Specificity of Early Childhood Hyperphagia Profiles in Neurogenetic Conditions.

Hyperphagia is highly penetrant in Prader-Willi syndrome (PWS) and has increasingly been reported in other neurogenetic conditions (NGC). The Hyperphagia Questionnaire (HQ) was completed by caregivers of 4-8-year-olds with PWS (n = 17), Angelman syndrome (AS; n = 22), Williams syndrome (WS; n = 25), or low-risk controls (LRC; n = 35). All NGC groups were significantly elevated in HQ Total and Behavior scores compared to LRC. Only AS and WS were significantly elevated in the Drive domain, and only PWS in the Severity domain. After controlling for externalizing behavior, HQ Total scores were higher for PWS relative to other groups. Hyperphagic symptoms may not differentiate PWS from other NGCs in early childhood. However, hyperphagic phenotypes may be most severe in PWS. Further investigation of these profiles may inform etiology and syndrome-specific treatments.

Everyday language input and production in 1,001 children from six continents.

Language is a universal human ability, acquired readily by young children, who otherwise struggle with many basics of survival. And yet, language ability is variable across individuals. Naturalistic and experimental observations suggest that children's linguistic skills vary with factors like socioeconomic status and children's gender. But which factors really influence children's day-to-day language use? Here, we leverage speech technology in a big-data approach to report on a unique cross-cultural and diverse data set: >2,500 d-long, child-centered audio-recordings of 1,001 2- to 48-mo-olds from 12 countries spanning six continents across urban, farmer-forager, and subsistence-farming contexts. As expected, age and language-relevant clinical risks and diagnoses predicted how much speech (and speech-like vocalization) children produced. Critically, so too did adult talk in children's environments: Children who heard more talk from adults produced more speech. In contrast to previous conclusions based on more limited sampling methods and a different set of language proxies, socioeconomic status (operationalized as maternal education) was not significantly associated with children's productions over the first 4 y of life, and neither were gender or multilingualism. These findings from large-scale naturalistic data advance our understanding of which factors are robust predictors of variability in the speech behaviors of young learners in a wide range of everyday contexts.

Semi-Automatic Assessment of Vocalization Quality for Children With and Without Angelman Syndrome.

Automated methods for processing of daylong audio recordings are efficient and may be an effective way of assessing developmental stage for typically developing children; however, their utility for children with developmental disabilities may be limited by constraints of algorithms and the scope of variables produced. Here, we present a novel utterance-level processing (ULP) system that 1) extracts utterances from daylong recordings, 2) verifies automated speaker tags using human annotation, and 3) provides vocal maturity metrics unavailable through automated systems. Study 1 examines the reliability and validity of this system in low-risk controls (LRC); Study 2 extends the ULP to children with Angelman syndrome (AS). Results showed that ULP annotations demonstrated high coder agreement across groups. Further, ULP metrics aligned with language assessments for LRC but not AS, perhaps reflecting limitations of language assessments in AS. We argue that ULP increases accuracy, efficiency, and accessibility of detailed vocal analysis for syndromic populations.

Diagnostic Accuracy of Primary Care Clinicians Across a Statewide System of Autism Evaluation.

OBJECTIVES: To evaluate the diagnostic accuracy of the Early Autism Evaluation (EAE) Hub system, a statewide network that provides specialized training and collaborative support to community primary care providers in the diagnosis of young children at risk for autism spectrum disorder (ASD). METHODS: EAE Hub clinicians referred children, aged 14 to 48 months, to this prospective diagnostic study for blinded follow-up expert evaluation including assessment of developmental level, adaptive behavior, and ASD symptom severity. The primary outcome was agreement on categorical ASD diagnosis between EAE Hub clinician (index diagnosis) and ASD expert (reference standard). RESULTS: Among 126 children (mean age: 2.6 years; 77% male; 14% Latinx; 66% non-Latinx white), 82% (n = 103) had consistent ASD outcomes between the index and reference evaluation. Sensitivity was 81.5%, specificity was 82.4%, positive predictive value was 92.6%, and negative predictive value was 62.2%. There was no difference in accuracy by EAE Hub clinician or site. Across measures of development, there were significant differences between true positive and false negative (FN) cases (all Ps < .001; Cohen's d = 1.1-1.4), with true positive cases evidencing greater impairment. CONCLUSIONS: Community-based primary care clinicians who receive specialty training can make accurate ASD diagnoses in most cases. Diagnostic disagreements were predominately FN cases in which EAE Hub clinicians had difficulty differentiating ASD and global developmental delay. FN cases were associated with a differential diagnostic and phenotypic profile. This research has significant implications for the development of future population health solutions that address ASD diagnostic delays.

