Childhood aggression and the co-occurrence of behavioural and emotional problems : results across ages 3–16 years from multiple raters in six cohorts in the EU-ACTION project

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Author(s): Title: Year: Version: Copyright: Rights: Rights url: Please cite the original version: CC BY 4.0 https://creativecommons.org/licenses/by/4.0/ Childhood aggression and the co-occurrence of behavioural and emotional problems : results across ages 3–16 years from multiple raters in six cohorts in the EU-ACTION project © The Authors 2018 Published version Bartels, Meike; Hendriks, Anne; Mauri, Matteo; Krapohl, Eva; Whipp, Alyce; Bolhuis, Koen; Conde, Lucia Colodro; Luningham, Justin; Ip, Hill Fung; Hagenbeek, Fiona; Roetman, Peter; Gatej, Raluca; Lamers, Audri; Nivard, Michel; van Dongen, Jenny; Lu, Yi; Middeldorp, Christel; van Beijsterveldt, Toos; Vermeiren, Robert; Hankemeijer, Thomas; Kluft, Cees; Medland, Sarah; Lundström, Sebastian; Rose, Richard; Pulkkinen, Lea; Vuoksimaa, Eero; Korhonen, Tellervo; Martin, Nicholas G.; Lubke, Gitta; Finkenauer, Catrin; Fanos, Vassilios; Tiemeier, Henning; Lichtenstein, Paul; Plomin, Robert; Kaprio, Jaakko; Boomsma, Dorret I. Bartels, M., Hendriks, A., Mauri, M., Krapohl, E., Whipp, A., Bolhuis, K., Conde, L. C., Luningham, J., Ip, H. F., Hagenbeek, F., Roetman, P., Gatej, R., Lamers, A., Nivard, M., van Dongen, J., Lu, Y., Middeldorp, C., van Beijsterveldt, T., Vermeiren, R., . . . Boomsma, D. I. (2018). Childhood aggression and the co-occurrence of behavioural and emotional problems : results across ages 3–16 years from multiple raters in six cohorts in the EU-ACTION project. European Child and Adolescent Psychiatry, 27(9), 1105-1121. https://doi.org/10.1007/s00787-018-1169-1 2018 Vol.:(0123456789) 1 3 European Child & Adolescent Psychiatry (2018) 27:1105–1121 https://doi.org/10.1007/s00787-018-1169-1 ORIGINAL CONTRIBUTION Childhood aggression andtheco-occurrence ofbehavioural andemotional problems: results acrossages 3–16years frommultiple raters insix cohorts intheEU-ACTION project MeikeBartels1,2,3 · AnneHendriks1,2· MatteoMauri4· EvaKrapohl5· AlyceWhipp6· KoenBolhuis7· LuciaColodroConde8· JustinLuningham9· HillFungIp1,2· FionaHagenbeek1,2· PeterRoetman10· RalucaGatej10· AudriLamers10· MichelNivard1,2· JennyvanDongen1,2· YiLu11· ChristelMiddeldorp1,3,12· ToosvanBeijsterveldt1,2· RobertVermeiren10,13· ThomasHankemeijer14· CeesKluft15· SarahMedland8· SebastianLundström16,17· RichardRose18· LeaPulkkinen19· EeroVuoksimaa6,20· TellervoKorhonen6,20,21· NicholasG.Martin22· GittaLubke9· CatrinFinkenauer1,23· VassiliosFanos4· HenningTiemeier7,24,25· PaulLichtenstein11· RobertPlomin5· JaakkoKaprio6,20· DorretI.Boomsma1,2,3 Received: 27 January 2017 / Accepted: 16 May 2018 / Published online: 29 May 2018 © The Author(s) 2018 Abstract Childhood aggression and its resulting consequences inflict a huge burden on affected children, their relatives, teachers, peers and society as a whole. Aggression during childhood rarely occurs in isolation and is correlated with other symptoms of childhood psychopathology. In this paper, we aim to describe and improve the understanding of the co-occurrence of aggression with other forms of childhood psychopathology. We focus on the co-occurrence of aggression and other childhood behavioural and emotional problems, including other externalising problems, attention problems and anxiety–depression. The data were brought together within the EU-ACTION (Aggression in Children: unravelling gene-environment interplay to inform Treatment and InterventiON strategies) project. We analysed the co-occurrence of aggression and other childhood behavioural and emotional problems as a function of the child’s age (ages 3 through 16years), gender, the person rating the behaviour (father, mother or self) and assessment instrument. The data came from six large population-based European cohort studies from the Netherlands (2x), the UK, Finland and Sweden (2x). Multiple assessment instruments, including the Child Behaviour Checklist (CBCL), the Strengths and Difficulties Questionnaire (SDQ) and Multidimensional Peer Nomination Inventory (MPNI), were used. There was a good representation of boys and girls in each age category, with data for 30,523 3to 4-year-olds (49.5% boys), 20,958 5to 6-year-olds (49.6% boys), 18,291 7to 8-year-olds (49.0% boys), 27,218 9to 10-year-olds (49.4% boys), 18,543 12to 13-year-olds (48.9% boys) and 10,088 15to 16-year-olds (46.6% boys). We replicated the well-established gender differences in average aggression scores at most ages for parental ratings. The gender differences decreased with age and were not present for self-reports. Aggression co-occurred with the majority of other behavioural and social problems, from both externalising and internalising domains. At each age, the co-occurrence was particularly prevalent for aggression and oppositional and ADHD-related problems, with correlations of around 0.5 in general. Aggression also showed substantial associations with