adjustment; temperament; children of alcoholics; emotion regulation; substance use/abuse
The authors examined the relations of maternal supportive parenting to effortful control and internalizing problems (i.e., separation distress, inhibition to novelty), externalizing problems, and social competence when toddlers were 18 months old (n = 256) and a year later (n = 230). Mothers completed the Coping With Toddlers' Negative Emotions Scale, and their sensitivity and warmth were observed. Toddlers' effortful control was measured with a delay task and adults' reports (Early Childhood Behavior Questionnaire). Toddlers' social functioning was assessed with the Infant/Toddler Social and Emotional Assessment. Within each age, children's regulation significantly mediated the relation between supportive parenting and low levels of externalizing problems and separation distress, and high social competence. When using stronger tests of mediation, controlling for stability over time, the authors found only partial evidence for mediation. The findings suggest these relations may be set at an early age.
toddlers' effortful control; maternal socialization; social functioning; problem behaviors
Stability in frontal brain electrical activity (i.e., electroencephalographic or EEG) asymmetry at 10 and 24 months was examined with respect to maternal ratings of internalizing and externalizing behaviors at 30 months in a sample of 48 children. Children with stable left frontal EEG asymmetry during infancy were rated higher in externalizing behaviors by their mothers, whereas children with stable right frontal EEG asymmetry were rated higher in internalizing behaviors. These findings highlight the need to focus on the early stability in physiological measures that may be implicated later in developing behavioral problems.
EEG; frontal asymmetry; human infants; human toddlers; internalizing; externalizing
Despite evidence for the importance of individual differences in expressive language during toddlerhood in predicting later literacy skills, few researchers have examined individual and contextual factors related to language abilities across the toddler years. Furthermore, a gap remains in the literature about the extent to which the relations of negative emotions and parenting to language skills may differ for girls and boys. The purpose of this longitudinal study was to investigate the associations among maternal sensitivity, children’s observed anger reactivity, and expressive language when children were 18 (T1; n = 247) and 30 (T2; n = 216) months. At each age, mothers reported on their toddlers’ expressive language, and mothers’ sensitive parenting behavior was observed during an unstructured free-play task. Toddlers’ anger expressions were observed during an emotion-eliciting task. Using path modeling, results showed few relations at T1. At T2, maternal sensitivity was negatively related to anger, and in turn, anger was associated with lower language skills. However, moderation analyses showed that these findings were significant for boys but not for girls. In addition, T1 maternal sensitivity and anger positively predicted expressive language longitudinally for both sexes. Findings suggest that the relations between maternal sensitivity, anger reactivity and expressive language may vary depending on the child’s developmental stage and sex.
expressive language; toddlers’ negative emotions; anger; maternal sensitivity; child sex
The purpose of the current study was to predict the development of aggressive behavior from young children’s respiratory sinus arrhythmia (RSA) and environmental quality. In a longitudinal sample of 213 children, baseline RSA, RSA suppression in response to a film of crying babies, and a composite measure of environmental quality (incorporating socioeconomic status and marital adjustment) were measured, and parent-reported aggression was assessed from 18 to 54 months of age. Predictions based on biological sensitivity-to-context/differential susceptibility and diathesis-stress models, as well as potential moderation by child sex, were examined. The interaction of baseline RSA with environmental quality predicted the development (slope) and 54-month intercept of mothers’ reports of aggression. For girls only, the interaction between baseline RSA and environmental quality predicted the 18-month intercept of fathers’ reports. In general, significant negative relations between RSA and aggression were found primarily at high levels of environmental quality. In addition, we found a significant Sex × RSA interaction predicting the slope and 54-month intercept of fathers’ reports of aggression, such that RSA was negatively related to aggression for boys but not for girls. Contrary to predictions, no significant main effects or interactions were found for RSA suppression. The results provide mixed but not full support for differential susceptibility theory and provide little support for the diathesis-stress model.
