Cortisol response marks biological sensitivity to kindergartners' social hierarchies for emerging school engagement.

This longitudinal study investigated how kindergartners' position in the classroom social hierarchy and cortisol response relate to their change in school engagement across the first year of kindergarten (N = 332, M = 5.3 years, 51% boys, 41% White, 18% Black). We used naturalistic classroom observations of social hierarchy positions, laboratory-based challenges to elicit salivary cortisol response, and teacher, parent, and child reports of emotional engagement with school. Robust, clustered regression models revealed that in the fall, lower cortisol response (but not social hierarchy position) was associated with greater school engagement. However, by spring, significant interactions emerged. Highly reactive, subordinate children showed increases in school engagement from fall to spring of the kindergarten year, whereas highly reactive, dominant children showed decreases in school engagement. This is some of the first evidence that higher cortisol response marks biological sensitivity to early peer-based social contexts.

Translating the Biology of Adversity and Resilience Into New Measures for Pediatric Practice.

As the science of adversity and resilience advances, and public awareness of the health consequences of stress grows, primary care providers are being increasingly asked to address the effects of adverse experiences on child wellbeing. Given limited tools for assessing these effects early in life, the authors explore how enhanced capacity to measure stress activation directly in young children could transform the role and scope of pediatric practice. When employed within a trusted relationship between caregivers and clinicians, selective use of biological measures of stress responses would help address the documented limitations of rating scales of adverse childhood experiences as a primary indicator of individual risk and strengthen the ability to focus on variation in intervention needs, assess their effectiveness, and guide ongoing management. The authors provide an overview of the potential benefits and risks of such expanded measurement capacity, as well as an introduction to candidate indicators that might be employed in an office setting. The ultimate value of such measures for both pediatricians and parents will require vigilant attention to the ethical responsibilities of assuring their correct interpretation and minimizing the harm of inappropriate labeling, especially for children and families experiencing the hardships and threats of racism, poverty, and other structural inequities. Whereas much work remains to be done to advance measurement development and ensure its equitable use, the potential of validated markers of stress activation and resilience to strengthen the impact of primary health care on the lives of young children facing significant adversity demands increased attention.

Change of pace: How developmental tempo varies to accommodate failed provision of early needs.

The interplay of genes and environments (GxE) is a fundamental source of variation in behavioral and developmental outcomes. Although the role of developmental time (T) in the unfolding of such interactions has yet to be fully considered, GxE operates within a temporal frame of reference across multiple timescales and degrees of biological complexity. Here, we consider GxExT interactions to understand adversity-induced developmental acceleration or deceleration whereby environmental conditions hasten or hinder children's development. To date, developmental pace changes have been largely explained through a focus on the individual: for example, how adversity "wears down" aging biological systems or how adversity accelerates or decelerates maturation to optimize reproductive fitness. We broaden such theories by positing shifts in developmental pace in response to the parent-child dyad's capacity or incapacity for meeting children's early, physiological and safety needs. We describe empirical evidence and potential neurobiological mechanisms supporting this new conceptualization of developmental acceleration and deceleration. We conclude with suggestions for future research on the developmental consequences of early adverse exposures.

Travels with Curly: A personal, collegial tribute to Professor Marla Sokolowski.

Marla Sokolowski's work and humanity has influenced the careers of hundreds, perhaps thousands, of younger scientists. Her fundamental research on the neurogenetic underpinnings of behavior in Drosophila melanogaster is remarkable not only for its scientific brilliance, but for the humility, care, and humor with which it was conducted.

Leveraging the Biology of Adversity and Resilience to Transform Pediatric Practice.