anxiety–depression and other internalizing symptoms (correlations around 0.4). Co-occurrence for self-reported problems was somewhat higher than for parental reports, but we found neither rater differences, nor differences across assessment instruments in co-occurrence patterns. There were large similarities in co-occurrence patterns across the different European countries. Finally, co-occurrence was generally stable across age and sex, and if any change was observed, it indicated stronger correlations when children grew older. We present an online tool to visualise these associations as a function of rater, gender, instrument and cohort. In addition, we present a description of the full EU-ACTION projects, its first results and the future perspectives. This article is part of the focused issue ‘Conduct Disorder and Aggressive Behaviour in Children and Adolescents’. Extended author information available on the last page of the article 1106 European Child & Adolescent Psychiatry (2018) 27:1105–1121 1 3 Keywords Aggression· Childhood· Comorbidity· Co-occurence· Behavioural and emotional problems Introduction Prevention strategies and behavioural and pharmacological interventions for aggressive behaviour and conduct disorder are effective in some children, although a substantial number of children do not respond to prevention strategies, do not benefit from interventions or may even experience an escalation of symptom [9, 10]. One reason for this might be the heterogeneity of aggression. A second reason, which is related to the heterogeneous nature and occurrence of childhood aggressive problems, might be that children with aggressive problems often have co-occurring problems. Due to a multitude of problems, children may not respond to prevention or intervention targeting aggression, or the co-occurring problems may mask aggression, leaving it untreated. In 12 year olds, Bartels and colleagues [11] observed that at least half of the children who were deviant on aggressive behaviour (T score ≥ 67) also were deviant on rule-breaking behaviour, i.e. at least 50% of the children with clinical levels of aggression also showed a co-occurrence of clinically relevant rule-breaking behaviour. Strong links between aggression and attention-deficit/hyperactivity disorder (ADHD) [12] are often seen in the clinical presentation of ADHD [13], and it has been suggested that the strong association between ADHD and aggression may explain gender differences in clinical referral. For example, teachers rated boys with a DSM-based ADHD diagnosis as having higher levels of attention problems and aggression than girls with a similar ADHD diagnosis [14]. Aggression not only co-occurs with psychopathologies on the externalizing spectrum. Aggression also tends to co-occur with anxiety, and it has been proposed that anxiety needs to be given a central role in the treatment of aggression [15]. In more extreme cases, aggression was not found to co-occur solely with ADHD symptoms, such as attention problems, or anxiety but rather with both of these forms of psychopathology. This pattern of behavioural problems is referred to as the dysregulation profile [16–18], and has been described as a potential marker for severe childhood psychopathologies [19, 20]. To gain insight into the aetiology of individual differences in childhood aggression and in co-occurring behavioural and emotional problems, ACTION (Aggression in Children: unravelling gene-environment interplay to inform Treatment and InterventiON strategies; http://www.actio n-eupro ject. eu/) created a consortium with access to large childhood prospective twin, population-based and clinical cohorts. ACTION brings together multiple large cohort studies in genetically informative populations (see Table1 and Appendix 1). The focus of ACTION is to inform on the aetiology of differences in aggression between children by unravelling its genetic architecture using univariate, multivariate and longitudinal genetic and epigenetic modelling in twin and genetic and epigenetic association studies. A strong focus of ACTION includes biomarker and metabolomics research [21]. In the current study, the aim is to describe and improve the understanding of the co-occurrence of aggression with other forms of childhood psychopathology by analysing data from the large ACTION phenotype databases in large samples of children. We analysed data on aggression and common emotional and behavioural problems in children aged 3–16years. Multiple raters, i.e. fathers and mothers during childhood and also youngsters themselves during adolescence, provided information on different aggression measures. The two Dutch cohorts (The Netherlands Twin Register and Generation R) used the Achenbach System of Empirically Based Assessment (ASEBA [22]), which included the Child Behaviour Checklist (CBCL) and the Youth Self-Report (YSR). The UK-based Twins Early Development Study employed the Strengths and Difficulties Questionnaire (SDQ [23]). The Swedish Twin study of Child and Adolescent Development used the