Identifying SARS-CoV-2 regional introductions and transmission clusters in real time

The unprecedented SARS-CoV-2 global sequencing effort has suffered from an analytical bottleneck. Many existing methods for phylogenetic analysis are designed for sparse, static datasets and are too computationally expensive to apply to densely sampled, rapidly expanding datasets when results are needed immediately to inform public health action. For example, public health is often concerned with identifying clusters of closely related samples, but the sheer scale of the data prevents manual inspection and the current computational models are often too expensive in time and resources. Even when results are available, intuitive data exploration tools are of critical importance to effective public health interpretation and action. To help address this need, we present a phylogenetic summary statistic which quickly and efficiently identifies newly introduced strains in a region, resulting clusters of infected individuals, and their putative geographic origins. We show that this approach performs well on simulated data and is congruent with a more sophisticated analysis performed during the pandemic. We also introduce Cluster Tracker (https://clustertracker.gi.ucsc.edu/), a novel interactive web-based tool to facilitate effective and intuitive SARS-CoV-2 geographic data exploration and visualization. Cluster-Tracker is updated daily and automatically identifies and highlights groups of closely related SARS-CoV-2 infections resulting from inter-regional transmission across the United States, streamlining public health tracking of local viral diversity and emerging infection clusters. The combination of these open-source tools will empower detailed investigations of the geographic origins and spread of SARS-CoV-2 and other densely-sampled pathogens.

Numbers of close contacts of individuals infected with SARS-CoV-2 and their association with government intervention strategies.

BackgroundContact tracing is conducted with the primary purpose of interrupting transmission from individuals who are likely to be infectious to others. Secondary analyses of data on the numbers of close contacts of confirmed cases could also: provide an early signal of increases in contact patterns that might precede larger than expected case numbers; evaluate the impact of government interventions on the number of contacts of confirmed cases; or provide data information on contact rates between age cohorts for the purpose of epidemiological modelling. MethodsWe analysed data from 140,204 contacts of 39861 cases in Ireland from 1st May to 1st December 2020. Only close contacts were included in the analysis. A close contact was defined as any individual who had had > 15 minutes face-to-face (<2 m) contact with a case; any household contact; or any individual sharing a closed space for longer than 2 hours, in any setting. ResultsThe number of contacts per case was overdispersed, the mean varied considerably over time, and was temporally associated with government interventions. Negative binomial regression models highlighted greater numbers of contacts within specific population demographics, after correcting for temporal associations. Separate segmented regression models of the number of cases over time and the average number of contacts per case indicated that a breakpoint indicating a rapid decrease in the number of contacts per case in October 2020 preceded a breakpoint indicating a reduction in the number of cases by 11 days. DiscussionThese data were collected for a specific purpose and therefore any inferences must be made with caution. The data are representative of contact rates of cases, and not of the overall population. However, the data may be a more accurate indicator of the likely degree of onward transmission than might be the case if a random sample of the population were taken. Furthermore, since we analysed only the number of close contacts, the total number of contacts per case would have been higher. Nevertheless, this analysis provides useful information for monitoring the impact of government interventions on the number of contacts; for helping pre-empt increases or decreases in case numbers, and for triangulating assumptions regarding the contact mixing rates between different age cohorts for epidemiological modelling.

Effects of a school readiness intervention on electrophysiological indices of external response monitoring in children in foster care.

This study examined the impact of a school readiness intervention on external response monitoring in children in foster care. Behavioral and event-related potential (ERP) data were collected during a flanker task from children who received the Kids In Transition to School (KITS) Program (n = 26) and children who received services as usual (n = 19) before and after the intervention. While there were no significant group differences on the behavioral data, the ERP data for the two groups of children significantly differed. Specifically, in contrast to the children who received services as usual, the children who received the KITS Program displayed greater amplitude differences between positive and negative performance feedback over time for the N1, which reflects early attention processes, and feedback-related negativity, which reflects evaluation processes. In addition, although the two groups did not differ on amplitude differences between positive and negative performance feedback for these ERP components before the intervention, the children who received the KITS Program displayed greater amplitude differences than the children who received services as usual after the intervention. These results suggest that the KITS Program had an effect on responsivity to external performance feedback, which may be beneficial during the transition into kindergarten.

Improving kindergarten readiness in children with developmental disabilities: Changes in neural correlates of response monitoring.

