Faculty Bibliography

BACKGROUND/UNASSIGNED:Autism spectrum disorder (ASD) shows significant clinical variability, likely due to a combination of genetic and environmental factors. Preterm birth is a known risk factor for ASD, occurring in approximately 13% of diagnosed individuals. While genetic factors contribute to preterm birth in the general population, the relationship between genetic variation, preterm birth, and ASD heterogeneity remains unclear. METHODS/UNASSIGNED:We investigated the genetic factors associated with preterm birth in 31,947 autistic individuals using data from the SPARK (Simons Foundation Powering Autism Research for Knowledge) sample. We conducted 3 ancestry-specific genome-wide association studies for African/African American, admixed American, and non-Finnish European ancestries, followed by a meta-analysis of 3308 preterm cases and 28,639 controls using METAL. Functional mapping and gene-based analyses were performed using FUMA, and genetic correlations were estimated using LDSC and Popcorn. Polygenic risk scores (PRSs) were computed with BridgePRS, using PRS of preterm birth in the general population. RESULTS/UNASSIGNED:Our study identified ancestry-specific genetic loci associated with preterm birth in ASD cases. Although the meta-analysis results were not statistically significant, the estimated single nucleotide polymorphism heritability was 14%, indicating a meaningful contribution of common genetic variants. Across ancestry groups, preterm birth status was not significantly associated with PRSs for any psychiatric or medical conditions analyzed. However, polygenic liability to preterm birth in the general population was linked to several congenital anomalies after multiple testing adjustments. CONCLUSIONS/UNASSIGNED:These findings highlight the importance of diverse ancestries and early-life exposures in understanding ASD heterogeneity. Future research should replicate these findings in larger samples and explore rare variants associated with preterm birth to better understand the relationship between gestational duration and clinical and genetic differences in ASD.

Clinical, neuroimaging and genomics evidence have increasingly underscored a degree of overlap between autism and attention-deficit/hyperactivity disorder (ADHD). This study explores the specific contribution of their core symptoms to shared biology in N = 166 verbal children (6-12 years) with rigorously-established primary diagnoses of either autism or ADHD (without autism). We investigated the associations between inter-individual differences in low motion whole-brain intrinsic functional connectivity (iFC) and dimensional measures of autism and ADHD symptoms indexed by clinician-based observation and parent interview, respectively. Additionally, we explored their linked gene expression patterns in silico. Whole-brain multivariate distance matrix regression revealed a transdiagnostic association between autism severity and iFC of two nodes primarily on the left hemisphere: the middle frontal gyrus of the frontoparietal network and the posterior cingulate cortex of the default mode network. Across children, the greater the iFC between these nodes, the more severe the autism symptoms, even after controlling for ADHD ratings. Results from secondary segregation analyses were consistent with primary findings, underscoring the significance of internetwork iFC for autism symptom severity across diagnoses. No statistically significant brain-behavior relationships were observed for ADHD symptoms. Genetic enrichment analyses of the iFC maps associated with autism symptoms implicated genes known to: (i) have greater rate of variance in autism and ADHD, and (ii) be involved in neuron projections, suggesting shared genetic mechanisms for this specific brain-clinical phenotype. These findings underscore the relevance of transdiagnostic dimensional approaches in linking clinically-defined and observation-based phenomena to shared presentations at the macroscale circuit- and genomic-levels across diagnoses.

This review showcases the ways that studying the neural basis of Behavioral Inhibition (BI) and maternal anxiety in infancy has advanced our understanding of the developmental pathophysiology of anxiety. We demonstrate that infants with BI and those who have been exposed to maternal anxiety/stress exhibit differences in neural processes associated with bottom-up attention and top-down control, both when we measure the brain at rest and when we measure the brain during stimulus processing. Differences in infant stimulus processing are particularly robust-not only do they emerge in at-risk infants, but they also shape risk trajectories from infancy through adolescence. Throughout this review, we underscore the value in a focus on infancy and early childhood. We also point to several key future directions for this work, including prioritizing a longitudinal, multi-modal approach for studying neurobehavioral profiles of early-life risk. Together, this work demonstrates that neural processes involved in attention and control are central to BI and early-life risk for anxiety across the lifespan.

BACKGROUND:The obesity epidemic in the United States affects not only adults, but children and adolescents. SOURCES OF MATERIAL/UNASSIGNED:An extensive review of the literature including 85 articles has been completed with the aim of providing the most current definitions and recommendations for this chronic condition. ABSTACT OF FINDINGS/UNASSIGNED:This article reviews the definition of pediatric obesity, the increasing prevalence of obesity in children and adolescents, genetic and environmental risk factors, as well as the unique aspects and implications of this condition and its associated comorbidities for this population in comparison to adults. Current management recommendations are also discussed which include Intensive Health Behavioral and Lifestyle Treatment (IHBLT), metabolic surgery, and pharmacologic therapy including glucago-like peptide-1 receptor agonists (GLP-1RAs). CONCLUSION/CONCLUSIONS:Childhood obesity is a unique condition in its progression and management requirements, and should be approached with a focus on prevention as well as on the high-risk individual.