Autism–Tics, ADHD and other Comorbidities inventory (A-TAC [24]), and the Swedish Child and Adolescent Twin Study the ASEBA questionnaires. In Finland, the Multidimensional Peer Nomination Inventory (MPNI) was employed. For several age groups from different countries, aggression assessed with identical instruments was available. For example, parental ratings with the CBCL were available for 7to 8-year-olds and 12to 13-year-olds in the Netherlands (NTR) and Sweden (TCHAD). In addition to indicators of aggression, all instruments provided quantitative scores on other childhood psychopathologies from the externalising and internalising spectrum. We investigated patterns of co-occurrence across age, rater, instrument and gender. Methods Participants Six large population-based cohorts (NTR and GenR from the Netherlands, TEDS from the UK, CATSS and TCHAD from Sweden and FinnTwin12 from Finland) analysed the co-occurrence of aggression measures with other psychopathologies. For a link to cohort-specific websites, see Table1 and for a detailed description of the cohorts, please also see Appendix I. The twin cohorts were requested to randomly select one of the twins per pair, with an equal 1107European Child & Adolescent Psychiatry (2018) 27:1105–1121 1 3 representation of firstand second-born children, to obtain parameter estimates that were not biased due to effects of family clustering. In our previous work [25], we have shown that children with an illness or disability that interfered with daily function tend to display more than twice as much problem behaviour across the entire age range compared to other twins, so they were excluded. Age-, genderand raterspecific sample sizes are presented in Tables2, 3, 4 and 5. Data were available for 30,523 3to 4-year-olds (49.5% boys), 20,958 5to 6-year-olds (49.6% boys), 18,291 7to 8-year-olds 49% boys), 27,218 9to 10-year-olds (49.4% boys), 18,543 11to 12-year-olds (48.9% boys) and 10,088 15to 16-yearolds (46.6% boys). Due to the longitudinal structure of most cohorts, these data points are not statistically independent observations, since overlapping groups of children were assessed at multiple ages. All data used in the current analyses were collected under protocols that have been approved by the appropriate ethics committees, and studies were performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments. Measures The Child Behaviour Checklist (CBCL) 1,5–5 [26] and 6–18 [22] were used by GenR (age 6 and 10), TCHAD (ages 8, 13 and 16) and NTR (ages 3, 7, 9 and 12). The Youth SelfReport (YSR) [22] was used by TCHAD (ages 13 and 16). The CBCL and YSR are part of the Achenbach System of Empirical-Based Assessment and designed to measure childhood and adolescent behavioural and emotional problems. The response format was on a three-point scale (with response options ‘not true’, ‘somewhat true or sometimes true’ and ‘very or often true’). With the CBCL 1,5–5 seven syndrome scales are obtained (emotionally reactive, anxious–depressed, somatic complaints, withdrawn, overactive behaviour, aggressive behaviour, sleep problems), while with the CBCL 6–18 eight syndrome scales are obtained (anxious–depressed, withdrawn, somatic complaints, social problems, thought problems, attention problems, rule-breaking behaviour, aggressive behaviour). With the YSR, eight syndrome scales are obtained (anxious–depressed, somatic complaints, withdrawn–depressed, social problems, thought problems, attention problems, rule-breaking behaviour and aggressive behaviour). The Strengths and Difficulties Questionnaire (SDQ) [23] was used by TEDs (ages 4, 7, 9, 16) and CATSS (age 15). The SDQ is a 25-item questionnaire designed to measure common mental health problems during childhood and adolescence. Ratings were on a three-point scale (with response options ‘not true’, ‘somewhat true’ and ‘certainly true’). The 25 items form 5 scales, emotional symptoms, conduct problems, hyperactivity/inattention, peer relationship problem Table 1 Sample sizes for different age groups of the ACTION cohort Register Age Webpages 1–2 3–4 5–6 7–8 9–10 11–12 13–14 15–16 17–18 19–20 21–22 NTR 106.7 37.9 31.2 23.2 18.1 15.1 8.0 5.7 1.7 6.0 http://www.Tweel ingen regis ter.org Qtwin 2.4 1.4 1.8 0.9 http://www.qimrb ergho fer.edu.au/qtwin / TEDS 12.6 28.4 29.2 6.8 11.8 6.7 10.2 http://www.Teds.ac.uk TCHAD 2.0 2.0 2.0 2.0 http://ki.se/en/meb/twin-study -of-child -and-adole scent -devel opmen t-tchad CATSS 22.3 6.5 11.1 8.7 http://ki.se/en/meb/the-child -and-adole scent -twin-study -in-swede n-catss FT12 5.3 4.7 4.2 1.3 https ://wiki.helsi nki.fi/displ ay/twine ng/Twins tudy GenR 4.5 5.2 7.8 5.0 http://www.gener ation r.nl Indiv (x 1000) 123.8 71.5 39 54.4 40.4 45 22.8 24.7 8.1 8 2.2 1108 European Child & Adolescent Psychiatry (2018) 27:1105–1121 1 3 and prosocial behaviour. The conduct problem scale was used as a proxy for aggressive behaviour. NTR used the short Devereux Child Behaviour (DCB) rating scale for 5year olds. The DCB consists of questions about problem behaviour in children rated