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Background: Psychiatric taxonomy segregates pediatric anxiety symptoms into distinct diagnostic subtypes. However, typical mixed symptom presentations pose significant challenges for diagnosis, treatment, and research. Pediatric anxiety alternatively may manifest along multiple, inter-connected domains in ways poorly captured by current classification systems. To evaluate this possibility, we utilize network analytic approaches to characterize pediatric anxiety as a network of symptom domains. Quantifying this network structure could inform our clinical conceptualization of pediatric anxiety, and, accordingly, clinical practice and research. Methods: Participants were 4,964 youths (ages 5-17 years) from seven international sites. Participants completed the Screen for Child Anxiety Related Emotional Disorders which assesses symptom severity along domains that follow pediatric anxiety DSM diagnostic categories (generalized anxiety, social anxiety, separation anxiety, and panic disorders; additionally, school avoidance). We used network analytic methods to quantify patterns of associations among these symptom domains and to relate network variation to important moderators of anxiety symptom expression (age, sex). Findings: The anxiety symptoms network was estimated with high accuracy and featured a highly inter-connected structure. Anxiety patients and healthy youth demonstrated comparable network structures. Sex differences were noted in network structure. Longitudinal data over a three-year period demonstrated specific network structure changes during childhood but not adolescence. Generalized anxiety and panic symptoms consistently emerged as central domains in the symptom network. Interpretation: Pediatric anxiety manifests along inter-connected symptom domains. The revealed pattern of domain associations, alongside moderation effects by age and sex, could inform conceptualization, treatment, and study of pediatric anxiety. Funding Statement: This research was supported (in part) by the NIMH Intramural Research Program (ZIAMH002781-15, NCT00018057), and grants R01 MH094633, R34 MH097931, UH2 MH101470; the Netherlands Organisation for Health Research and Development, ZonMW (grant number 200210010). Declaration of Interests: All authors declare no conflict of interests with regard to this manuscript. Ethics Approval Statement: At each site, the study was performed in compliance with the Code of Ethics of the World Medical Association (Declaration of Helsinki), approved by the local Institutional Review Board. Prior to participation, informed consent and assent were obtained from parents and youth, respectively.

Additional file 1. Exclusion criteria, Rationale for analyzing CD as a categorical measure and ICU and ARI as continuous measures and Rationale for including age and IQ as covariates and sex as a group variable in the MANCOVAs.

Additional file 2: Table S1. Results of MANCOVAs involving ICU and ARI raw scores and excluding participants prescribed antipsychotic medications. Table S2. Results for the MANCOVAs involving ICU and ARI raw scores and excluding participants prescribed antipsychotic medications by question (questions are paraphrased). Bolded numbers in the MANCOVA table indicate significance. Table S3. Results of group-based MANCOVAs including MDD and GAD diagnostic status as fixed factors. Table S4. Results for the group-based MANCOVA including MDD and GAD diagnostic status as fixed factors by question (questions are paraphrased). Bolded numbers in the MANCOVA table indicate significance.

Anxiety disorders are highly prevalent and disabling but seem particularly tractable to investigation with translational neuroscience methodologies. Neuroimaging has informed our understanding of the neurobiology of anxiety disorders, but research has been limited by small sample sizes and low statistical power, as well as heterogenous imaging methodology. The ENIGMA‐Anxiety Working Group has brought together researchers from around the world, in a harmonized and coordinated effort to address these challenges and generate more robust and reproducible findings. This paper elaborates on the concepts and methods informing the work of the working group to date, and describes the initial approach of the four subgroups studying generalized anxiety disorder, panic disorder, social anxiety disorder, and specific phobia. At present, the ENIGMA‐Anxiety database contains information about more than 100 unique samples, from 16 countries and 59 institutes. Future directions include examining additional imaging modalities, integrating imaging and genetic data, and collaborating with other ENIGMA working groups. The ENIGMA consortium creates synergy at the intersection of global mental health and clinical neuroscience, and the ENIGMA‐Anxiety Working Group extends the promise of this approach to neuroimaging research on anxiety disorders., Anxiety disorders are highly prevalent and disabling but seem particularly tractable to investigation with translational neuroscience methodologies. Neuroimaging has informed our understanding of the neurobiology of anxiety disorders, but research has been limited by small sample sizes and low statistical power, as well as heterogenous imaging methodology. The ENIGMA‐Anxiety Working Group has brought together researchers from around the world, in a harmonized and coordinated effort to address these challenges and generate more robust and reproducible findings. The ENIGMA consortium creates synergy at the intersection of global mental health and clinical neuroscience, and the ENIGMA‐Anxiety Working Group extends the promise of this approach to neuroimaging research on anxiety disorders.

Severe irritability is one of the commonest reasons prompting referral to mental health services. It is frequently seen in neurodevelopmental disorders that manifest early in development, especially attention-deficit/hyperactivity disorder (ADHD). However, irritability can also be conceptualized as a mood problem because of its links with anxiety/depressive disorders; notably DSM-5 currently classifies severe, childhood-onset irritability as a mood disorder. Investigations into the genetic nature of irritability are lacking although twin studies suggest it shares genetic risks with both ADHD and depression. We investigated the genetic underpinnings of irritability using a molecular genetic approach, testing the hypothesis that early irritability (in childhood/adolescence) is associated with genetic risk for ADHD, as indexed by polygenic risk scores (PRS). As a secondary aim we investigated associations between irritability and PRS for major depressive disorder (MDD). Three UK samples were utilized: two longitudinal population-based cohorts with irritability data from childhood (7 years) to adolescence (15-16 years), and one ADHD patient sample (6-18 years). Irritability was defined using parent reports. PRS were derived from large genome-wide association meta-analyses. We observed associations between ADHD PRS and early irritability in our clinical ADHD sample and one of the population samples. This suggests that early irritability traits share genetic risk with ADHD in the general population and are a marker of higher genetic loading in individuals with an ADHD diagnosis. Associations with MDD PRS were not observed. This suggests that early-onset irritability could be conceptualized as a neurodevelopmental difficulty, behaving more like disorders such as ADHD than mood disorders.