respiratory sinus arrhythmia (RSA); vagal tone; aggression; socioeconomic status; differential susceptibility
The LPR and STin2 polymorphisms of the serotonin transporter gene (SLC6A4) were combined into haplotypes that, together with quality of maternal parenting, were used to predict initial levels and linear change in children’s (N = 138) noncompliance and aggression from age 18 –54 months. Quality of mothers’ parenting behavior was observed when children were 18 months old, and nonparental caregivers’ reports of noncompliance and aggression were collected annually from 18 to 54 months of age. Quality of early parenting was negatively related to the slope of noncompliance only for children with the LPR-S/STin2-10 haplotype and to 18-month noncompliance only for children with haplotypes that did not include LPR-S. The findings support the notion that SLC6A4 haplotypes index differential susceptibility to variability in parenting quality, with certain haplotypes showing greater reactivity to both supportive and unsupportive environments. These different genetic backgrounds likely reflect an evolutionary response to variation in the parenting environment.
differential susceptibility; serotonin transporter gene; aggression; noncompliance; SLC6A4 (5-HTT)
In a sample (n = 235) of 30-, 42-, and 54-month-olds, the relations among parenting, effortful control (EC), impulsivity, and children’s committed compliance were examined. Parenting was assessed with mothers’ observed sensitivity and warmth; EC was measured by mothers’ and caregivers’ reports, as well as a behavioral task; impulsivity was assessed by mothers’ and caregivers’ reports; and committed compliance was observed during a cleanup and prohibition task, as well as measured by adults’ reports. Using path modeling, there was evidence that 30-month parenting predicted high EC and low impulsivity a year later when the stability of the outcomes was controlled, and there was evidence that 30- and 42-month EC, but not impulsivity, predicted higher committed compliance a year later, controlling for earlier levels of the outcomes. Moreover, 42-month EC predicted low impulsivity a year later. Fixed effects models, which are not biased by omitted time-invariant variables, also were conducted and showed that 30-month parenting still predicted EC a year later, and 42-month EC predicted later low impulsivity. Findings are discussed in terms of the importance of differentiating between effortful control and impulsivity and the potential mediating role of EC in the relations between parenting and children’s committed compliance.
committed compliance; effortful control; regulation; impulsivity; maternal responsiveness
A forum of the Human Variome Project (HVP) was held as a satellite to the 2012 Annual Meeting of the American Society of Human Genetics in San Francisco, California. The theme of this meeting was “Getting Ready for the Human Phenome Project.” Understanding the genetic contribution to both rare single-gene “Mendelian” disorders and more complex common diseases will require integration of research efforts among many fields and better defined phenotypes. The HVP is dedicated to bringing together researchers and research populations throughout the world to provide the resources to investigate the impact of genetic variation on disease. To this end, there needs to be a greater sharing of phenotype and genotype data. For this to occur, many databases that currently exist will need to become interoperable to allow for the combining of cohorts with similar phenotypes to increase statistical power for studies attempting to identify novel disease genes or causative genetic variants. Improved systems and tools that enhance the collection of phenotype data from clinicians are urgently needed. This meeting begins the HVP’s effort toward this important goal.
meeting report; database; phenotype; database interoperability
Longitudinal associations among maternal personality, emotional expressions, and parenting were examined.
Maternal parenting (sensitivity and intrusiveness) and positive emotional expressions were observed during a free-play session with toddlers at 18 (T1, n = 246) and 30 (T3, n = 216) months. Mothers completed a personality measure at T1 and a questionnaire measuring their emotional expressiveness (positive and negative) when toddlers were 24 months old (T2, n = 213).
Dimensions of maternal personality and maternal emotional expressiveness were related to individual differences in maternal parenting behaviors, in particular to maternal sensitivity. Conscientiousness and Agreeableness at T1 were positively associated with observed positive emotional expressions at T1. Agreeableness, Openness to Experience, and Extraversion at T1 also were positively related to positive emotional expressions reported by mothers at T2. Maternal positive emotional expressions (T1 and T2), in turn, were associated with more sensitive behavior observed with toddlers at T3.
In addition to direct effects of maternal personality on maternal parenting, mothers’ emotional expressiveness was found to be a possible pathway for explaining relations of maternal personality and parenting.