by the parents [27]. The short version includes 42 items that measure seven different aspects of problem behaviour in children. Parents were asked to indicate on a five-point scale whether the statements were applicable (0 = never, 1 = rarely, 2 = occasionally, 3 = frequently, 4 = very frequently). The items of the questionnaire cover the following aspects of problem behaviour: emotional liability (five items, e.g. “markedly impatient”), social isolation (three items, e.g. “quite timid or shy”), aggressive behaviour (seven items, e.g. “hits, bites and scratches other children”), attention problems (five items, e.g. “jumps from one activity to another”), dependency (five items, e.g. “does not want to do things for himself”), anxiety problems (six items, e.g. “concern about his physical health”) and physical coordination (five items, e.g. “gets dirty and untidy”). In 9and 12-year-old in the CATSS sample from Sweden, information on ODD/CD and other psychopathologies was gathered through a telephone interview with parents, using The Autism–Tics, ADHD and other Comorbidities inventory (A-TAC) [24]. A-TAC is a comprehensive screening interview for autism spectrum disorders (ASDs), attentiondeficit/hyperactivity disorder (AD/HD), tic disorders (TD), developmental coordination disorder (DCD), learning disorders (LD) and other childhood mental disorders that have been associated with these neurodevelopmental disorders. In the FinnTwin12 sample from Finland, aggressive behaviour was assessed at ages 12, 14 and 17 by versions of the Multidimensional Peer Nomination Inventory (MPNI). The MPNI includes 37 items comprising three subscales, the two subscales used here include: externalising behavioural problems (aggression, hyperactivity–impulsivity and inattention) and internalising emotional problems (anxiety and depression) [28]. For each question (e.g. ‘Does the child tease smaller or weaker children?’), the informant rated how well the description fit the twin in question on a scale from 0 (the characteristic does not fit the child at all) to 3 (the characteristic fits the child very well). Parents rated the children at age 12, and the child rated him or herself at ages 14 and 17years. Analyses To ensure homogenous handling of data and identical analyses, all cohorts received a standard operating procedure that specified details of the comorbidity analyses. Following the SOP average scores and Pearson correlations for aggression with all other scales assessing psychopathology was obtained by a local analyst using their preferred statistical Table 2 Means and standard deviations for the empirical scales of the Child Behaviour Checklist (CBCL) 1.5–5 ASEBACBCL 1.5–5 Rater Age Sex N Aggressive behaviour Attention problems Withdrawn Anxious– depressed Emotional reactivity Somatic complaints Sleep problems Gen R Mother 3 Boy 2271 7.58 (5.37) 1.56 (1.64) 0.98 (1.43) 1.08 (1.56) 1.67 (1.82) 1.61 (1.61) 1.98 (2.16) 3 Girl 2246 6.37 (4.91) 1.44 (1.56) 0.84 (1.24) 0.99 (1.48) 1.55 (1.79) 1.57 (1.74) 1.92 (2.09) Gen R Father 3 Boy 1840 8.24 (5.60) 1.80 (1.72) 1.03 (1.40) 1.16 (1.54) 1.86 (1.99) 1.64 (1.79) 2.08 (2.24) 3 Girl 1897 7.14 (5.03) 1.55 (1.61) 0.93 (1.27) 1.10 (1.52) 1.67 (1.89) 1.52 (1.67) 1.91 (2.04) NTR Mother 3 Boy 9277 11.48 (6.85) 2.34 (1.97) 1.47 (1.69) 1.95 (1.99) 2.92 (2.66) 1.76 (1.84) 1.86 (2.18) 3 Girl 9360 9.95 (6.30) 2.03 (1.84) 1.39 (1.56) 2.05 (2.00) 2.96 (2.57) 1.86 (1.92) 1.93 (2.20) Gen R Mother 6 Boy 2887 6.65 (5.79) 1.84 (1.85) 1.33 (1.64) 1.51 (1.93) 1.97 (2.38) 1.56 (1.89) 1.49 (1.93) 6 Girl 2856 5.93 (4.90) 1.30 (1.59) 1.02 (1.35) 1.46 (1.83) 1.68 (2.06) 1.61 (1.89) 1.51 (1.93) 1109European Child & Adolescent Psychiatry (2018) 27:1105–1121 1 3 Table 3 Means and standard deviations for the empirical scales of the ASEBA taxonomy (CBCL and YSR) ASEBA 6–18 Rater age Sex N Aggressive behaviour Attention problems Rule breaking Social problems Anxious– depressed Withdrawn– depressed Thought problems Somatic complaints NTR Mother 7 Boy 5720 5.74 (5.29) 3.48 (3.13) 1.58 (2.02) 2.17 (2.48) 2.12 (2.53) 1.14 (1.63) 1.66 (2.14) 1.10 (1.57) 7 Girl 5853 4.38 (4.28) 2.56 (2.79) 1.07 (1.55) 1.91 (2.24) 2.31 (2.58) 1.09 (1.53) 1.29 (1.77) 1.26 (1.68) NTR Father 7 Boy 4134 4.98 (4.75) 3.13 (2.97) 1.37 (1.85) 1.80 (2.18) 1.62 (2.04) 0.95 (1.45) 1.33 (1.85) 0.81 (1.28) 7 Girl 4182 3.81 (4.01) 2.26 (2.59) 0.95 (1.47) 1.58 (1.95) 1.77 (2.19) 0.86 (1.36) 0.91 (1.46) 0.91 (1.39) TCHAD Parent 8 Boy 552 5.49 (5.42) 1.91 (2.40) 1.18 (1.63) 0.99 (1.57) 1.74 (2.61) 0.99 (1.24) 0.13 (0.59) 0.56 (1.04) 8 Girl 534 4.77 (4.89) 1.32 (2.07) 0.79 (1.28) 0.84 (1.52) 2.01 (2.75) 1.13 (1.35) 0.13 (0.53) 0.75 (1.28) NTR Mother 9 Boy 4543 5.09 (5.16) 3.43 (3.21) 1.43 (2.06) 2.05 (2.54) 2.14 (2.67) 1.24 (1.75) 1.61 (2.14) 1.07 (1.59) 9 Girl 4689 3.94 (4.20) 2.42 (2.75) 0.93 (1.55) 1.83 (2.34) 2.39 (2.80) 1.13 (1.64) 1.25 (1.80) 1.28 (1.78) NTR Father 9 Boy 3210 4.18 (4.57) 3.07 (3.11) 1.17 (1.78) 1.72 (2.33) 1.65 (2.21) 1.00 (1.60) 1.27 (1.88) 0.83 (1.38) 9 Girl 3255 3.34 (3.82) 2.17 (2.64) 0.79 (1.38) 1.55 (2.07) 1.86 (2.33) 0.91 (1.46) 0.93 (1.48) 0.88 (1.39) Gen R Mother 10 Boy 2250 3.26 (4.08) 3.76 (3.35) 1.24 (1.67) 1.84 (2.35) 2.14 (2.72) 1.29 (1.78) 1.80 (2.36) 1.34 (1.92) 10 Girl 2310 2.54 (3.34) 2.81 (3.00) 0.81 (1.27) 1.62 (2.13) 2.28 (2.64) 1.01 (1.48) 1.50 (2.01) 1.59 (2.02) Gen R Father 10 Boy 1624 3.28 (4.16) 3.81 (3.31) 1.36 (1.69) 1.96 (2.35) 2.05 (2.54) 1.36 (1.74) 1.92 (2.39) 1.25 (1.72) 10 Girl 1670 1.47 (3.24 2.87 (2.81) 0.89 (1.30) 1.71 (2.01) 2.11 (2.58) 1.00 (1.48) 1.43 (1.82) 1.41 (1.80) NTR Mother 12 Boy 3870 4.18 (4.63) 3.21 (3.20) 1.28 (1.87) 1.72 (2.45) 1.90 (2.56) 1.25 (1.81) 1.36 (2.02) 0.89 (1.41) 12 Girl 4010 3.27 (3.82) 2.12 (2.59) 0.79 (1.37) 1.46 (2.17) 2.18 (2.70) 1.10 (1.76) 1.03 (1.64) 1.03 (1.58) NTR Father 12 Boy 2764 3.65 (4.36) 3.02 (3.14) 1.15 (1.78) 1.58 (2.39) 1.59 (2.39) 1.10 (1.76) 1.12 (1.77) 0.72 (1.26) 12 Girl 2839 2.80 (3.52) 1.95 (2.49) 0.71 (1.29) 1.23 (1.90) 1.70 (2.29) 0.95 (1.58) 0.77 (1.35) 0.73 (1.26) TCHAD Parent 13 Boy 535 3.90 (4.30) 1.59 (2.08) 1.14 (1.56) 0.79 (1.29) 1.28 (2.01) 1.01 (1.31) 0.13 (0.60) 0.62 (1.13) 13 Girl 522 3.71 (4.60) 1.21 (1.97) 0.82 (1.52) 0.75 (1.53) 2.06 (3.31) 1.27 (1.64) 0.18 (0.67) 0.78 (1.37) TCHAD Self 13 Boy 560 8.07 (4.96) 3.57 (2.78) 2.94 (2.26) 2.02 (2.05) 3.78 (3.72) 2.12 (1.88) 1.31 (1.53) 1.47 (1.76) 13 Girl 551 7.94 (4.33) 3.75 (2.64) 2.64 (2.36) 1.89 (1.80) 5.09 (4.75) 2.42 (1.91) 1.76 (1.98) 2.19 (2.36) TCHAD Parent 16 Boy 532 3.06 (3.83) 1.24 (1.85) 1.12 (1.54) 0.57 (1.08) 1.14 (1.87) 0.90 (1.27) 0.10 (0.41) 0.65 (1.15) 16 Girl 507 3.25 (3.97) 1.21 (1.98) 1.11 (1.94) 0.55 (1.17) 2.18 (3.44) 1.11 (1.51) 0.18 (0.68) 1.09 (1.78) TCHAD Self 16 Boy 583 7.10 (4.38) 3.44 (2.69) 2.93 (2.23) 1.77 (1.91) 2.97 (3.61) 2.01 (1.89) 1.08 (1.65) 1.21 (1.60) 16 Girl 606 7.77 (4.41) 4.14 (2.69) 3.02 (2.39) 1.78 (1.76) 5.60 (4.66) 2.85 (2.07) 1.45 (1.78) 2.34 (2.50) 1110 European Child & Adolescent Psychiatry (2018) 27:1105–1121 1 3 software. Average scores and correlations were computed by gender and age of children, separately for each rater and country. Results were uploaded to a shared server. Given the large datasets included in these analyses, leading to significance even if differences between average scores or between correlations being relatively small, we interpreted all results relative to each other and took the 95% confidence intervals into account. With the multi-instrument, multi-rater and multi-age assessments of aggression and of other emotional and behavioural problems, we established whether co-occurrence was stronger or weaker given different measurement instruments, raters and ages. Results Tables2, 3, 4 and 5 provide an overview of the sample sizes and mean levels of aggression and all other traits. We replicated the well-established gender differences in average aggression scores at most ages for parental ratings. The gender difference was smaller or close to absent for selfreports. For example, while the difference between boys and girls is in general about 1.5–2 points on the CBCL and SDQ parental reports, the differences based on self-report ranged between 0.05 and 0.67. Mean levels based on similar instruments across countries were almost identical. For example, the mean level of aggression based on maternal ratings of 7-year-old boys in the Netherlands was 5.74 (SD 5.29), while mean level of aggression based on parental ratings of 8-year-old boys in Sweden was 5.49 (SD 5.42). We observed differences between raters in nearly every country in the same direction. Based on maternal ratings, higher levels of psychopathology were seen than when based on paternal ratings. These differences were observed both for boys and girls, at ages 3–12 for the CBCL and SDQ. The exception was an absence of differences in maternal and paternal ratings when using the Devereux Child Behaviour rating scale. With respect to our main question of the co-occurrence of aggression and other behavioural and emotional problems, findings are presented in Tables6, 7, 8 and 9. Strong correlations were found between aggression and other externalising traits, especially rule-breaking behaviour. Correlations of almost similar strength were also observed for aggression and attention problems and hyperactivity. However, correlations were lower between aggression and internalising behaviours including withdrawn–depression and somatic complaints. Correlations between aggression and all other emotional and behavioural problems and their 95% confidence intervals are also provided in an interactive application which can be found at http://www.actio n-eupro ject.eu/ Comor bidit yChil dAggr essio n. Table 4 Means and standard deviations for the scales of the Strengths and Difficulties Questionnaire (SDQ) SDQ Rater Age Sex N Conduct problems Hyperactivity Peer problems Emotion–anxiety Prosocial TEDS Parent 4 Boy 3581 2.23 (1.58) 4.35 (2.34) 1.58 (1.51) 1.35 (1.39) 7.07 (1.85) 4 Girl 3788 1.93 (1.49) 3.64 (2.20) 1.34 (1.41) 1.42 (1.47) 7.66 (1.77) TEDS Parent 7 Boy 2740 1.89 (1.73) 3.94 (2.61) 1.05 (1.46) 2.02 (1.74) 7.93 (1.84) 7 Girl 2892 1.45 (1.47) 3.09 (2.35) 0.83 (1.23) 2.28 (1.82) 8.54 (1.55) TEDS Parent 9 Boy 1055 1.35 (1.43) 3.56 (2.45) 1.05 (1.56) 1.47 (1.67) 7.91 (1.85) 9 Girl 1245 1.08 (1.30) 2.68 (2.08) 0.91 (1.33) 1.82 (1.88) 8.67 (1.48) TEDS Self 9 Boy 1055 2.39 (1.89) 4.13 (2.72) 1.93 (1.74) 2.99 (2.28) 7.39 (1.95) 9 Girl 1245 1.92 (1.69) 3.43 (2.15) 1.76 (1.71) 3.38 (2.40) 8.38 (1.62) TEDS Parent 12 Boy 1828 1.42 (1.48) 3.33 (2.36) 1.18 (1.58) 1.67 (1.80) 8.25 (1.74) 12 Girl 2117 1.16 (1.33) 2.28 (1.99) 0.93 (1.35) 1.90 (1.94) 8.86 (1.50) TEDS Self 12 Boy 1828 2.09 (1.48) 3.85 (2.33) 1.47 (1.63) 1.94 (1.93) 6.98 (1.96) 12 Girls 2117 1.64 (1.50) 3.09 (2.16) 1.22 (1.48) 2.43 (2.10) 7.95 (1.69) CATSS Parent 15 Boys 2083 0.93 (1.21) 2.34 (2.23) 1.29 (1.66) 0.83 (1.34) 8.03 (1.85) 15 Girls 2199 0.99 (1.30) 1.72 (1.93) 1.21 (1.61) 1.43 (1.76) 8.49 (1.80) CATSS Self 15 Boys 2258 1.78 (1.52) 3.42 (2.19) 1.79 (1.55) 2.00 (1.80) 7.37 (1.88) 15 Girls 2806 1.73 (1.39) 3.42 (2.19) 1.79 (1.55) 2.00 (1.80) 7.37 (1.88) TEDS Parent 16 Boys 2134 1.26 (1.40) 2.58 (2.08) 7.92 (2.00) 16 Girls 2632 1.18 (1.35) 1.93 (1.80) 8.50 (1.83) TEDS Self 16 Boys 2134 1.78 (1.52) 3.60 (2.32) 1.58 (1.46) 1.95 (1.86) 6.52 (1.97) 16 Girls 2632 1.58 (1.44) 3.50 (2.28) 1.53 (1.46) 3.43 (3.32) 7.64 (1.77) 1111European Child & Adolescent Psychiatry (2018) 27:1105–1121 1 3 Some more remarkable findings included the relatively low correlation between aggression and obsessive–compulsive behaviour and the similarly relatively low correlation between aggression and social isolation and aggression and dependency. We, furthermore, observed a relatively low correlation between aggression and peer problems from the SDQ (ranging from 0.18 to 31). However, CBCL social problems showed stronger correlations with aggression (ranging from 0.34 to 0.66). The overarching picture that emerged suggests that correlations are largely stable across rater and age. If any change is observed, it is indicative of stronger correlations when children grow older. The correlations patterns of boys are markedly similar to the correlational patterns of girls. The only exception was the ATAC-based correlation between ODD/CD and OCD based on parental ratings at age 12. Correlations were stronger when based on the CBCL in comparison to the other measures, especially for parental ratings, while the ATAC, which is a clinical interview rather than a survey, provided somewhat lower correlations. The Devereux Child Behaviour (DCB) rating scale provides the interesting finding of similar strength in correlations between aggressive behaviour and attention problems and anxiety problems, but also with physical coordination problems. Discussion One of the aims of ACTION is to describe and improve the understanding of the co-occurrence of aggression with other forms of childhood psychopathology. Here, we presented the correlations of aggression with other psychopathologies in large European samples of children between ages 3 and 16years old. We showed that aggression co-occurred with almost all other behavioural and social problems. More specifically, aggression co-occurred with oppositional and ADHD-related problems, and at later ages with rule-breaking. In addition to the high correlations of aggression with externalising problems, we also observed substantial associations with anxiety–depression and other internalising symptoms. This co-occurrence of internalising and externalising problems has previously been shown to persist over childhood and adolescence [29]. Both for externalising and internalising problems, the patterns of co-occurrence were largely gender and rater independent, and were similar even when aggression and the other psychopathologies were assessed by different instruments, such as the CBCL and the SDQ. Also, there were large similarities in co-occurrence patterns across countries in the Northern part of Europe. In ACTION, we compared co-occurrence patterns across different countries and cultures. These comparisons are somewhat hampered by the fact that in almost all cases Table 5 Means and standard deviations for the scales of the Devereux Child Behaviour rating scale (DCB), Autism–Tics, ADHD and other Comorbidities inventory (A-TAC) and Multidimensional Peer Nomination Inventory (MPNI) DCB Rater Age Sex N Aggressive behaviour Attention problems Social isolation Anxiety problems Emotion liability Dependency Physical skill NTR Mother 5 Boy 7520 12.35 (3.77) 11.87 (3.57) 4.26 (1.45) 10.66 (3.29) 11.67 (3.50) 11.45 (3.05) 9.86 (3.13) 5 Girl 7695 11.68 (3.42) 11.32 (3.44) 4.36 (1.40) 10.99 (3.40) 11.19 (3.33) 10.73 (2.87) 8.45 (2.71) NTR Father 5 Boy 6808 12.65 (3.84) 12.02 (3.34) 4.40 (1.47) 10.84 (3.22) 11.78 (3.29) 11.70 (3.03) 10.26 (3.13) 5 Girl 6985 12.05 (3.55) 11.61 (3.26) 4.46 (1.43) 11.23 (3.30) 11.40 (3.22) 11.11 (2.85) 9.05 (2.88) A-TAC Rater Age Sex N CD ADHD Autism ODD CATSS Parent 9 Boy 5610 0.11 (0.39) 2.50 (3.42) 1.00 (1.83) 0.52 (0.91) 9 Girl 5516 0.08 (0.32) 1.65 (2.72) 0.63 (1.33) 0.41 (0.81) CATSS Parent 12 Boy 1649 0.11 (0.11) 