Early communication development in infants and toddlers with Fragile X syndrome.

Background and Aims: Individuals with fragile X syndrome (FXS) characteristically struggle with language and communication throughout the life course, but there is limited research on the development of communication before 24 months. The purpose of this study is to describe the early communication of infants and toddlers with FXS using the Communication and Symbolic Behavior Scales-Caregiver Questionnaire (CSBS-CQ), a standardized communication screening measure, as compared to the reported normative data of the CSBS-CQ and identify the percentage of infants and toddlers who scored within the range of concern. Documenting how children with FXS perform on screening measures can provide a quick snapshot of skills to help clinicians determine the need for services. Methods: Participants were 22 infants and toddlers with FXS between 6 and 29 months. Performance on the CSBS-CQ was compared to the measure's normative data. The CSBS-CQ was completed by mothers, and children were administered the Mullen Scales of Early Learning. Because co-occurring autism is common in FXS, the presence of autism was determined using a clinical best estimate procedure. Results: Overall and within the domains and subdomains of the CSBS-CQ, infants and toddlers with FXS had significantly lower scores than the normative data. Further, 68.2% of our sample was in the range of concern for their overall communication score. The presence of autism led to consistently lower scores, and more infants and toddlers with FXS + autism scored within the range of concern. Conclusions: Our findings suggest that delays in early communication are evident in comparison to typically developing norms before 24 months. These findings also emphasize that infants and toddlers with FXS would likely benefit from early language intervention given that 68.2% of our sample was in the range of concern for their overall communication score. Implications: Early identification and developmental monitoring of children with FXS will help to determine concerns in communication and other domains of development. While early communication broadly may not be an early indicator of autism in FXS, some specific skills, such as eye gaze, may serve as such an indicator. Screening measures, like the CSBS-CQ, may help monitor both early communication impairments and autism symptoms. Infants and toddlers with FXS, regardless of autism status, will benefit from early language interventions.

Mother-infant convergence of event-related potentials elicited by face and object processing.

Prior work has provided conceptual support for developmental changes in face and object processing, such that: face processing, as captured by the N290 event-related potential (ERP) component in infancy, may develop into the N170 in adulthood; and motivated attention, as captured by the negative central (Nc) in infancy, may develop into the late positive potential (LPP). The present study examined these neural correlates in 12-month-old infants and their mothers (N = 33 dyads). Dyads completed a viewing task consisting of familiar and novel face and toy stimuli while electroencephalography was recorded. Results suggest that for mothers, the N170 was larger for faces than toys, regardless of familiarity, and the LPP was largest for familiar faces. In infants, the N290 was somewhat larger for faces than toys (p < .10); the Nc did not vary by condition. Adult ERPs demonstrated fair to good reliability; reliability of infant ERPs was lower and was influenced by looking behaviors. Intergenerational associations were strongest between the LPP and Nc, particularly when electrode and time window were taken into account. Refinement of data handling and ERP scoring procedures for infant ERPs are crucial next steps for estimation of intergenerational associations and further examination of developmental changes in face and object processing.

Describing Vocalizations in Young Children: A Big Data Approach Through Citizen Science Annotation.