The Human Phenotype Ontology (HPO) project, available at http://www.human-phenotype-ontology.org, provides a structured, comprehensive and well-defined set of 10,088 classes (terms) describing human phenotypic abnormalities and 13,326 subclass relations between the HPO classes. In addition we have developed logical definitions for 46% of all HPO classes using terms from ontologies for anatomy, cell types, function, embryology, pathology and other domains. This allows interoperability with several resources, especially those containing phenotype information on model organisms such as mouse and zebrafish. Here we describe the updated HPO database, which provides annotations of 7,278 human hereditary syndromes listed in OMIM, Orphanet and DECIPHER to classes of the HPO. Various meta-attributes such as frequency, references and negations are associated with each annotation. Several large-scale projects worldwide utilize the HPO for describing phenotype information in their datasets. We have therefore generated equivalence mappings to other phenotype vocabularies such as LDDB, Orphanet, MedDRA, UMLS and phenoDB, allowing integration of existing datasets and interoperability with multiple biomedical resources. We have created various ways to access the HPO database content using flat files, a MySQL database, and Web-based tools. All data and documentation on the HPO project can be found online.
The use of ontologies to standardize biological data and facilitate comparisons among datasets has steadily grown as the complexity and amount of available data have increased. Despite the numerous ontologies available, one area currently lacking a robust ontology is the description of vertebrate traits. A trait is defined as any measurable or observable characteristic pertaining to an organism or any of its substructures. While there are several ontologies to describe entities and processes in phenotypes, diseases, and clinical measurements, one has not been developed for vertebrate traits; the Vertebrate Trait Ontology (VT) was created to fill this void.
Significant inconsistencies in trait nomenclature exist in the literature, and additional difficulties arise when trait data are compared across species. The VT is a unified trait vocabulary created to aid in the transfer of data within and between species and to facilitate investigation of the genetic basis of traits. Trait information provides a valuable link between the measurements that are used to assess the trait, the phenotypes related to the traits, and the diseases associated with one or more phenotypes. Because multiple clinical and morphological measurements are often used to assess a single trait, and a single measurement can be used to assess multiple physiological processes, providing investigators with standardized annotations for trait data will allow them to investigate connections among these data types.
The annotation of genomic data with ontology terms provides unique opportunities for data mining and analysis. Links between data in disparate databases can be identified and explored, a strategy that is particularly useful for cross-species comparisons or in situations involving inconsistent terminology. The VT provides a common basis for the description of traits in multiple vertebrate species. It is being used in the Rat Genome Database and Animal QTL Database for annotation of QTL data for rat, cattle, chicken, swine, sheep, and rainbow trout, and in the Mouse Phenome Database to annotate strain characterization data. In these databases, data are also cross-referenced to applicable terms from other ontologies, providing additional avenues for data mining and analysis. The ontology is available at http://bioportal.bioontology.org/ontologies/50138.
Quantitative trait loci; Gene association; Trait ontology
The Mammalian Phenotype Ontology (MP) is a structured vocabulary for describing mammalian phenotypes and serves as a critical tool for efficient annotation and comprehensive retrieval of phenotype data. Importantly, the ontology contains broad and specific terms, facilitating annotation of data from initial observations or screens and detailed data from subsequent experimental research. Using the ontology structure, data are retrieved inclusively, i.e., data annotated to chosen terms and to terms subordinate in the hierarchy. Thus, searching for “abnormal craniofacial morphology” also returns annotations to “megacephaly” and “microcephaly,” more specific terms in the hierarchy path. The development and refinement of the MP is ongoing, with new terms and modifications to its organization undergoing continuous assessment as users and expert reviewers propose expansions and revisions. A wealth of phenotype data on mouse mutations and variants annotated to the MP already exists in the Mouse Genome Informatics database. These data, along with data curated to the MP by many mouse mutagenesis programs and mouse repositories, provide a platform for comparative analyses and correlative discoveries. The MP provides a standard underpinning to mouse phenotype descriptions for existing and future experimental and large-scale phenotyping projects. In this review we describe the MP as it presently exists, its application to phenotype annotations, the relationship of the MP to other ontologies, and the integration of the MP within large-scale phenotyping projects. Finally we discuss future application of the MP in providing standard descriptors of the phenotype pipeline test results from the International Mouse Phenotype Consortium projects.