Among children diagnosed with developmental delays, difficulties in self-regulation are prominent and have been linked to school readiness problems. The current study sought to examine the impact of the Kids in Transition to School (KITS) school readiness intervention program on self-regulation, with a specific focus on response monitoring skills, among children with developmental delays. Children (n = 20 in the KITS group and n = 21 in a services as usual group) were administered a flanker task during which event-related potential data were collected to examine group differences in response monitoring. Findings indicated that children in the KITS group showed significant enhancement of a neural index of response monitoring post-intervention. Specifically, the KITS group showed a significant change in the magnitude of their feedback-related negativity in response to negative performance feedback from baseline to post-intervention, whereas children in the services as usual group did not. There were no significant differences between the groups for the error-related negativity or the error-related positivity on incorrect trials nor were there group differences in behavioral performance on the task at the post-intervention assessment. Overall, these findings provide support for the plasticity of response monitoring skills in young children and support the growing literature demonstrating improved self-regulation outcomes via intervention that enhances children's response monitoring.

The effects of early foster care intervention on attention biases in previously institutionalized children in Romania.

Children raised in institutions experience psychosocial deprivation that can negatively impact attention skills and emotion regulation, which subsequently may influence behavioral regulation and social relationships. The current study examined visual attention biases in 8-year-old children who were part of the Bucharest Early Intervention Project (BEIP). Relations among attention biases and concurrent social outcomes were also investigated. In early childhood, 136 children abandoned at birth or shortly thereafter into institutional care were randomized to receive a high-quality foster care intervention or care-as-usual within the context of the Bucharest Early Intervention Project (BEIP). At 8 years of age, 50 care-as-usual, 55 foster care, and 52 community controls performed a behavioral dot-probe task, and indices of attention biases to threat and positive stimuli were calculated. Concurrent data on social behavior were collected. Children placed into the foster care intervention had a significant attention bias toward positive stimuli, while children who received care-as-usual had a significant bias toward threat. Children in the foster care intervention had a significantly larger positive bias when compared to the care-as-usual group. A positive bias was related to more social engagement, more prosocial behavior, less externalizing disorders, and less emotionally withdrawn behavior. The magnitude of positive bias was predicted by age of placement into foster care among children with a history of institutionalization. An attention bias towards positive stimuli was associated with reduced risk for behavioral problems amongst children who experienced early psychosocial deprivation. Research assessing attention biases in children experiencing early environmental stress may refine our understanding of the mechanisms underlying risk for later psychiatric and social disorders and inform prevention efforts.

Cognitive control moderates early childhood temperament in predicting social behavior in 7-year-old children: an ERP study.

Behavioral inhibition (BI) is a temperament associated with heightened vigilance and fear of novelty in early childhood, and social reticence and increased risk for anxiety problems later in development. However, not all behaviorally inhibited children develop signs of anxiety. One mechanism that might contribute to the variability in developmental trajectories is the recruitment of cognitive-control resources. The current study measured N2 activation, an ERP (event-related potential) associated with cognitive control, and modeled source-space activation (LORETA; Low Resolution Brain Electromagnetic Tomography) at 7 years of age while children performed a go/no-go task. Activation was estimated for the entire cortex and then exported for four regions of interest: ventromedial prefrontal cortex (VMPFC), ventrolateral prefrontal cortex (VLPFC), dorsal anterior cingulate cortex (dorsal ACC), and dorsal lateral prefrontal cortex (DLPFC). BI was measured in early childhood (ages 2 and 3 years). Anxiety problems and social reticence were measured at 7 years of age to ascertain stability of temperamental style. Results revealed that BI was associated with increased performance accuracy, longer reaction times, greater (more negative) N2 activation, and higher estimated dorsal ACC and DLPFC activation. Furthermore, early BI was only associated with social reticence at age 7 at higher (more negative) levels of N2 activation or higher estimated dorsal ACC or DLPFC activation. Results are discussed in the context of overcontrolled behavior contributing to social reticence and signs of anxiety in middle childhood.

Psychosocial deprivation, executive functions, and the emergence of socio-emotional behavior problems.

Early psychosocial deprivation can negatively impact the development of executive functions (EFs). Here we explore the impact of early psychosocial deprivation on behavioral and physiological measures (i.e., event-related potentials; ERPs) of two facets of EF, inhibitory control and response monitoring, and their associations with internalizing and externalizing outcomes in the Bucharest Early Intervention Project (BEIP; Zeanah et al., 2003). This project focuses on two groups of children placed in institutions shortly after birth and then randomly assigned in infancy to either a foster care intervention or to remain in their current institutional setting. A group of community controls was recruited for comparison. The current study assesses these children at 8-years of age examining the effects of early adversity, the potential effects of the intervention on EF and the role of EF skills in socio-emotional outcomes. Results reveal exposure to early psychosocial deprivation was associated with impaired inhibitory control on a flanker task. Children in the foster care intervention exhibited better response monitoring compared to children who remained in the institution on the error-related positivity (Pe). Moreover, among children in the foster care intervention those who exhibited larger error-related negativity (ERN) responses had lower levels of socio-emotional behavior problems. Overall, these data identify specific aspects of EF that contribute to adaptive and maladaptive socio-emotional outcomes among children experiencing early psychosocial deprivation.