Advances in science are fundamentally changing the way we understand how inextricable interactions among genetic predispositions, physical and social environments, and developmental timing influence early childhood development and the foundations of health and how significant early adversity can lead to a lifetime of chronic health impairments. This article and companion article illustrate the extent to which differential outcomes are shaped by ongoing interactive adaptations to context that begin at or even before conception and continue throughout life, with increasing evidence pointing to the importance of the prenatal period and early infancy for the developing brain, the immune system, and metabolic regulation. Although new discoveries in the basic sciences are transforming tertiary medical care and producing breakthrough outcomes in treating disease, this knowledge is not being leveraged effectively to inform new approaches to promoting whole-child development and preventing illness. The opportunity for pediatrics to serve as the leading edge of science-based innovation across the early childhood ecosystem has never been more compelling. In this article, we present a framework for leveraging the frontiers of scientific discovery to inform new strategies in pediatric practice and advocacy to protect all developing biological systems from the disruptive effects of excessive early adversity beyond providing information on child development for parents and enriched learning experiences for young children.

Genes, Environments, and Time: The Biology of Adversity and Resilience.

Exposures to adverse environments, both psychosocial and physicochemical, are prevalent and consequential across a broad range of childhood populations. Such adversity, especially early in life, conveys measurable risk to learning and behavior and to the foundations of both mental and physical health. Using an interactive gene-environment-time (GET) framework, we survey the independent and interactive roles of genetic variation, environmental context, and developmental timing in light of advances in the biology of adversity and resilience, as well as new discoveries in biomedical research. Drawing on this rich evidence base, we identify 4 core concepts that provide a powerful catalyst for fresh thinking about primary health care for young children: (1) all biological systems are inextricably integrated, continuously "reading" and adapting to the environment and "talking back" to the brain and each other through highly regulated channels of cross-system communication; (2) adverse environmental exposures induce alterations in developmental trajectories that can lead to persistent disruptions of organ function and structure; (3) children vary in their sensitivity to context, and this variation is influenced by interactions among genetic factors, family and community environments, and developmental timing; and (4) critical or sensitive periods provide unmatched windows of opportunity for both positive and negative influences on multiple biological systems. These rapidly moving frontiers of investigation provide a powerful framework for new, science-informed thinking about health promotion and disease prevention in the early childhood period.

Externalizing and Internalizing Problems: Associations with Family Adversity and Young Children's Adrenocortical and Autonomic Functioning.

The development of child mental health problems has been associated with experiences of adversity and dysregulation of stress response systems; however, past research has largely focused on externalizing or internalizing problems (rather than their co-occurrence) and single physiological systems in high-risk adolescent samples. The present study examined whether cumulative family adversity, functioning in the hypothalamic-pituitary-adrenal axis (i.e., cortisol) and the parasympathetic nervous system (i.e., respiratory sinus arrhythmia [RSA]), and their interactions, predicted trajectories of co-occurring externalizing and internalizing problems among young children. Participants included 338 socioeconomically and racially diverse children (M age = 5.32 years, SD = .32; male = 51.8%) from a community sample. Family adversity (assessed with six measures) and child daily cortisol output and resting RSA were assessed in kindergarten. Parents, teachers, and children reported on children's externalizing and internalizing psychopathology up to three times from kindergarten to grade 1. Latent class growth analyses identified stable trajectories of externalizing and internalizing psychopathology. Trajectories were combined to create groups: co-occurring externalizing and internalizing (13.1%), externalizing-only (14.0%), internalizing-only (11.3%), and low problems (61.3%). Family adversity and resting RSA significantly positively predicted co-occurring group membership. Tests for interactions showed adversity did not significantly interact with physiological indicators to predict group membership. However, the two physiological systems interacted, such that higher and lower daily cortisol predicted internalizing group membership for children with lower and higher resting RSA, respectively. Findings support the importance of considering family context and multiple physiological systems to inform understanding of the development of mental health problems, and their co-occurrence, in early childhood.

Maternal Stress During Pregnancy Predicts Infant Infectious and Noninfectious Illness.

