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1.  Genome-wide association study of response to cognitive–behavioural therapy in children with anxiety disorders 
The British Journal of Psychiatry  2016;209(3):236-243.
Background
Anxiety disorders are common, and cognitive–behavioural therapy (CBT) is a first-line treatment. Candidate gene studies have suggested a genetic basis to treatment response, but findings have been inconsistent.
Aims
To perform the first genome-wide association study (GWAS) of psychological treatment response in children with anxiety disorders (n = 980).
Method
Presence and severity of anxiety was assessed using semi-structured interview at baseline, on completion of treatment (post-treatment), and 3 to 12 months after treatment completion (follow-up). DNA was genotyped using the Illumina Human Core Exome-12v1.0 array. Linear mixed models were used to test associations between genetic variants and response (change in symptom severity) immediately post-treatment and at 6-month follow-up.
Results
No variants passed a genome-wide significance threshold (P = 5 × 10−8) in either analysis. Four variants met criteria for suggestive significance (P<5 × 10−6) in association with response post-treatment, and three variants in the 6-month follow-up analysis.
Conclusions
This is the first genome-wide therapygenetic study. It suggests no common variants of very high effect underlie response to CBT. Future investigations should maximise power to detect single-variant and polygenic effects by using larger, more homogeneous cohorts.
doi:10.1192/bjp.bp.115.168229
PMCID: PMC5007453  PMID: 26989097
2.  A Genome-Wide Test of the Differential Susceptibility Hypothesis Reveals a Genetic Predictor of Differential Response to Psychological Treatments for Child Anxiety Disorders 
Psychotherapy and Psychosomatics  2016;85(3):146-158.
Background
The differential susceptibly hypothesis suggests that certain genetic variants moderate the effects of both negative and positive environments on mental health and may therefore be important predictors of response to psychological treatments. Nevertheless, the identification of such variants has so far been limited to preselected candidate genes. In this study we extended the differential susceptibility hypothesis from a candidate gene to a genome-wide approach to test whether a polygenic score of environmental sensitivity predicted response to cognitive behavioural therapy (CBT) in children with anxiety disorders.
Methods
We identified variants associated with environmental sensitivity using a novel method in which within-pair variability in emotional problems in 1,026 monozygotic twin pairs was examined as a function of the pairs' genotype. We created a polygenic score of environmental sensitivity based on the whole-genome findings and tested the score as a moderator of parenting on emotional problems in 1,406 children and response to individual, group and brief parent-led CBT in 973 children with anxiety disorders.
Results
The polygenic score significantly moderated the effects of parenting on emotional problems and the effects of treatment. Individuals with a high score responded significantly better to individual CBT than group CBT or brief parent-led CBT (remission rates: 70.9, 55.5 and 41.6%, respectively).
Conclusions
Pending successful replication, our results should be considered exploratory. Nevertheless, if replicated, they suggest that individuals with the greatest environmental sensitivity may be more likely to develop emotional problems in adverse environments but also benefit more from the most intensive types of treatment.
doi:10.1159/000444023
PMCID: PMC5079103  PMID: 27043157
Differential response; Child; Anxiety disorders
3.  Non-replication of the association between 5HTTLPR and response to psychological therapy for child anxiety disorders 
The British Journal of Psychiatry  2016;208(2):182-188.
Background
We previously reported an association between 5HTTLPR genotype and outcome following cognitive–behavioural therapy (CBT) in child anxiety (Cohort 1). Children homozygous for the low-expression short-allele showed more positive outcomes. Other similar studies have produced mixed results, with most reporting no association between genotype and CBT outcome.
Aims
To replicate the association between 5HTTLPR and CBT outcome in child anxiety from the Genes for Treatment study (GxT Cohort 2, n = 829).
Method
Logistic and linear mixed effects models were used to examine the relationship between 5HTTLPR and CBT outcomes. Mega-analyses using both cohorts were performed.
Results
There was no significant effect of 5HTTLPR on CBT outcomes in Cohort 2. Mega-analyses identified a significant association between 5HTTLPR and remission from all anxiety disorders at follow-up (odds ratio 0.45, P = 0.014), but not primary anxiety disorder outcomes.