2.39 (3.25) 0.99 (1.82) 0.49 (0.87) 12 Girl 1598 0.05 (0.24) 1.36 (2.34) 0.60 (1.24) 0.32 (0.66) MPNI Rater Age Sex N Aggression Inattention Hyperactive– impulsivity Social anxiety Depression Prosocial FT12 Parent 12 Boy 1188 0.63 (0.42) 0.82 (0.52) 0.82 (0.54) 0.79 (0.61) 0.75 (0.43) 1.93 (0.37) 12 Girl 1173 0.54 (0.39) 0.57 (0.45) 0.63 (0.47) 0.87 (0.61) 0.78 (0.43) 2.03 (0.37) 1112 European Child & Adolescent Psychiatry (2018) 27:1105–1121 1 3 more than one parameter varies between the different countries and cultures. For example, both NTR, a Dutch sample, and TEDs, a UK sample, have parental ratings at age 9, but NTR used the CBCL while TEDS used the SDQ. Any differences in correlations may thus be attributable to cultural differences or country differences between the Netherlands and the UK, instrument differences or any other protocol or unobserved difference. However, given all these sources of difference in this large co-occurrence study, it is even more striking that most correlations are so similar. The large associations of aggression with other emotional and behavioural problems may form one of the obstacles for prevention and treatment of aggression. These findings indicate that an exclusive focus on aggression might not be the most feasible approach for the development of effective prevention and intervention programs. The complexity of psychopathology, partly due to the co-occurrence of behavioural and emotional problems, needs to be addressed and its aetiology explored through genetic, longitudinal and causal modelling: do the strong associations of aggression and other emotional and behavioural problems reflect a shared genetic vulnerability for multiple disorders, or do some disorders causally lead to other problems? The absence of rater differences in co-occurrence patterns does not imply that rater’s views are interchangeable. Previous research suggested that, in general, mothers observe more behaviour problems in their children than fathers do [30]. We also see this pattern in the current paper, and consistently observe it across all counties. The differences in assessment between fathers and mothers in the levels of behavioural problems they observe may indicate that they both introduce their rater-specific view on the behaviour of the child [31], or that fathers and mothers interact with their offspring in different contexts. The similarities across raters and countries indicate that large-scale gene-finding efforts of aggressive behaviour and its co-occurring psychopathologies across multiple cohorts will be feasible/successful. Such an effort is currently in progress within the ACTION consortium in collaboration with other cohorts and consortia that have collected measures of aggression in children as well as DNA samples for genotyping [32]. The results of this international genome-wide association meta-analysis (GWAMA) are expected to yield insight into the genetic variants that influence aggression across childhood and offer possibilities for the construction of polygenic scores which may be used in prediction models [33, 34] and gene-environment modelling [35]. Besides a GWAMA approach, which includes samples from multiple age groups, genome-wide epigenetic profiling will be done to compare methylation in several statistically well-powered contrasts (such as genetically identical twin pairs discordant for aggression) in children. Monozygotic (MZ) twins pairs who are longitudinally discordant of aggression, also offer Table 6 Phenotypic correlations between aggression and other empirical scales of the Child Behaviour Checklist (CBCL) 1.5-5 ASBACBCL 1.5–5 Rater Age Sex N Attention problems Withdrawn Anxious– depressed Emotional reactivity Somatic complaints Sleep problems Gen R Mother 3 Boys 2271 0.60 [0.57, 0.63] 0.43 [0.39, 0.47] 0.44 [0.40, 0.48] 0.67 [0.64, 0.70] 0.39 [0.35, 0.43] 0.38 [0.34, 0.42] 3 Girls 2246 0.59 [0.56, 0.62] 0.42 [0.38, 0.46] 0.46 [0.42, 0.50] 0.68 [0.65, 0.71] 0.38 [0.34, 0.42] 0.40 [0.36, 0.44] Gen R Father 3 Boys 1840 0.67 [0.64, 0.70] 0.45 [0.41, 0.49] 0.47 [0.43, 0.51] 0.69 [0.66, 0.72] 0.39 [0.35, 0.43] 0.41 [0.37, 0.45] 3 Girls 1897 0.59 [0.55, 0.63] 0.44 [0.40, 0.48] 0.50 [0.46, 0.54] 0.71 [0.68, 0.74] 0.39 [0.35, 0.43] 0.42 [0.38, 0.46] NTR Mother 3 Boys 9277 0.58 [0.56, 0.60] 0.45 [0.43, 0.47] 0.47 [0.45, 0.49] 0.64 [0.62, 0.66] 0.36 [0.34, 0.38] 0.35 [0.33, 0.37] 3 Girls 9360 0.55 [0.53, 0.57] 0.41 [0.39, 0.43] 0.48 [0.46, 0.50] 0.65 [0.63, 0.67] 0.37 [0.35, 0.39] 0.38 [0.36, 0.40] Gen R Mother 6 Boys 2887 0.59 [0.56, 0.62] 0.58 [0.55, 0.61] 0.55 [0.52, 0.58] 0.73 [0.71, 0.75] 0.40 [0.37, 0.43] 0.41 [0.38, 0.44] 6 Girls 2856 0.55 [0.52, 0.58] 0.50 [0.47, 0.53] 0.55 [0.52, 0.58] 0.75 [0.73, 0.77] 0.42 [0.39, 0.45] 0.41 [0.38, 0.44] 1119European Child & Adolescent Psychiatry (2018) 27:1105–1121 1 3 questionnaire assessments of both twins and parents at baseline, starting with a family questionnaire (returned by 2,724 families, 87% participation rate) that was mailed late in the year before the twins reached age 12, with