Integrative multi-omics analysis of genomic, epigenomic, and metabolomics data leads to new insights for Attention-Deficit/Hyperactivity Disorder.

The evolving field of multi-omics combines data and provides methods for simultaneous analysis across several omics levels. Here, we integrated genomics (transmitted and non-transmitted polygenic scores [PGSs]), epigenomics, and metabolomics data in a multi-omics framework to identify biomarkers for Attention-Deficit/Hyperactivity Disorder (ADHD) and investigated the connections among the three omics levels. We first trained single- and next multi-omics models to differentiate between cases and controls in 596 twins (cases = 14.8%) from the Netherlands Twin Register (NTR) demonstrating reasonable in-sample prediction through cross-validation. The multi-omics model selected 30 PGSs, 143 CpGs, and 90 metabolites. We confirmed previous associations of ADHD with glucocorticoid exposure and the transmembrane protein family TMEM, show that the DNA methylation of the MAD1L1 gene associated with ADHD has a relation with parental smoking behavior, and present novel findings including associations between indirect genetic effects and CpGs of the STAP2 gene. However, out-of-sample prediction in NTR participants (N = 258, cases = 14.3%) and in a clinical sample (N = 145, cases = 51%) did not perform well (range misclassification was [0.40, 0.57]). The results highlighted connections between omics levels, with the strongest connections between non-transmitted PGSs, CpGs, and amino acid levels and show that multi-omics designs considering interrelated omics levels can help unravel the complex biology underlying ADHD.

Neurobiological correlates of antisociality across adolescence and young adulthood: a multi-sample, multi-method study.

BACKGROUND: Antisociality across adolescence and young adulthood puts individuals at high risk of developing a variety of problems. Prior research has linked antisociality to autonomic nervous system and endocrinological functioning. However, there is large heterogeneity in antisocial behaviors, and these neurobiological measures are rarely studied conjointly, limited to small specific studies with narrow age ranges, and yield mixed findings due to the type of behavior examined. METHODS: We harmonized data from 1489 participants (9-27 years, 67% male), from six heterogeneous samples. In the resulting dataset, we tested relations between distinct dimensions of antisociality and heart rate, pre-ejection period (PEP), respiratory sinus arrhythmia, respiration rate, skin conductance levels, testosterone, basal cortisol, and the cortisol awakening response (CAR), and test the role of age throughout adolescence and young adulthood. RESULTS: Three dimensions of antisociality were uncovered: 'callous-unemotional (CU)/manipulative traits', 'intentional aggression/conduct', and 'reactivity/impulsivity/irritability'. Shorter PEPs and higher testosterone were related to CU/manipulative traits, and a higher CAR is related to both CU/manipulative traits and intentional aggression/conduct. These effects were stable across age. CONCLUSIONS: Across a heterogeneous sample and consistent across development, the CAR may be a valuable measure to link to CU/manipulative traits and intentional aggression, while sympathetic arousal and testosterone are additionally valuable to understand CU/manipulative traits. Together, these findings deepen our understanding of the fundamental mechanisms underlying different components of antisociality. Finally, we illustrate the potential of using current statistical techniques for combining multiple datasets to draw robust conclusions about biobehavioral associations.

Integrative Multi-omics Analysis of Childhood Aggressive Behavior.

This study introduces and illustrates the potential of an integrated multi-omics approach in investigating the underlying biology of complex traits such as childhood aggressive behavior. In 645 twins (cases = 42%), we trained single- and integrative multi-omics models to identify biomarkers for subclinical aggression and investigated the connections among these biomarkers. Our data comprised transmitted and two non-transmitted polygenic scores (PGSs) for 15 traits, 78,772 CpGs, and 90 metabolites. The single-omics models selected 31 PGSs, 1614 CpGs, and 90 metabolites, and the multi-omics model comprised 44 PGSs, 746 CpGs, and 90 metabolites. The predictive accuracy for these models in the test (N = 277, cases = 42%) and independent clinical data (N = 142, cases = 45%) ranged from 43 to 57%. We observed strong connections between DNA methylation, amino acids, and parental non-transmitted PGSs for ADHD, Autism Spectrum Disorder, intelligence, smoking initiation, and self-reported health. Aggression-related omics traits link to known and novel risk factors, including inflammation, carcinogens, and smoking.