Indices of physiological regulation (i.e., resting respiratory sinus arrhythmia [RSA] and RSA suppression) and observed fearfulness were tested as predictors of empathy-related reactions to an unfamiliar person’s simulated distress within and across 18 (T1, N = 247) and 30 (T2, N = 216) months of age. Controlling for T1 helping, high RSA suppression and low fearfulness at T1 predicted T2 helping. In a structural model, empathic concern was marginally positively related to resting RSA at both assessments whereas personal distress was related to RSA suppression within time (marginally positively at T1 and significantly negatively at T2). Fearfulness was associated with self-oriented, distress-related reactions within time. Comfort seeking (an index of personal distress) declined in mean level with age whereas helping increased, and both behaviors exhibited differential continuity (as did resting RSA). Individual, as well as developmental, differences in the types of reactions that young children exhibit when witnessing others’ suffering and distress were discussed.
empathy; emotion regulation; respiratory sinus arrhythmia; fear
Optimal curation of human diseases requires an ontology or structured vocabulary that contains terms familiar to end users, is robust enough to support multiple levels of annotation granularity, is limited to disease terms and is stable enough to avoid extensive reannotation following updates. At Mouse Genome Informatics (MGI), we currently use disease terms from Online Mendelian Inheritance in Man (OMIM) to curate mouse models of human disease. While OMIM provides highly detailed disease records that are familiar to many in the medical community, it lacks structure to support multilevel annotation. To improve disease annotation at MGI, we evaluated the merged Medical Subject Headings (MeSH) and OMIM disease vocabulary created by the Comparative Toxicogenomics Database (CTD) project. Overlaying MeSH onto OMIM provides hierarchical access to broad disease terms, a feature missing from the OMIM. We created an extended version of the vocabulary to meet the genetic disease-specific curation needs at MGI. Here we describe our evaluation of the CTD application, the extensions made by MGI and discuss the strengths and weaknesses of this approach.
Ontologies are widely used to represent knowledge in biomedicine. Systematic approaches for detecting errors and disagreements are needed for large ontologies with hundreds or thousands of terms and semantic relationships. A recent approach of defining terms using logical definitions is now increasingly being adopted as a method for quality control as well as for facilitating interoperability and data integration.
We show how automated reasoning over logical definitions of ontology terms can be used to improve ontology structure. We provide the Java software package GULO (Getting an Understanding of LOgical definitions), which allows fast and easy evaluation for any kind of logically decomposed ontology by generating a composite OWL ontology from appropriate subsets of the referenced ontologies and comparing the inferred relationships with the relationships asserted in the target ontology. As a case study we show how to use GULO to evaluate the logical definitions that have been developed for the Mammalian Phenotype Ontology (MPO).
Logical definitions of terms from biomedical ontologies represent an important resource for error and disagreement detection. GULO gives ontology curators a fast and simple tool for validation of their work.
In a sample of 18-, 30-, and 42-month-olds, the relations among parenting, effortful control (EC), and maladjustment were examined. Parenting was assessed with mothers’ reports and observations; EC was measured with mothers’ and caregivers’ reports, as well as a behavioral task; and externalizing and internalizing symptoms were assessed with parents’ and caregivers’ reports. Although 18-month unsupportive (vs. supportive) parenting negatively predicted EC at 30 months, when the stability of these variables was taken into account, there was no evidence of additional potentially causal relations between these two constructs. Although EC was negatively related to both internalizing and externalizing problems within all three ages as well as across 1 year, EC did not predict maladjustment once the stability of the constructs and within time covariation between the constructs were taken into account. In addition, externalizing problems at 30 months negatively predicted EC at 42 months, and internalizing problems at 30 months positively predicted EC at 42 months, but only when the effects of externalizing on EC were controlled. The findings are discussed in terms of the reasons for the lack of causal relations over time.
A phenotypic ontology that can be used for the analysis of phenotype-genotype data across multiple species, paving the way for truly cross species translational research.
Phenotype ontologies are typically constructed to serve the needs of a particular community, such as annotation of genotype-phenotype associations in mouse or human. Here we demonstrate how these ontologies can be improved through assignment of logical definitions using a core ontology of phenotypic qualities and multiple additional ontologies from the Open Biological Ontologies library. We also show how these logical definitions can be used for data integration when combined with a unified multi-species anatomy ontology.