OBJECTIVES: To examine the association between prenatal stress and infant physical health in the first year of life within an understudied, racially and ethnically diverse, highly stressed community sample. We expected that greater stress exposure would predict higher rates of infant illness. STUDY DESIGN: Low-income, racially/ethnically diverse, overweight women with low medical risk pregnancies were recruited (2011-2014) during pregnancy. Pregnancy Stressful Life Events were assessed retrospectively (mean, 11.88 months postpartum). Perceived stress was assessed twice during pregnancy (at a mean of 17.4 weeks and again at a mean of 25.6 weeks) and at 6 months postpartum. Women with live births (n = 202) were invited; 162 consented to the offspring study. Medical records from pediatric clinics and emergency departments for 148 infants were abstracted for counts of total infectious illnesses, total noninfectious illness, and diversity of illnesses over the first year of life. RESULTS: The final analytic sample included 109 women (mean age, 28.08 years) and their infants. In covariate-adjusted negative binomial models, maternal perceptions of stress across pregnancy were positively associated with infant illness. Each 1-point increase in average stress was associated with a 38% increase in incidence of infant infections (Incidence rate ratio, 1.38; 95% CI, 1.01-1.88; P < .05), a 73% increase in noninfectious illness (IRR, 1.73; 95% CI, 1.34-2.23; P < .05), and a 53% increase in illness diversity (IRR, 1.53; 95% CI, 1.25, 1.88; P < .01); effect sizes were larger for perceived stress later in pregnancy. Stressful life events count and postnatal stress were not uniquely associated with illness. CONCLUSIONS: In line with recommendations from the American Academy of Pediatrics to screen for maternal perinatal depression, screening and support for stress reduction during pregnancy may benefit both maternal and child health.

Genes and environments, development and time.

A now substantial body of science implicates a dynamic interplay between genetic and environmental variation in the development of individual differences in behavior and health. Such outcomes are affected by molecular, often epigenetic, processes involving gene-environment (G-E) interplay that can influence gene expression. Early environments with exposures to poverty, chronic adversities, and acutely stressful events have been linked to maladaptive development and compromised health and behavior. Genetic differences can impart either enhanced or blunted susceptibility to the effects of such pathogenic environments. However, largely missing from present discourse regarding G-E interplay is the role of time, a "third factor" guiding the emergence of complex developmental endpoints across different scales of time. Trajectories of development increasingly appear best accounted for by a complex, dynamic interchange among the highly linked elements of genes, contexts, and time at multiple scales, including neurobiological (minutes to milliseconds), genomic (hours to minutes), developmental (years and months), and evolutionary (centuries and millennia) time. This special issue of PNAS thus explores time and timing among G-E transactions: The importance of timing and timescales in plasticity and critical periods of brain development; epigenetics and the molecular underpinnings of biologically embedded experience; the encoding of experience across time and biological levels of organization; and gene-regulatory networks in behavior and development and their linkages to neuronal networks. Taken together, the collection of papers offers perspectives on how G-E interplay operates contingently within and against a backdrop of time and timescales.

Associations between multisystem stress reactivity and peer nominated aggression in early childhood vary by sex.

There is emerging evidence that the development of problematic aggression in childhood may be associated with specific physiological stress response patterns, with both biological overactivation and underactivation implicated. This study tested associations between sex-specific patterns of stress responses across the sympathetic nervous system (SNS) and hypothalamic-pituitary-adrenal (HPA) axis and peer nominations of aggression among 271 kindergarten children (Mean age = 5.32 years; 52% Female; 44% White). Upon entry to kindergarten, children participated in a multidomain standardized stress paradigm. Changes in pre-ejection period (PEP) and salivary cortisol were assessed. On a separate day, children provided peer ratings of physical and relational aggression in a standardized interview. As expected, there was a significant three-way interaction between PEP, cortisol reactivity, and sex, but only for physical aggression. Among boys, cortisol reactivity was positively associated with physical aggression only for those with higher SNS reactivity. Findings suggest that for boys, asymmetrical and symmetrical HPA/SNS reactivity may be associated with lower and higher risk for peer-directed physical aggression, respectively. Understanding the complex associations between multisystem physiology, child sex and peer-directed aggression in early childhood may offer insight into individual differences underlying the emergence of behavioral dysregulation in early peer contexts.