Likelihood of identifying autistic traits with the autism spectrum quotient (AQ) in male juveniles with autism spectrum disorder (ASD) and severe behavioral problems (SBPs).

BACKGROUND: When screening for autism spectrum disorders (ASD), the Autism Spectrum Quotient (AQ) is generally considered to be useful. Whether the AQ is also a suitable screener for ASD in juveniles with severe behavioral problems (SBPs) is unknown. Due to the overlap of symptoms between ASD and SBPs, particularly in juveniles low on empathy, the screening capacity of the AQ might be constrained. The aim of the present study was to investigate whether (comorbid) SBPs affect the screening capacity of the AQ. The hypothesis is that male juveniles with SBPs - but without a diagnosis of ASD - will score higher than male juveniles without both SBPs and ASD. METHOD: The AQ was completed by 216 male juveniles aged 15-18 years treated at an outpatient department of child and adolescent psychiatry. The 216 participants were categorized into four groups according to a clinical diagnosis of ASD and SBPs (defined as disruptive behavior disorder and/or delinquent behavior). Using multinomial logistic regression, we investigated whether the four identified groups, based on a diagnosis of ASD and SBPs, scored differently for the total score and subscales of the AQ. RESULTS: Participants in the group with ASD (ASD+) but without SBPs (SBP-) were more likely to report higher levels of autistic traits than the reference group without both ASD and SBPs (ASD-SBP-), except for the subscale on attention to detail (ASD+SBP- OR = 1.04; 95%CI = 0.98-1.11). Participants in the group with both ASD and SBPs were more likely to report higher levels for the total AQ score (ASD+SBP+ OR = 1.03; 95%CI = 1.00-1.05) and the communication subscale of the AQ (ASD+SBP+ OR = 1.18; 95%CI = 1.07-1.31) than the reference group without both ASD and SBPs. CONCLUSION: In outpatient male juveniles, SBPs do not affect the screening capacity of the AQ for autistic traits. In spite of the well-known overlap of symptoms between ASD and SBPs, male juveniles with SBPs but without a diagnosis of ASD do not score higher on the AQ than male juveniles without SBPs and without a diagnosis of ASD.

Improving Collaboration Between Youth Peer Support Workers and Non-peer Colleagues in Child and Adolescent Mental Health Services.

The involvement of youth peer workers (YPSWs) in child and adolescent mental health services (CAMHS) stimulates hope, destigmatization, and more culturally and developmentally appropriate support. Nevertheless, the collaboration between YPSWs and non-peer colleagues remains challenging, as it requires services to embed a new type of expert into practice. To stimulate the involvement of YPSWs in practice, this study reports on 27 semi-structured interviews with YPSWs and non-peer colleagues to provide insight into the barriers and facilitators in the collaboration process. The study took place in the Netherlands. A total of 10 interviews with YPSWs, and 17 interviews with non-peer colleagues in different healthcare occupations in CAMHS were conducted. Overall, the participants perceived relatively more barriers compared to facilitators in the collaboration process. Barriers to operate efficiently with YPSWs in multidisciplinary teams included: condescending attitudes and professional stigma towards YPSWs; concerns for YPSW boundaries; bureaucratic and clinical language usage by non-peer colleagues; conflicts due to different sets of expertise; and, lack of role clarity and guidelines for YPSWs. To improve the partnership between YPSWs and non-peer colleagues, participants described the importance of supervision and monitoring of YPSW activities. Moreover, participants also stressed the need for clear guidelines, and introduction and evaluation sessions to facilitate the collaboration process. While YPSWs seem to be an asset to CAMHS, there are a number of barriers to overcome. To overcome these barriers, organizational commitment, supervision (especially from peer colleagues), flexibility by non-peer colleagues, training non-peer staff to support YPSWs, and consistent evaluation of the implementation of YPSWs in services is recommended.

