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Identifying Novel Types of Irritability Using a Developmental Genetic Approach.

ABSTRACT: OBJECTIVE:Irritability, which is strongly associated with impairment and negative outcomes, is a common reason for referral to mental health services but is a nosological and treatment challenge. A major issue is how irritability should be conceptualized. The authors used a developmental approach to test the hypothesis that there are several forms of irritability, including a "neurodevelopmental/ADHD-like" type, with onset in childhood, and a "depression/mood" type, with onset in adolescence. METHODS:Data were analyzed from the Avon Longitudinal Study of Parents and Children, a prospective U.K. population-based cohort. Irritability trajectory classes were estimated for 7,924 individuals with data at multiple time points across childhood and adolescence (four possible time points from approximately ages 7 to 15). Psychiatric diagnoses were assessed at approximately ages 7 and 15. Psychiatric genetic risk was indexed by polygenic risk scores (PRSs) for attention deficit hyperactivity disorder (ADHD) and depression, derived using large genome-wide association study results. RESULTS:Five irritability trajectory classes were identified: low (81.2%), decreasing (5.6%), increasing (5.5%), late-childhood limited (5.2%), and high-persistent (2.4%). The early-onset high-persistent trajectory was associated with male preponderance, childhood ADHD (odds ratio=108.64, 95% CI=57.45-204.41), and ADHD PRS (odds ratio=1.31, 95% CI=1.09-1.58). The adolescent-onset increasing trajectory was associated with female preponderance, adolescent depression (odds ratio=5.14, 95% CI=2.47-10.73), and depression PRS (odds ratio=1.20, 95% CI=1.05-1.38). Both the early-onset high-persistent and adolescent-onset increasing trajectory classes were associated with adolescent depression diagnosis and ADHD PRS. CONCLUSIONS:The developmental context of irritability may be important in its conceptualization: early-onset persistent irritability may be more neurodevelopmental/ADHD-like and later-onset irritability more depression/mood-like. These findings have implications for treatment as well as nosology.

SUBMITTER: Riglin L

PROVIDER: S-EPMC6677571 | biostudies-literature | 2019 Aug

REPOSITORIES: biostudies-literature

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Identifying Novel Types of Irritability Using a Developmental Genetic Approach.

Riglin Lucy L Eyre Olga O Thapar Ajay K AK Stringaris Argyris A Leibenluft Ellen E Pine Daniel S DS Tilling Kate K Davey Smith George G O'Donovan Michael C MC Thapar Anita A

The American journal of psychiatry 20190701 8

<h4>Objective</h4>Irritability, which is strongly associated with impairment and negative outcomes, is a common reason for referral to mental health services but is a nosological and treatment challenge. A major issue is how irritability should be conceptualized. The authors used a developmental approach to test the hypothesis that there are several forms of irritability, including a "neurodevelopmental/ADHD-like" type, with onset in childhood, and a "depression/mood" type, with onset in adolesc ...[more]

PMID: 31256611

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Project description:BACKGROUND:Glycans are complex sugar chains, crucial to many biological processes. By participating in binding interactions with proteins, glycans often play key roles in host-pathogen interactions. The specificities of glycan-binding proteins, such as lectins and antibodies, are governed by motifs within larger glycan structures, and improved characterisations of these determinants would aid research into human diseases. Identification of motifs has previously been approached as a frequent subtree mining problem, and we extend these approaches with a glycan notation that allows recognition of terminal motifs. RESULTS:In this work, we customised a frequent subtree mining approach by altering the glycan notation to include information on terminal connections. This allows specific identification of terminal residues as potential motifs, better capturing the complexity of glycan-binding interactions. We achieved this by including additional nodes in a graph representation of the glycan structure to indicate the presence or absence of a linkage at particular backbone carbon positions. Combining this frequent subtree mining approach with a state-of-the-art feature selection algorithm termed minimum-redundancy, maximum-relevance (mRMR), we have generated a classification pipeline that is trained on data from a glycan microarray. When applied to a set of commonly used lectins, the identified motifs were consistent with known binding determinants. Furthermore, logistic regression classifiers trained using these motifs performed well across most lectins examined, with a median AUC value of 0.89. CONCLUSIONS:We present here a new subtree mining approach for the classification of glycan binding and identification of potential binding motifs. The Carbohydrate Classification Accounting for Restricted Linkages (CCARL) method will assist in the interpretation of glycan microarray experiments and will aid in the discovery of novel binding motifs for further experimental characterisation.