Biological sensitivity to context: A test of the hypothesized U-shaped relation between early adversity and stress responsivity.

We conducted signal detection analyses to test for curvilinear, U-shaped relations between early experiences of adversity and heightened physiological responses to challenge, as proposed by biological sensitivity to context theory. Based on analysis of an ethnically diverse sample of 338 kindergarten children (4-6 years old) and their families, we identified levels and types of adversity that, singly and interactively, predicted high (top 25%) and low (bottom 25%) rates of stress reactivity. The results offered support for the hypothesized U-shaped curve and conceptually replicated and extended the work of Ellis, Essex, and Boyce (2005). Across both sympathetic and adrenocortical systems, a disproportionate number of children growing up under conditions characterized by either low or high adversity (as indexed by restrictive parenting, family stress, and family economic condition) displayed heightened stress reactivity, compared with peers growing up under conditions of moderate adversity. Finally, as hypothesized by the adaptive calibration model, a disproportionate number of children who experienced exceptionally stressful family conditions displayed blunted cortisol reactivity to stress.

Associations between classroom climate and children's externalizing symptoms: The moderating effect of kindergarten children's parasympathetic reactivity.

Classrooms are key social settings that impact children's mental health, though individual differences in physiological reactivity may render children more or less susceptible to classroom environments. In a diverse sample of children from 19 kindergarten classrooms (N = 338, 48% female, M age = 5.32 years), we examined whether children's parasympathetic reactivity moderated the association between classroom climate and externalizing symptoms. Independent observers coded teachers' use of child-centered and teacher-directed instructional practices across classroom social and management domains. Children's respiratory sinus arrhythmia reactivity to challenge tasks was assessed in fall and a multi-informant measure of externalizing was collected in fall and spring. Both the social and the management domains of classroom climate significantly interacted with children's respiratory sinus arrhythmia reactivity to predict spring externalizing symptoms, controlling for fall symptoms. For more reactive children, as classrooms shifted toward greater proportional use of child-centered methods, externalizing symptoms declined, whereas greater use of teacher-dominated practices was associated with increased symptoms. Conversely, among less reactive children, exposure to more teacher-dominated classroom management practices was associated with lower externalizing. Consistent with the theory of biological sensitivity to context, considering variability in children's physiological reactivity aids understanding of the salience of the classroom environment for children's mental health.

Informant-specific reports of peer and teacher relationships buffer the effects of harsh parenting on children's oppositional defiant disorder during kindergarten.

Harsh and restrictive parenting are well-established contributors to the development of oppositional defiant disorder (ODD) among children. However, few studies have explored whether interpersonal relationships that develop outside the family environment attenuate the risk for ODD that is associated with harsh parenting. The current study tested multireporter measures of teacher-child closeness and peer acceptance as moderators of the association between harsh parenting and children's ODD as children's social worlds widen during the kindergarten year (N = 338 children, 48% girls, M age = 5.32 years). Harsh parenting interacted with peer nominations of peer acceptance and children's report of teacher-child closeness to predict children's ODD symptoms in the spring, adjusting for fall symptoms. Children exposed to harsh parenting exhibited greater symptom increases when they were less liked/accepted playmates and in the context of lower teacher-child closeness. However, harsh parenting was not associated with symptom change among children with higher levels of peer-nominated acceptance and those who reported closer relationships with teachers. There were no significant interactions using teacher's report of peer acceptance or teacher's report of teacher-child closeness. Findings highlight positive peer and teacher relationships as promising targets of intervention among children exposed to harsh parenting and support the importance of assessing multiple perspectives of children's social functioning.

The PedBE clock accurately estimates DNA methylation age in pediatric buccal cells.