A comparison of methods to harmonize cortical thickness measurements across scanners and sites.

Results of neuroimaging datasets aggregated from multiple sites may be biased by site-specific profiles in participants' demographic and clinical characteristics, as well as MRI acquisition protocols and scanning platforms. We compared the impact of four different harmonization methods on results obtained from analyses of cortical thickness data: (1) linear mixed-effects model (LME) that models site-specific random intercepts (LMEINT), (2) LME that models both site-specific random intercepts and age-related random slopes (LMEINT+SLP), (3) ComBat, and (4) ComBat with a generalized additive model (ComBat-GAM). Our test case for comparing harmonization methods was cortical thickness data aggregated from 29 sites, which included 1,340 cases with posttraumatic stress disorder (PTSD) (6.2-81.8 years old) and 2,057 trauma-exposed controls without PTSD (6.3-85.2 years old). We found that, compared to the other data harmonization methods, data processed with ComBat-GAM was more sensitive to the detection of significant case-control differences (Χ2(3) = 63.704, p < 0.001) as well as case-control differences in age-related cortical thinning (Χ2(3) = 12.082, p = 0.007). Both ComBat and ComBat-GAM outperformed LME methods in detecting sex differences (Χ2(3) = 9.114, p = 0.028) in regional cortical thickness. ComBat-GAM also led to stronger estimates of age-related declines in cortical thickness (corrected p-values < 0.001), stronger estimates of case-related cortical thickness reduction (corrected p-values < 0.001), weaker estimates of age-related declines in cortical thickness in cases than controls (corrected p-values < 0.001), stronger estimates of cortical thickness reduction in females than males (corrected p-values < 0.001), and stronger estimates of cortical thickness reduction in females relative to males in cases than controls (corrected p-values < 0.001). Our results support the use of ComBat-GAM to minimize confounds and increase statistical power when harmonizing data with non-linear effects, and the use of either ComBat or ComBat-GAM for harmonizing data with linear effects.

Exploring the course of adolescent anxiety and depression: associations with white matter tract microstructure.

Cross-sectional Diffusion Tensor Imaging (DTI) studies have reported alterations in white matter (WM) microstructure in adolescents with internalizing psychopathology. Yet, longitudinal studies investigating the course of WM microstructure are lacking. This study explored WM alterations and its relation to clinical symptoms over time in adolescents with internalizing disorders. DTI scans were acquired at baseline and after three months in 22 adolescents with clinical depression and comorbid anxiety (INT), and 21 healthy peers (HC) (age: 12-18). Tract-based spatial statistics was used for three voxelwise analyses: i) changes in WM microstructure between and within the INT and HC group; ii) associations between changes in symptom severity and changes in WM microstructure within youths with INT; and iii) associations between baseline WM parameters with changes in symptom severity within youths with INT. Data did not reveal changes in WM microstructure between or within groups over three months' time nor associations between changes in WM microstructure and changes in self-reported symptoms (analyses corrected for age, gender and puberty stage). Lower baseline levels of fractional anisotropy (FA) in the right posterior corona radiata (PCR) and right cingulum were associated with a higher decrease of depressive symptoms within the INT group. Post hoc analysis of additional WM parameters in the significant FA clusters showed that higher levels of baseline mean diffusivity and radial diffusivity in the PCR were associated with a lower decrease in depressive symptoms. Baseline WM microstructure characteristics were associated with a higher decrease in depressive symptoms over time. These findings increase our understanding of neurobiological mechanisms underlying the course of internalizing disorders in adolescents.

Clinical decision support methods for children and youths with mental health disorders in primary care.