The mouse has long been an important model for the study of human genetic disease. Through the application of genetic engineering and mutagenesis techniques, the number of unique mutant mouse models and the amount of phenotypic data describing them are growing exponentially. Describing phenotypes of mutant mice in a computationally useful manner that will facilitate data mining is a major challenge for bioinformatics. Here we describe a tool, the Mammalian Phenotype Ontology (MP), for classifying and organizing phenotypic information related to the mouse and other mammalian species. The MP Ontology has been applied to mouse phenotype descriptions in the Mouse Genome Informatics Database (MGI, http://www.informatics.jax.org/), the Rat Genome Database (RGD, http://rgd.mcw.edu), the Online Mendelian Inheritance in Animals (OMIA, http://omia.angis.org.au/) and elsewhere. Use of this ontology allows comparisons of data from diverse sources, can facilitate comparisons across mammalian species, assists in identifying appropriate experimental disease models, and aids in the discovery of candidate disease genes and molecular signaling pathways.
Ontology; Phenotype; Mammal; Annotation; Model System
The relations of childhood fearfulness (observed and adult reported) and adult-reported shyness at 18 (n = 256) and 30 (n = 230) months of age were assessed. Fear was positively related to shyness concurrently and longitudinally, but slightly more consistently at 18 months. The moderating roles of observed maternal sensitivity and children’s sex in the relation between 18-month fearfulness and 30-month shyness, and between 18- and 30-month shyness, were tested. The positive relation between mother-reported fearfulness and shyness was strongest for sons of insensitive mothers but was not significant for daughters of sensitive, average, or insensitive mothers. The positive relation between mother-reported 18- and 30-month shyness was strongest for sons of insensitive mothers and for daughters of sensitive mothers. Moreover, when using scores of fear or shyness that were independent of each other, 18-month mother-reported fearfulness continued to interact with sex and sensitivity to predict 30-month shyness; however, the positive relation between Time 1 and Time 2 shyness was consistent across sex and levels of sensitivity.
The relations of cumulative demographic risk and children’s temperament to mothers’ parenting behaviors were examined when children were 18 (T1, n = 247) and 30 (T2, n = 216) months of age. Mothers, nonparental caregivers (e.g., child care providers), and observers reported on children’s temperament to create a temperament composite, and mothers reported on demographic risk variables. Maternal responsivity and control were observed during 2 mother–child interactions at both time points. Cumulative demographic risk was related to low maternal responsivity concurrently and longitudinally, even after controlling for earlier temperament and responsivity, and demographic risk was positively related to maternal control at T1 and T2. Regulated temperament (i.e., low frustration and high regulation) was linked with high maternal responsivity at T1 and T2 and low maternal control at T2. Moreover, the positive relation between cumulative risk and maternal control at T1 was stronger when children were viewed as less regulated.
The mRNAs encoding postsynaptic components at the neuromuscular junction are concentrated in the synaptic region of muscle fibers. Accumulation of these RNAs in the synaptic region is mediated, at least in part, by selective transcription of the corresponding genes in synaptic myofiber nuclei. The transcriptional mechanisms that are responsible for synapse-specific gene expression are largely unknown, but an Ets site in the promoter regions of acetylcholine receptor (AChR) subunit genes and other “synaptic” genes is required for synapse-specific transcription. The Ets domain transcription factor GA-binding protein (GABP) has been implicated to mediate synapse-specific gene expression. Inactivation of GABPα, the DNA-binding subunit of GABP, leads to early embryonic lethality, preventing analysis of synapse formation in gabpα mutant mice. To study the role of GABP at neuromuscular synapses, we conditionally inactivated gabpα in skeletal muscle and studied synaptic differentiation and muscle gene expression. Although expression of rb, a target of GABP, is elevated in muscle tissue deficient in GABPα, clustering of synaptic AChRs at synapses and synapse-specific gene expression are normal in these mice. These data indicate that GABP is dispensable for synapse-specific transcription and maintenance of normal AChR expression at synapses.
The Mammalian Phenotype (MP) Ontology enables robust annotation of mammalian phenotypes in the context of mutations, quantitative trait loci and strains that are used as models of human biology and disease.
The Mammalian Phenotype (MP) Ontology enables robust annotation of mammalian phenotypes in the context of mutations, quantitative trait loci and strains that are used as models of human biology and disease. The MP Ontology supports different levels and richness of phenotypic knowledge and flexible annotations to individual genotypes. It continues to develop dynamically via collaborative input from research groups, mutagenesis consortia, and biological domain experts. The MP Ontology is currently used by the Mouse Genome Database and Rat Genome Database to represent phenotypic data.