Purpose Recording young children's vocalizations through wearables is a promising method to assess language development. However, accurately and rapidly annotating these files remains challenging. Online crowdsourcing with the collaboration of citizen scientists could be a feasible solution. In this article, we assess the extent to which citizen scientists' annotations align with those gathered in the lab for recordings collected from young children. Method Segments identified by Language ENvironment Analysis as produced by the key child were extracted from one daylong recording for each of 20 participants: 10 low-risk control children and 10 children diagnosed with Angelman syndrome, a neurogenetic syndrome characterized by severe language impairments. Speech samples were annotated by trained annotators in the laboratory as well as by citizen scientists on Zooniverse. All annotators assigned one of five labels to each sample: Canonical, Noncanonical, Crying, Laughing, and Junk. This allowed the derivation of two child-level vocalization metrics: the Linguistic Proportion and the Canonical Proportion. Results At the segment level, Zooniverse classifications had moderate precision and recall. More importantly, the Linguistic Proportion and the Canonical Proportion derived from Zooniverse annotations were highly correlated with those derived from laboratory annotations. Conclusions Annotations obtained through a citizen science platform can help us overcome challenges posed by the process of annotating daylong speech recordings. Particularly when used in composites or derived metrics, such annotations can be used to investigate early markers of language delays.

Bringing the Laboratory Home: PANDABox Telehealth-Based Assessment of Neurodevelopmental Risk in Children.

BACKGROUND: Advances in clinical trials have revealed a pressing need for outcome measures appropriate for children with neurogenetic syndromes (NGS). However, the field lacks a standardized, flexible protocol for collecting laboratory-grade experimental data remotely. To address this challenge, we developed PANDABox (Parent-Administered Neurodevelopmental Assessment), a caregiver-facilitated, remotely administered assessment protocol for collecting integrated and high quality clinical, behavioral, and spectral data relevant to a wide array of research questions. Here, we describe PANDABox development and report preliminary data regarding: (1) logistics and cost, (2) caregiver fidelity and satisfaction, and (3) data quality. METHODS: We administered PANDABox to a cohort of 16 geographically diverse caregivers and their infants with Down syndrome. Tasks assessed attention, language, motor, and atypical behaviors. Behavioral and physiological data were synchronized and coded offline by trained research assistants. RESULTS: PANDABox required low resources to administer and was well received by families, with high caregiver fidelity (94%) and infant engagement (91%), as well as high caregiver-reported satisfaction (97% positive). Missing data rates were low for video frames (3%) and vocalization recordings (6%) but were higher for heart rate (25% fully missing and 13% partially missing) and discrete behavioral presses (8% technical issues and 19% not enough codable behavior), reflecting the increased technical demands for these activities. CONCLUSION: With further development, low-cost laboratory-grade research protocols may be remotely administered by caregivers in the family home, opening a new frontier for cost-efficient, scalable assessment studies for children with NGS other neurodevelopmental disorders.

Autism Spectrum Disorder-Associated Behaviour in Infants with Down Syndrome.

BACKGROUND: Individuals with Down syndrome (DS) are at high risk for autism spectrum disorder (ASD) with ~20% of individuals meeting diagnostic criteria for ASD. Despite the high risk, there is no research documenting early signs of ASD in infants with DS or potential prodromal ASD-associated behaviors. AIM: This preliminary case-control study described ASD-associated behaviors in infants with DS contrasted to typically developing (TD) infants. PATIENTS AND METHODS: The Autism Observation Scale for Infants (AOSI) was used to describe ASD-related behaviors in 18 infants with DS (7-18 months) and 18 TD infants (9-14 months). RESULTS: Thirty nine percent (7 out of 18) of infants with DS in our sample were designated "at risk" for ASD on the AOSI with 100% of infants with DS demonstrating at least one feature of ASD. In contrast, only 11% (2 out of 18) of TD infants were designated "at risk" for ASD on the AOSI. Social and communication impairments appear to represent early signs of elevated ASD-associated behavior in infants with DS. CONCLUSIONS: Early signs of ASD-associated behavior appear present and detectable in infants with DS. These early signs mirror findings of other populations at risk for ASD with social communication as the primary behavioral impairment to signal elevated risk for the emergence of ASD. This study contributes to the refinement of the DS behavioral phenotype and identifies important next steps to help improve the identification, diagnosis, and treatment of ASD in DS.