BACKGROUND: Mental health disorders among children and youths are common and often have negative consequences for children, youths, and families if unrecognized and untreated. With the goal of early recognition, primary care physicians (PCPs) play a significant role in the detection and referral of mental disorders. However, PCPs report several barriers related to confidence, knowledge, and interdisciplinary collaboration. Therefore, initiatives have been taken to assist PCPs in their clinical decision-making through clinical decision support methods (CDSMs). OBJECTIVES: This review aimed to identify CDSMs in the literature and describe their functionalities and quality. METHODS: In this review, a search strategy was performed to access all available studies in PubMed, PsychINFO, Embase, Web of Science, and COCHRANE using keywords. Studies that involved CDSMs for PCP clinical decision-making regarding psychosocial or psychiatric problems among children and youths (0-24 years old) were included. The search was conducted according to PRISMA-Protocols. RESULTS: Of 1,294 studies identified, 25 were eligible for inclusion and varied in quality. Eighteen CDSMs were described. Fourteen studies described computer-based methods with decision support, focusing on self-help, probable diagnosis, and treatment suggestions. Nine studies described telecommunication methods, which offered support through interdisciplinary (video) calls. Two studies described CDSMs with a combination of components related to the two CDSM categories. CONCLUSION: Easy-to-use CDSMs of good quality are valuable for advising PCPs on the detection and referral of children and youths with mental health disorders. However, valid multicentre research on a combination of computer-based methods and telecommunication is still needed.

Mental health problems among children and youths are common and have impacts, not only on the person affected but also on families and communities. They are often not recognized and acted upon by primary care providers (PCPs), such as general practitioners. This may be due to a lack of confidence in talking to young people or insufficient knowledge about mental health problems. PCPs make decisions about managing or referring these problems to mental health specialists, which can be assisted through clinical decision support methods (CDSMs). CDSMs can be divided into electronic and non-electronic. This study provided an overview of both types of CDSMs. We focused on the capabilities of CDSMs and how they help PCPs in their decision-making. More than half of the reviewed CDSMs were electronic CDSMs; several CDSMs involved telecommunication between PCPs and mental health specialists. Two of the CDSMs comprised a combination of components of both types of CDSMs. CDSMs offered patients more information about their health while providing PCPs with suggestions for their decision-making.

Psychiatric Emergencies in Minors: The Impact of Sex and Age.

OBJECTIVE: Little information is available on young children (age 4-12 years) with mental health problems who are seen by the psychiatric emergency services. We therefore described this population to identify (1) variables that differentiated children from those aged 13 to 18 years who had been referred for psychiatric emergency consultation; and (2) to describe sex differences. METHOD: We extracted data for a 9-year period from the records of the mobile psychiatric emergency services in 2 urban areas in the Netherlands. In this period, 79 children aged 4 to 12 years (37.2% girls) and 1695 children aged 12 to 18 years (62.2% girls) had been referred for psychiatric emergency consultation. Demographic and process factors were recorded. Clinical characteristics included diagnostic and statistical manual of mental disorders, 4th edition classifications and the Severity of Psychiatric Illness scale. Logistic regression analyses were used to examine differences between the girls and boys in the 2 age groups. RESULTS: Young children aged 4 to 12 years had been involved in 4.5% of all consultations of minors. In contrast with adolescents, a higher percentage of young children seen for emergency consultation were boys, and a lower percentage was admitted to a psychiatric hospital (7.7%). In boys and girls alike, a DSM classification of behavioral disorder was associated with younger age. CONCLUSIONS: The young group of children referred for psychiatric emergency consultation comprised relatively more children with behavioral disorders. Decisions to refer them for urgent psychiatric consultation seemed to be influenced by the suspicion of psychotic symptoms or of danger to themselves or others.

Family group conferences for suicidal adolescents: Promising results from naturalistic case study research.

Can thwarted belongingness and perceived burdensomeness, risk factors for suicidal adolescents, be turned around by family group conferences? In this case study on Nick, a 17-year-old who undertook six suicide attempts, we (including Nick) share insights and learning opportunities on how family group conferences can be used. The thematic analysis suggests that family group conferences might be a promising intervention for suicidal adolescents. For Nick, the conference was a turning point in his life, correcting perceptions of being a burden, pushing back passiveness, and boosting connection with and support from the broad social network.