The development of biological markers of aging has primarily focused on adult samples. Epigenetic clocks are a promising tool for measuring biological age that show impressive accuracy across most tissues and age ranges. In adults, deviations from the DNA methylation (DNAm) age prediction are correlated with several age-related phenotypes, such as mortality and frailty. In children, however, fewer such associations have been made, possibly because DNAm changes are more dynamic in pediatric populations as compared to adults. To address this gap, we aimed to develop a highly accurate, noninvasive, biological measure of age specific to pediatric samples using buccal epithelial cell DNAm. We gathered 1,721 genome-wide DNAm profiles from 11 different cohorts of typically developing individuals aged 0 to 20 y old. Elastic net penalized regression was used to select 94 CpG sites from a training dataset (n = 1,032), with performance assessed in a separate test dataset (n = 689). DNAm at these 94 CpG sites was highly predictive of age in the test cohort (median absolute error = 0.35 y). The Pediatric-Buccal-Epigenetic (PedBE) clock was characterized in additional cohorts, showcasing the accuracy in longitudinal data, the performance in nonbuccal tissues and adult age ranges, and the association with obstetric outcomes. The PedBE tool for measuring biological age in children might help in understanding the environmental and contextual factors that shape the DNA methylome during child development, and how it, in turn, might relate to child health and disease.

Integration of DNA methylation patterns and genetic variation in human pediatric tissues help inform EWAS design and interpretation.

BACKGROUND: The widespread use of accessible peripheral tissues for epigenetic analyses has prompted increasing interest in the study of tissue-specific DNA methylation (DNAm) variation in human populations. To date, characterizations of inter-individual DNAm variability and DNAm concordance across tissues have been largely performed in adult tissues and therefore are limited in their relevance to DNAm profiles from pediatric samples. Given that DNAm patterns in early life undergo rapid changes and have been linked to a wide range of health outcomes and environmental exposures, direct investigations of tissue-specific DNAm variation in pediatric samples may help inform the design and interpretation of DNAm analyses from early life cohorts. In this study, we present a systematic comparison of genome-wide DNAm patterns between matched pediatric buccal epithelial cells (BECs) and peripheral blood mononuclear cells (PBMCs), two of the most widely used peripheral tissues in human epigenetic studies. Specifically, we assessed DNAm variability, cross-tissue DNAm concordance and genetic determinants of DNAm across two independent early life cohorts encompassing different ages. RESULTS: BECs had greater inter-individual DNAm variability compared to PBMCs and highly the variable CpGs are more likely to be positively correlated between the matched tissues compared to less variable CpGs. These sites were enriched for CpGs under genetic influence, suggesting that a substantial proportion of DNAm covariation between tissues can be attributed to genetic variation. Finally, we demonstrated the relevance of our findings to human epigenetic studies by categorizing CpGs from published DNAm association studies of pediatric BECs and peripheral blood. CONCLUSIONS: Taken together, our results highlight a number of important considerations and practical implications in the design and interpretation of EWAS analyses performed in pediatric peripheral tissues.

Differences in Febrile and Respiratory Illnesses in Minority Children: The Sociodemographic Context of Restrictive Parenting.

OBJECTIVE: To examine the moderating role of restrictive parenting on the relation of socioeconomic status (SES) to febrile illnesses (FIs) and upper respiratory illnesses (URIs) among ethnic minority and non-minority children. METHODS: Children from diverse ethnic backgrounds (Caucasian, African American, Asian, Latino, other, or multiethnic) were followed across the course of the kindergarten year. Parents reported on SES and parenting. A nurse completed 13 physical exams per child over the year to assess FIs and URIs. RESULTS: During the school year, 28% of children (n = 199, 56% ethnic minority) exhibited one or more FIs (range, 0-6) and 90% exhibited one or more URIs (range, 0-10). No main or moderating effects of SES or restrictive parenting on FIs or URIs were found among Caucasian children; however, among ethnic minority children, the relation of SES to FIs was conditional upon restrictive parenting (ß = .66; P = .02), as the fewest FIs were found for lower SES minority children whose parents reported more restrictive practices. Additionally, among minority children, more restrictive parenting was marginally associated with fewer URIs (ß = -.21; P = .05). CONCLUSIONS: Unexpectedly, among minority children the fewest illnesses occurred among lower SES children whose parents endorsed more restrictive parenting. This may be due to unique appraisals of this rearing style among minority children in lower SES environments and its potential to influence immune functioning. Results suggest variability in the effects of parenting on offspring health and support context-specific evaluations of parenting in efforts to ameliorate early health disparities.