Emotion recognition following early psychosocial deprivation.

An important function of the brain is to scan incoming sensory information for the presence of relevant signals and act on this information. For humans, the most salient signals are often social in nature, such as the identity and the emotional expression of the faces we encounter in our everyday lives. It can be argued that our survival as a species depends in large measure on these skills.

Temperamental exuberance and executive function predict propensity for risk taking in childhood.

The present study utilized a multilevel approach to examine developmental trajectories in risk-taking propensity. We examined the moderating role of specific executive function components, attention shifting and inhibitory control, on the link between exuberant temperament in infancy and propensity for risk taking in childhood. Risk taking was assessed using a task previously associated with sensation seeking and antisocial behaviors. Two hundred ninety-one infants were brought into the lab and behaviors reflecting exuberance were observed at 4, 9, 24, and 36 months of age. Executive function was assessed at 48 months of age. Risk-taking propensity was measured when children were 60 months of age. The results indicated that exuberance and attention shifting, but not inhibitory control, significantly interacted to predict propensity for risk taking. Exuberance was positively associated with risk-taking propensity among children who were relatively low in attention shifting but unrelated for children high in attention shifting. These findings illustrated the multifinality of developmental outcomes for temperamentally exuberant young children and pointed to the distinct regulatory influences of different executive functions for children of differing temperaments. Attention shifting likely affords a child the ability to consider both positive and negative consequences and moderates the relation between early exuberance and risk-taking propensity.

Neural activation underlying cognitive control in the context of neutral and affectively charged pictures in children.

The neural correlates of cognitive control for typically developing 9-year-old children were examined using dense-array ERPs and estimates of cortical activation (LORETA) during a go/no-go task with two conditions: a neutral picture condition and an affectively charged picture condition. Activation was estimated for the entire cortex after which data were exported for four regions of interests (ROIs): ventrolateral prefrontal cortex (VLPFC), dorsal anterior cingulate cortex (dACC), dorsolateral prefrontal cortex (DLPFC), and orbitofrontal/ventromedial prefrontal cortex (OFC/VMPFC). Results revealed faster reaction times, greater N2 activation, and greater prefrontal activation for the affectively charged picture condition than the neutral picture condition. The findings are discussed in reference to the impact of affective stimuli on recruitment of specific brain regions involved in cognitive control.

Behavioral inhibition and anxiety: the moderating roles of inhibitory control and attention shifting.

Behavioral inhibition (BI), a temperament identified in early childhood, is associated with social reticence in childhood and an increased risk for anxiety problems in adolescence and adulthood. However, not all behaviorally inhibited children remain reticent or develop an anxiety disorder. One possible mechanism accounting for the variability in the developmental trajectories of BI is a child's ability to successfully recruit cognitive processes involved in the regulation of negative reactivity. However, separate cognitive processes may differentially moderate the association between BI and later anxiety problems. The goal of the current study was to examine how two cognitive processes-attention shifting and inhibitory control-laboratory assessed at 48 months of age moderated the association between 24-month BI and anxiety symptoms in the preschool years. Results revealed that high levels of attention shifting decreased the risk for anxiety problems in children with high levels of BI, whereas high levels of inhibitory control increased this risk for anxiety symptoms. These findings suggest that different cognitive processes may influence relative levels of risk or adaptation depending upon a child's temperamental reactivity.

Attention biases to threat link behavioral inhibition to social withdrawal over time in very young children.

Behaviorally inhibited children display a temperamental profile characterized by social withdrawal and anxious behaviors. Previous research, focused largely on adolescents, suggests that attention biases to threat may sustain high levels of behavioral inhibition (BI) over time, helping link early temperament to social outcomes. However, no prior studies examine the association between attention bias and BI before adolescence. The current study examined the interrelations among BI, attention biases to threat, and social withdrawal already manifest in early childhood. Children (N=187, 83 Male, M (age)=61.96 months) were characterized for BI in toddlerhood (24 & 36 months). At 5 years, they completed an attention bias task and concurrent social withdrawal was measured. As expected, BI in toddlerhood predicted high levels of social withdrawal in early childhood. However, this relation was moderated by attention bias. The BI-withdrawal association was only evident for children who displayed an attention bias toward threat. The data provide further support for models associating attention with socioemotional development and the later emergence of clinical anxiety.

Attention biases to threat and behavioral inhibition in early childhood shape adolescent social withdrawal.