Using generalizability theory to evaluate the comparative reliability of developmental measures in neurogenetic syndrome and low-risk populations.

BACKGROUND: The lack of available measures that can reliably characterize early developmental skills in children with neurogenetic syndromes (NGS) poses a significant challenge for research on early development in these populations. Although syndrome-specific measures may sometimes be necessary, a more cost- and time-efficient solution would be to identify existing measures that are appropriate for use in special populations or optimize existing measures to be used in these groups. Reliability is an important metric of psychometric rigor to consider when auditing and optimizing assessment tools for NGS. In this study, we use Generalizability Theory, an extension of classical test theory, as a novel approach for more comprehensively characterizing the reliability of existing measures and making decisions about their use in the field of NGS research. METHODS: We conducted generalizability analyses on a popular early social communication screener, the Communication and Symbolic Behavior Scales-Infant-Toddler Checklist (CSBS-ITC), collected on 172 children (41 Angelman syndrome, 30 Prader-Willi syndrome, 42 Williams syndrome, 59 low-risk controls). RESULTS: Overall, the CSBS-ITC demonstrated at least adequate reliability in the NGS groups included in this study, particularly for the Prader-Willi and Williams syndrome groups. However, the sources of systematic error variance in the CSBS-ITC varied greatly between the low-risk control and NGS groups. Moreover, as unassessed in previous research, the CSBS-ITC demonstrated substantial differences in variance sources among the NGS groups. Reliability of CSBS-ITC scores was highest when averaging across all measurement points for a given child and was generally similar or better in the NGS groups compared to the low-risk control group. CONCLUSIONS: Our findings suggest that the CSBS-ITC communicates different information about the reliability of stability versus change, in low-risk control and NGS samples, respectively, and that psychometric approaches like Generalizability Theory can provide more complete information about the reliability of existing measures and inform decisions about how measures are used in research on early development in NGS.

Intergenerational Transmission of Frontal Alpha Asymmetry Among Mother-Infant Dyads.

BACKGROUND: Frontal alpha asymmetry (FAA) is a well-established neurobiological indicator of depression risk. Reduced FAA relates to current and remitted depression in adults and is seen in offspring of mothers with depression as young as 3 months of age, suggesting a potentially transmittable mechanism of depression risk. It is unclear, however, whether direct familial associations exist for FAA. To address this gap, we evaluated the intergenerational transmission of FAA in a nonclinical cohort of mother-infant dyads. METHODS: Mothers and their 12-month-old infants (n = 34 dyads) completed parallel resting-state tasks while electroencephalography was recorded. We measured FAA across a range of putative frequency bands and calculated its reliability in mothers and infants. Finally, we evaluated the heritability of FAA based on the parent-offspring correlation. RESULTS: Mother and infant FAA convergence was strongest in the high alpha range for mothers (11-13 Hz) and broad alpha range for infants (6-9 Hz). Mother high FAA exhibited excellent split-half reliability (rSB = .99) and internal consistency after 80 seconds (α = .90); infant FAA exhibited good split-half reliability (rSB = .81) and fair internal consistency after 70 seconds (α = .74). Mother-infant FAA were moderately correlated (r = .41), which indicates narrow-sense heritability of up to 82%. CONCLUSIONS: FAA can be assessed reliably and relatively quickly in both adults and infants. There is a robust association of FAA between mothers and their infants, supporting intergenerational transmission. This finding is consistent with the possibility that reduced FAA may directly confer depression risk at the individual-family level.

Acoustic properties of early vocalizations in infants with fragile X syndrome.