INTRODUCTION/UNASSIGNED:This article features the application of Causal Data Science (CDS) methods to determine the mechanism for Posttraumatic Stress (PTS) in young, maltreated children, in order to advance knowledge for prevention. Advances in prevention require research that identifies causal factors, but the scientific literature that would inform the identification of causes are almost exclusively based on the application of correlational methods to observational data. Causal inferences from such research will frequently be in error. We conducted the present study to explore the application of CDS methods as an alternative-or a supplement-to experimental methods, which can rarely be applied in human research on causal factors for PTS. METHODS/UNASSIGNED:A data processing pipeline that integrates state-of-the-art CDS algorithms was applied to an existing observational, longitudinal data set collected by the Consortium for Longitudinal Studies in Child Abuse and Neglect (LONGSCAN). This data set contains a sample of 1,354 children who were identified in infancy to early childhood as being maltreated or at risk. RESULTS/UNASSIGNED:A causal network model of 251 variables (nodes) and 818 bivariate relations (edges) was discovered, revealing four direct causes (Emotional Maltreatment at age 0-4, Physical Assault at age 8, Feeling of Safety at age 8, and Witnessing Violence at age 8) and two direct effects (Negative Self-Image and Severe Assault from a Non-Caregiver at age 8) of PTS at age 8, within a network containing a broad diversity of causal pathways. DISCUSSION/UNASSIGNED:These results indicate that CDS methods show promise for research on the complex etiology of PTS in young, maltreated children.

INTRODUCTION/UNASSIGNED:Autism spectrum disorder (ASD) is characterized in part by differences in pragmatic (i.e., social) language use. However, few studies on pragmatic language have included a meaningful number of autistic females, and even fewer have evaluated pragmatic language profiles for sex-specific differences. The existing literature on pragmatic language in autistic individuals without intellectual disability suggests that females may have stronger social communication skills compared to males, but findings are mixed, and there is not a clear profile of specific pragmatic skills that are liable to sex differences. It is also important to develop novel methodologies, such as computational methods, to characterize pragmatic language in ways less labor-intensive than gold-standard hand-coding methods, which are extremely time consuming and typically not feasible in clinical settings. METHODS/UNASSIGNED:The present study examined hand coding of pragmatic language data samples alongside multiple computational linguistic methodological approaches to characterize sex differences in pragmatic language in autistic males and females across narrative and semi-structured conversational tasks that might reveal context-specific patterns across sex and diagnostic groups. RESULTS/UNASSIGNED:Results indicated that most pragmatic domains differed between autistic and non-autistic groups, with autistic males showing the most obvious pragmatic differences, and that differences between diagnostic groups were more pronounced in the semi-structured conversational context. The alignment between computational and hand-coded findings was strongest in domains with clear theoretical overlap (e.g., frequency of emotional words) but was less consistent in areas that were less theoretically aligned (e.g., conversational dynamics and single word function). DISCUSSION/UNASSIGNED:These findings support the promise of computational methods for characterizing narrative abilities, though further study including validation against hand-coded approaches is warranted.

BACKGROUND/UNASSIGNED:Pregnancy requires finely tuned immune changes that support implantation, placental development, maternal-fetal tolerance, and preparation for labor, yet the normative trajectories of circulating inflammatory proteins across gestation remain poorly defined. This cross-sectional study investigates how circulating inflammatory proteins vary with gestational age in pregnancy and examines the impacts of fundamental biological characteristics, such as gravidity and fetal sex. METHODS/UNASSIGNED:Data were drawn from 1154 pregnant individuals from six study sites of the National Institutes of Health Environmental influences on Child Health Outcomes (ECHO) Cohort. We used Olink high-throughput proteomic profiling to map cross-sectional associations between protein expression levels and gestational age at blood draw using linear, spline-based, and generalized additive modeling approaches. RESULTS/UNASSIGNED:Generalized additive models provided the best fit, revealing that immune changes across pregnancy were predominantly nonlinear. Sixty-one proteins showed significant associations with gestational age, with many exhibiting shared inflection points that aligned with major physiological transitions. A small subset of proteins also showed evidence of modification by fetal and maternal characteristics. CD244 displayed different gestational patterns by fetal sex, while CST5 and SIRT2 showed varied gestational associations by maternal gravidity. CONCLUSION/UNASSIGNED:The findings highlight pregnancy as a sequence of coordinated immune transitions rather than a simple linear shift and provide one of the most detailed characterizations to date of circulating inflammatory protein dynamics across human gestation. Establishing these normative trajectories offers a crucial reference for detecting early deviations that may signal risk for pregnancy complications and for identifying biomarkers in maternal and fetal health research.