Project description:OBJECTIVE:Advances in developmentally sensitive measurement have enabled differentiation of normative versus clinically salient irritability in early childhood. However, clinical application of these measures is still nascent. The authors developed an optimized model of clinically salient irritable behaviors at preschool age. Based on this model, the authors derived an empirically based cutoff in relation to concurrent DSM-5 irritability-related disorders (i.e., oppositional defiant disorder, disruptive mood dysregulation disorder, other depressive disorders) and used longitudinal models to test the predictive validity of the cutoff for impairment and irritability trajectories and later DSM disorders. METHOD:Preschool children oversampled for irritability were followed over 3 time points into early school age (N = 425; mean age at baseline 4.7 years, mean follow-up 2.9 years). Mothers reported on children's irritability using the developmentally validated Multidimensional Assessment of Profile of Disruptive Behavior (MAP-DB) Temper Loss scale, impairment using the Family Life Impairment Scale, and DSM categories using the Preschool Age Psychiatric Assessment and the Schedule for Affective Disorders and Schizophrenia-Present and Lifetime Version. RESULTS:Of 22 MAP-DB Temper Loss behaviors, 2 behaviors-1 normative (easily frustrated) and 1 rare dysregulated (destructive tantrums)-were uniquely related to cross-domain impairment. At baseline, these 2 irritability items identified diagnostic status (oppositional defiant disorder, disruptive mood dysregulation disorder, other depressive disorders) with good sensitivity (70-73%) and specificity (74-83%). Children above the irritability cutoff at baseline also exhibited more persistent irritability and impairment and greater likelihood of DSM disorders in early school age. CONCLUSION:Clinical identification of early-onset irritability can be enhanced using brief, developmentally optimized indicators. Further research to apply these findings to tiered early intervention is important.

Project description:ObjectiveIrritability is a dimensional trait that manifests from early life and is a robust transdiagnostic risk factor for psychopathology and impairment. A large, national dataset was leveraged to identify and broadly characterize trajectories from toddlerhood through adolescence, which is crucial for timely, targeted interventions.MethodData on irritability and a broad array of potential factors affecting irritability development from 4,462 children assessed longitudinally at ages 3, 5, 9, and 15 were included. Latent class growth models identified groups of children based on their nonlinear irritability trajectories from toddlerhood to adolescence. LASSO regression then identified key characteristics differentiating trajectory groups.ResultsFive distinct irritability trajectories were identified, two of which were stable, maintaining medium or high irritability from age 3 to 15. Three trajectories showed undulating change over development, with an inflection point at the transition to adolescence (age 9): Most children had consistently low irritability. Two smaller groups started with high irritability at age 3 but diverged, sharply decreasing or increasing until a turning point at age 9. Developmental patterning of harsh/neglectful parenting and child internalizing symptoms most strongly differentiated trajectory groups. Sociodemographic characteristics, attachment style, neighborhood support, cognitive functioning, and genetic variation also differentiated trajectories.ConclusionThe results demonstrated the importance of the transition to adolescence as a critical inflection point for youths with fluctuating irritability trajectories. Identifying these patterns and multiple malleable factors associated with stably high or rising trajectories is an important step toward targeted interventions for the most vulnerable subgroups.Diversity & inclusion statementWe worked to ensure sex and gender balance in the recruitment of human participants. We worked to ensure race, ethnic, and/or other types of diversity in the recruitment of human participants. One or more of the authors of this paper self-identifies as a member of one or more historically underrepresented racial and/or ethnic groups in science. One or more of the authors of this paper self-identifies as a member of one or more historically underrepresented sexual and/or gender groups in science. One or more of the authors of this paper self-identifies as living with a disability. One or more of the authors of this paper received support from a program designed to increase minority representation in science. We actively worked to promote sex and gender balance in our author group. We actively worked to promote inclusion of historically underrepresented racial and/or ethnic groups in science in our author group.

Project description:ObjectiveIrritability is a dimensional trait in typical development and a common presenting symptom in many psychiatric disorders, including depression. However, little is known about the developmental trajectory of irritability or how child irritability interacts with maternal depression. The present study identifies classes of irritability trajectories from toddlerhood to middle childhood; characterizes maternal depression and other family, social environment, and child variables within each irritability trajectory class; and, as a more exploratory analysis, examines bidirectional associations between maternal depression and child irritability.MethodA total of 4,898 families from the Fragile Families and Child Wellbeing Study reported on irritability symptoms at ages 3, 5, and 9 years, assessed with items from the Child Behavior Checklist. Parental major depressive episode was assessed using the Composite International Diagnostic Interview-Short Form at child ages 1, 3, 5, and 9 years.ResultsA latent class growth analysis identified 5 irritability classes: low decreasing; moderate decreasing; high steady; initially very high, then decreasing; and high increasing. Children with more severe irritability trajectories are more likely to have mothers with recurrent depression, and, with the exception of the most severe (high increasing irritability) class, were more likely to have mothers who were exposed to violence. Moreover, paternal depression and alcohol abuse, as well as maternal drug and alcohol abuse, were also risk factors for membership in the more severe irritability classes. A latent auto-regressive cross-lag model showed that child irritability at ages 3 and 5 years is associated with increased mother depression at ages 5 and 9, respectively. Conversely, mother depression at child ages 1 and 3 years is associated with increased child irritability at 3 and 5.ConclusionIrritability development across toddlerhood and middle childhood has 5 main trajectory types, which differ on maternal depression recurrence and exposure to violence. Maternal depression and child irritability influence each other bidirectionally, particularly early in development. Understanding irritability development and its bidirectional relationship with maternal depression and association with violence exposure may help identify intervention targets.

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Identifying Novel Types of Irritability Using a Developmental Genetic Approach.

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Identifying Novel Types of Irritability Using a Developmental Genetic Approach.

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