Fragile X syndrome (FXS) is a neurogenetic syndrome characterized by cognitive impairments and high rates of autism spectrum disorder (ASD). FXS is often highlighted as a model for exploring pathways of symptom expression in ASD due to the high prevalence of ASD symptoms in this population and the known single-gene cause of FXS. Early vocalization features-including volubility, complexity, duration, and pitch-have shown promise in detecting ASD in idiopathic ASD populations but have yet to be extensively studied in a population with a known genetic cause for ASD such as FXS. Investigating early trajectories of these features in FXS may inform our limited knowledge of potential mechanisms that predict later social communication outcomes. The present study addresses this need by presenting preliminary findings which (a) characterize early vocalization features in FXS relative to low-risk controls (LRC) and (b) test the specificity of associations between these features and language and ASD outcomes. We coded vocalization features during a standardized child-examiner interaction for 39 nine-month-olds (22 FXS, 17 LRC) whose clinical outcomes were assessed at 24 months. Our results provide preliminary evidence that within FXS, associations between vocalization features and 24-month language outcomes may diverge from those observed in LRC, and that vocalization features may be associated with later ASD symptoms. These findings provide a starting point for more research exploring these features as potential early markers of ASD in FXS, which in turn may lead to improved early identification methods, treatment approaches, and overall well-being of individuals with ASD. Autism Res2019. © 2019 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: Although vocal features of 9-month-olds with FXS did not differ from those of low-risk controls, several features were associated with later language and ASD outcomes at 24 months in FXS. These preliminary results suggest acoustic data may be related to clinical outcomes in FXS and potentially other high-risk populations. Further characterizing these associations may facilitate understanding of biological mechanisms and risk factors associated with social communication development and ASD.

Validating and Applying the CSBS-ITC in Neurogenetic Syndromes.

Although social communication skills are commonly delayed in children with neurogenetic syndromes (NGS), skill profiles in very young children are largely under characterized, in part due to the lack of validated assessment measures appropriate for these populations. We addressed this gap by validating and applying a popular early social communication screening measure, the Communication and Symbolic Behavior Scales Developmental Profile - Infant-Toddler Checklist (CSBS-ITC) in three previously understudied neurogenetic groups: Angelman, Prader-Willi, and Williams syndromes. Our results suggest that when used within the appropriate scope of screening and surveillance, the CSBS-ITC detects meaningful variability in skills across ages in young children with NGS and may provide useful information about both individual- and population-level social communication profiles in these populations.

Infant Temperament in the FMR1 Premutation and Fragile X Syndrome.

Although temperament has been studied for decades as a predictor of psychopathology in the general population, examining temperament in neurogenetic groups has unique potential to inform the genetic and biological factors that may confer risk for psychopathology in later development. The present study examined early temperament in two heritable neurogenetic conditions associated with atypical CGG repeat expansions on the FMR1 gene: the FMR1 premutation (FXpm; 55-200 repeats) and fragile X syndrome (FXS; > 200 repeats). We focus specifically on the FXpm, as the condition is highly prevalent (1:209-291 female individuals, 1:430-855 male individuals) and has been preliminarily associated with increased risk for pediatric psychopathology, including attention problems, autism, and anxiety. In contrast, FXS is a low-incidence disorder (1:7,143 males, 1:11,111 females) often associated with intellectual disability and severe co-occurring psychosocial conditions, particularly in male individuals. Given information on infant clinical phenotypes in the FXpm and FXS is sparse, we aimed to characterize parent-reported infant temperament in infants with the FXpm (n = 22) relative to FXS (n = 24) and controls (n = 24) assessed on 1 to 3 occasions each. Temperament in infants with the FXpm largely fell between TD and FXS groups, with trends toward suppressed negative affect in younger participants, similar to lower negative affect previously reported in FXS. The FXS group consistently demonstrated lower negative affect and surgency than TD controls. These data suggest that FMR1 gene mutations are associated with atypical temperament that emerges as early as infancy, particularly among infants with FXS, warranting further study of whether temperament may index emergent clinical risks in these populations.