Behavioral inhibition (BI) is a temperament characterized in young children by a heightened sensitivity to novelty, social withdrawal, and anxious behaviors. For many children, these social difficulties dissipate over time. For others, patterns of social withdrawal continue into adolescence. Over time, attention biases to threat may influence the stability of BI and its association with social withdrawal, ultimately modulating the risk for anxiety disorders in BI children. However, we know relatively little about the cognitive processes that accompany BI and shape later socio-emotional functioning. We examined the relations among BI in childhood, attention biases to threat in adolescence, and adolescent social withdrawal in a longitudinal study (N = 126, Mean age = 15 years). As has been reported in anxious adults, adolescents who were behaviorally inhibited as toddlers and young children showed heightened attention bias to threat. In addition, attention bias to threat moderated the relation between childhood BI and adolescent social withdrawal.

Variations in the serotonin-transporter gene are associated with attention bias patterns to positive and negative emotion faces.

Both attention biases to threat and a serotonin-transporter gene polymorphism (5-HTTLPR) have been linked to heightened neural activation to threat and the emergence of anxiety. The short allele of 5-HTTLPR may act via its effect on neurotransmitter availability, while attention biases shape broad patterns of cognitive processing. We examined individual differences in attention bias to emotion faces as a function of 5-HTTLPR genotype. Adolescents (N=117) were classified for presumed SLC6A4 expression based on 5-HTTLPR-low (SS, SL(G), or L(G)L(G)), intermediate (SL(A) or L(A)L(G)), or high (L(A)L(A)). Participants completed the dot-probe task, measuring attention biases toward or away from angry and happy faces. Biases for angry faces increased with the genotype-predicted neurotransmission levels (low>intermediate>high). The reverse pattern was evident for happy faces. The data indicate a linear relation between 5-HTTLPR allelic status and attention biases to emotion, demonstrating a genetic mechanism for biased attention using ecologically valid stimuli that target socioemotional adaptation.

Anger and Approach Motivation in Infancy: Relations to Early Childhood Inhibitory Control and Behavior Problems.

The relations among infant anger reactivity, approach behavior, and frontal EEG asymmetry, and their relations to inhibitory control and behavior problems in early childhood were examined within the context of a longitudinal study of temperament. Two hundred and nine infants' anger expressions to arm restraint were observed at 4 months of age. Infants' approach behaviors during play with an unpredictable toy and baseline frontal electroencephalogram (EEG) asymmetry were assessed at 9 months of age. Inhibitory control during a Go/No-Go task and parent-report of behavior problems were evaluated at 4 years of age. High anger-prone infants with left, but not right, frontal EEG asymmetry showed significantly more approach behaviors and less inhibitory control relative to less anger-prone infants. Although a link between anger proneness in infancy and behavior problems in early childhood was not found, a combination of low approach behaviors and poor inhibitory control was predictive of internalizing behaviors.

Using behavioral and electrophysiological measures to assess the effects of a preventive intervention: a preliminary study with preschool-aged foster children.

The current study was designed to explore the use of behavioral (i.e., accuracy and reaction times) and electrophysiological measures (i.e., event-related potentials) to assess the impact of a family-based preventive intervention for preschool-aged, maltreated children in foster care. These measures were recorded during a computerized flanker task designed to assess cognitive control and response monitoring. The sample was recruited from a larger randomized efficacy trial of Multidimensional Treatment Foster Care for Preschoolers (MTFC-P) and included foster children assigned to the intervention condition (n = 10), foster children assigned to a services-as-usual comparison condition (n = 13), and low-income, nonmaltreated community children (n = 11). The children's behavioral and electrophysiological performance on the task was generally consistent with previous research with adults and older children. There were no group differences on the behavioral measures of cognitive control or response monitoring. Notably, however, group differences were observed on the electrophysiological measures of response monitoring. Specifically, the foster children who received services as usual were significantly less responsive to performance feedback about errors than the foster children who received the intervention and the nonmaltreated children. Applications of this methodology and implications of the results for future prevention research are discussed.

Variations of the flanker paradigm: assessing selective attention in young children.

The development of selective attention and associated self-regulatory processes was assessed in young children, ages 4, 5, and 6, through the use of three alternative versions of the flanker paradigm utilizing colors, shapes, and fish. These variations were used to examine the influence of task differences on children's performance. The presence of cognitive self-regulatory strategies in young children was also assessed. Significant flanker interference effects, marked by significant task-linked response time differences, were found across all three versions of the paradigm. Although a significant portion of children demonstrated self-regulatory abilities, not every participant demonstrated the specific strategies of self-monitoring and response control. Furthermore, these differences were evident across all age groups. The implications of these results are discussed within the theoretical context of task development, taking into consideration the need to modify computerized attention paradigms for use with young children in order to reliably measure cognitive constructs across children and adults.