Children's biobehavioral reactivity to challenge predicts DNA methylation in adolescence and emerging adulthood.

A growing body of research has documented associations between adverse childhood environments and DNA methylation, highlighting epigenetic processes as potential mechanisms through which early external contexts influence health across the life course. The present study tested a complementary hypothesis: indicators of children's early internal, biological, and behavioral responses to stressful challenges may also be linked to stable patterns of DNA methylation later in life. Children's autonomic nervous system reactivity, temperament, and mental health symptoms were prospectively assessed from infancy through early childhood, and principal components analysis (PCA) was applied to derive composites of biological and behavioral reactivity. Buccal epithelial cells were collected from participants at 15 and 18 years of age. Findings revealed an association between early life biobehavioral inhibition/disinhibition and DNA methylation across many genes. Notably, reactive, inhibited children were found to have decreased DNA methylation of the DLX5 and IGF2 genes at both time points, as compared to non-reactive, disinhibited children. Results of the present study are provisional but suggest that the gene's profile of DNA methylation may constitute a biomarker of normative or potentially pathological differences in reactivity. Overall, findings provide a foundation for future research to explore relations among epigenetic processes and differences in both individual-level biobehavioral risk and qualities of the early, external childhood environment.

An exploratory qualitative study of life trajectories from preschool-age to young adulthood: Identifying early biologic sensitivity, facing challenges and moving forward.

BACKGROUND: This exploratory qualitative study explored the life experiences of young adults who participated in a cohort study in their child care center 26 years ago.The purpose of the study was to: (1) Describe the life trajectories of study participants who exhibited the extremes of high or low cardiovascular reactivity during their preschool ages. (2) Identify the life courses, processes, or outcomes for these young adults. (3) Describe exemplar cases of children with high and low reactivity who illustrated patterns of resilience or vulnerability. METHODS: Eight out of the 137 children who had combinations of extreme high or low reactivity and environmental adversity were identified and interviewed by a blinded researcher. Data were analyzed through iterative coding, development of major categories, matrix analysis and thematic analysis. RESULTS: The overall theme for all of the participants was facing challenges, and moving forward. The major categories which showed some variation between those with high and low reactivity were developing sources of support, overcoming adversity, and finding satisfaction/ dissatisfaction with life. CONCLUSION: These life histories provide a further understanding of how biologic sensitivity to challenges identified early in life may have impacted participants' trajectories from preschool to young adulthood, and indicate that further study would be warranted across the life course.

The biological embedding of early-life socioeconomic status and family adversity in children's genome-wide DNA methylation.

AIM: To examine variation in child DNA methylation to assess its potential as a pathway for effects of childhood social adversity on health across the life course. MATERIALS & METHODS: In a diverse, prospective community sample of 178 kindergarten children, associations between three types of social experience and DNA methylation within buccal epithelial cells later in childhood were examined. RESULTS: Family income, parental education and family psychosocial adversity each associated with increased or decreased DNA methylation (488, 354 and 102 sites, respectively) within a unique set of genomic CpG sites. Gene ontology analyses pointed to genes serving immune and developmental regulation functions. CONCLUSION: Findings provided support for DNA methylation as a biomarker linking early-life social experiences with later life health in humans.