis, the direction was the opposite of predicted and results did not replicate. Thus, we highlight the tentativeness of our findings; we have de-identified all the data and made it available for investigators to examine and to combine with other datasets in mega- and meta-analyses. Future studies should also include alternative control conditions and larger samples. CLINICAL TRIAL REGISTRATION/UNASSIGNED:https://clinicaltrials.gov/study/NCT04108273?cond=NCT04108273&rank=1.