Autistic youth visit the emergency department (ED) for psychiatric concerns, including suicidal ideation and behavior, at elevated rates. However, clinicians often report low levels of training and confidence in addressing suicide risk in autistic youth. In this pilot study, clinicians in a pediatric psychiatric emergency service were trained on community- and evidence-informed recommendations to improve suicide-related care for autistic youth and provided with resources to use with autistic youth for a 3-month period. Ratings on attitudes and confidence were obtained from ten providers before and after the training/implementation period and compared. Ratings of feasibility and utility of strategies and resources were obtained from 15 providers after training/implementation and analyzed. While no changes were found across attitudes items, confidence scores were significantly higher after the training/implementation period than before, particularly in the area of suicide risk assessment. Feasibility and utility ratings were generally high, with endorsement patterns aligning with common organizational and systems-level barriers. This pilot study demonstrated that targeted training and evidence-informed recommendations to improve suicide-related care for autistic youth were associated with increased clinician confidence. As research continues in the development of adapted suicide risk assessment tools and management strategies for autistic youth, it is important that both clinical guidance on best practices is provided and that systems-level barriers are addressed.

BACKGROUND:The COVID-19 pandemic exacerbated challenges faced by pregnant women, introducing new risks and intensifying existing disparities, particularly among those routinely experiencing race- and ethnicity-based discrimination. It remains unclear how the pandemic affected perceptions of perinatal quality of care (QoC). OBJECTIVES/OBJECTIVE:To explore mothers' experiences of pregnancy, birth, and the early postpartum period during the early COVID-19 pandemic, attending to both health care encounters and to the broader structural and social forces shaping those experiences. DESIGN/METHODS:The COVID-19 Mother Baby Outcomes (COMBO) Initiative is a longitudinal, prospective cohort study investigating maternal-child outcomes among women from a predominantly low socioeconomic status, Latinx community in New York City who delivered during the pandemic. This qualitative substudy analyzed a subset of participants using modified grounded theory. METHODS:Semi-structured interviews explored perinatal and pandemic experiences, perceptions of inequitable or poor treatment, and protective factors among 64 participants purposively sampled from the parent cohort. Analysis focused on 48 transcripts highlighting discrimination-related themes, which were transcribed and systematically coded using both inductive and deductive approaches. RESULTS:phenomenon. CONCLUSION/CONCLUSIONS:Giving birth during the pandemic worsened perceptions of perinatal QoC, with discrimination compounding negative experiences. Findings underscore the link between care quality and trust in medical institutions, highlighting the need for evidence-based crisis protocols that both reduce unnecessary risk while preserving patient agency, particularly for marginalized populations. The pandemic exposed longstanding structural inequities, presenting an opportunity to address these patient-level manifestations and strengthen support for populations facing systemic barriers.

A large body of evidence supports the role of the prenatal environment in shaping childhood development. The relative contributions of prenatal alcohol use (PAE), maternal socioeconomic, and nutritional status on child development vary in high- versus low-income settings. We analyzed data from a prospective cohort study among mother-infant dyads from Cape Town (CT), South Africa and the Northern Plains (NP), USA. The Mullen Scales of Early Learning were administered by trained assessors to evaluate cognitive, motor, and language development of 1-year old children. We used multiple linear regression models to assess standardized mean differences in development scores by (1) maternal prenatal factors, (2) delivery factors and (3) child factors within each study site. 1,728 infants from CT and 1,140 infants from the NP were included in the analyses. In CT, infants with moderate-to-high PAE had 0.17 SD (95% CI -0.30, -0.04) lower cognitive and 0.15 SD (-0.29, -0.2) lower expressive language scores compared to infants without PAE. In the NP, maternal obesity (BMI > 30 kg/m2) was significantly associated with -0.21 SD (-0.36, -0.06), and -0.13 SD (-0.27, -0.02) reductions in cognitive, and expressive language scores, respectively. Household crowding, lower levels of maternal educational attainment, prenatal maternal depression, low birthweight, admission to neonatal intensive care unit, and male sex had significant negative associations with cognitive and language development in both sites with effects ranging from -0.32 to -0.11 SDs. These results highlight the importance of assessing risk factors by populations across diverse social and cultural environments and emphasize the imperative to formulate intervention packages tailored to the local context.