follow-up of all twins at age 14 and 17½, as well as a later collection of questionnaires, psychiatric interviews and blood samples at age 22. For the epidemiological study of the first wave of data collection, we excluded families in which one or both co-twins were deceased or living outside Finland, families in which both co-twins lived apart from both biological parents, and families in which the Population Register Center contained no residential address for a twin. The Generation R Study from Rotterdam in the Netherlands is a population-based prospective cohort study from foetal life until young adulthood. The study is designed to identify early environmental and genetic causes of normal and abnormal growth, development and health during foetal life, childhood and adulthood. The study focuses on four primary areas of research: (1) growth and physical development; (2) behavioural and cognitive development; (3) diseases in childhood; and (4) health and healthcare for pregnant women and children. In total, 9,778 mothers with a delivery date from April 2002 until January 2006 were enrolled in the study. General follow-up rates until the age of 4years exceed 75%. Data collection in mothers, fathers and preschool children included questionnaires, detailed physical and ultrasound examinations, behavioural observations and biological samples. A genome-wide association screen is available in the participating children. Regular detailed hands-on assessments are performed from the age of 5years onwards. The Queensland Twin Register (Qtwin) study began in 1992 and collects data from twin and their siblings. Twins were recruited from primary and secondary schools in south east Queensland in Australia. Longitudinal data are collected from the twins, their siblings and their parents during visits to the Queensland Institue of Medical Research (QIMR Berghofer Medical Research Institute), which are scheduled as close as possible to the twins 12th, 14th and 16th birthdays. 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Front Genet 3:4. https :// doi.org/10.3389/fgene .2012.00004 1121European Child & Adolescent Psychiatry (2018) 27:1105–1121 1 3 Affiliations MeikeBartels1,2,3 · AnneHendriks1,2· MatteoMauri4· EvaKrapohl5· AlyceWhipp6· KoenBolhuis7· LuciaColodroConde8· JustinLuningham9· HillFungIp1,2· FionaHagenbeek1,2· PeterRoetman10· RalucaGatej10· AudriLamers10· MichelNivard1,2· JennyvanDongen1,2· YiLu11· ChristelMiddeldorp1,3,12· ToosvanBeijsterveldt1,2· RobertVermeiren10,13· ThomasHankemeijer14· CeesKluft15· SarahMedland8· SebastianLundström16,17· RichardRose18· LeaPulkkinen19· EeroVuoksimaa6,20· TellervoKorhonen6,20,21· NicholasG.Martin22· GittaLubke9· CatrinFinkenauer1,23· VassiliosFanos4· HenningTiemeier7,24,25· PaulLichtenstein11· RobertPlomin5· JaakkoKaprio6,20· DorretI.Boomsma1,2,3 * Meike Bartels m.bar[email protected] 1 Netherlands Twin Register, Department ofBiological Psychology, Vrije Universiteit Amsterdam, van der Boechorststraat 1, 1081BTAmsterdam, TheNetherlands 2 Amsterdam Public Health Research Institute, Faculty ofBehavioural andMovement Sciences, Vrije Universiteit Amsterdam, Amsterdam, TheNetherlands 3 Amsterdam Neuroscience, Amsterdam, TheNetherlands 4 University ofCagliari, Cagliari, Italy 5 Medical Research Council Social, Genetic, andDevelopmental Psychiatry Centre, Institute ofPsychiatry, Psychology, andNeuroscience, King’s College London, London, UK 6 Institute forMolecular Medicine Finland, University ofHelsinki, Helsinki, Finland 7 Department ofEpidemiology, Erasmus Medical Center, Rotterdam, TheNetherlands 8 Psychiatric Genetics Laboratory, QIMR Berghofer Medical Research Institute, Brisbane, Australia 9 Department ofPsychology, University ofNotre Dame, NotreDame, USA 10 Curium-LUMC, Academic Centre ofChild andYouth Psychiatry, Leiden University Medical Center, Leiden, TheNetherlands 11 Department ofMedical Epidemiology andBiostatistics, Karolinska Institutet, Stockholm, Sweden 12 University ofQueensland, Brisbane, Australia 13 VU Medical Centre, Amsterdam, TheNetherlands 14 Division ofAnalytical Biosciences, Leiden Academic Centre forDrug Research, Leiden University, Leiden, TheNetherlands 15 Good Biomarker Sciences, Leiden, TheNetherlands 16 Gillberg Neuropsychiatry Centre, University ofGothenburg, Gothenburg, Sweden 17 Centre forEthics, Law andMental Health (CELAM), University ofGothenburg, Gothenburg, Sweden 18 Department ofPsychological & Brain Sciences, Indiana University, Bloomington, IN, USA 19 Department ofPsychology, University ofJyvaskyla, Jyvaskyla, Finland 20 Department ofPublic Health, University ofHelsinki, Helsinki, Finland 21 Institute ofPublic Health andClinical Nutrition, University ofEastern Finland, Kuopio, Finland 22 QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia 23 Youth Studies, Interdisciplinary Center, Utrecht University, Utrecht, TheNetherlands 24 Department ofChild andAdolescent Psychiatry, Erasmus Medical Center, Rotterdam, TheNetherlands 25 Department ofPsychiatry, Erasmus Medical Center, Rotterdam, TheNetherlands