Conclusions
The association between 5HTTLPR genotype and CBT outcome did not replicate. Short-allele homozygotes showed more positive treatment outcomes, but with small, non-significant effects. Future studies would benefit from utilising whole genome approaches and large, homogenous samples.
doi:10.1192/bjp.bp.114.154997
PMCID: PMC4837384  PMID: 26294368
4.  Reactive Attachment Disorder and Disinhibited Social Engagement Disorder in School-Aged Foster Children - A Confirmatory Approach to Dimensional Measures 
This study aimed to investigate the factor structure and external correlates of the constructs Reactive Attachment Disorder (RAD) and Disinhibited Social Engagement Disorder (DSED) from the Diagnostic and Statistical Manual of Mental Disorders (DSM-5). The following were addressed: First, do our data support the DSM-5 conceptualization of RAD/DSED as two separate constructs? Second, are RAD and DSED distinct from other well-established dimensions of child psychopathology? Third, what are the external correlates of RAD/DSED in this sample? The study sample included 122 foster children aged 6–10 years. Foster parents completed the Strengths and Difficulties Questionnaire (SDQ), and the RAD/DSED-scale from the Developmental and Well-Being Assessment. Child protection caseworkers completed a questionnaire regarding exposure to maltreatment and placement history. Confirmatory factor analysis (CFA) of the RAD/DSED items identified a good fit for a model with a two-factor structure, which is congruent with the DSM-5 definition of RAD and DSED. A new CFA model, which included the RAD and DSED factors together with the four problem factors of the SDQ (emotional, conduct, hyperactivity-inattention, and peer problems), also demonstrated a good fit with our data. RAD and DSED were associated with the SDQ Impact scale and help seeking behavior. This was partly explained by the SDQ externalizing and peer problem subscales. Our findings lend support for the DSM-5 conceptualization of RAD and DSED as separate dimensions of child psychopathology. Thus, the assessment of RAD and DSED provides information beyond other mental health problems.
doi:10.1007/s10802-015-0045-4
PMCID: PMC4785216  PMID: 26126635
Reactive attachment disorder; Disinhibited social engagement disorder; Foster children; Confirmatory factor analysis; Maltreatment
5.  Clinical Predictors of Response to Cognitive-Behavioral Therapy in Pediatric Anxiety Disorders: The Genes for Treatment (GxT) Study 
Objective
The Genes for Treatment study is an international, multisite collaboration exploring the role of genetic, demographic, and clinical predictors in response to cognitive-behavioral therapy (CBT) in pediatric anxiety disorders. The current article, the first from the study, examined demographic and clinical predictors of response to CBT. We hypothesized that the child’s gender, type of anxiety disorder, initial severity and comorbidity, and parents’ psychopathology would significantly predict outcome.
Method
A sample of 1,519 children 5 to 18 years of age with a primary anxiety diagnosis received CBT across 11 sites. Outcome was defined as response (change in diagnostic severity) and remission (absence of the primary diagnosis) at each time point (posttreatment, 3-, 6-, and/or 12-month follow-up) and analyzed using linear and logistic mixed models. Separate analyses were conducted using data from posttreatment and follow-up assessments to explore the relative importance of predictors at these time points.
Results
Individuals with social anxiety disorder (SoAD) had significantly poorer outcomes (poorer response and lower rates of remission) than those with generalized anxiety disorder (GAD). Although individuals with specific phobia (SP) also had poorer outcomes than those with GAD at posttreatment, these differences were not maintained at follow-up. Both comorbid mood and externalizing disorders significantly predicted poorer outcomes at posttreatment and follow-up, whereas self-reported parental psychopathology had little effect on posttreatment outcomes but significantly predicted response (although not remission) at follow-up.
Conclusion
SoAD, nonanxiety comorbidity, and parental psychopathology were associated with poorer outcomes after CBT. The results highlight the need for enhanced treatments for children at risk for poorer outcomes.
doi:10.1016/j.jaac.2015.03.018
PMCID: PMC4469376  PMID: 26004660
anxiety disorders; treatment; predictors; cognitive-behavioral therapy
6.  Screening Foster Children for Mental Disorders: Properties of the Strengths and Difficulties Questionnaire 
PLoS ONE  2014;9(7):e102134.
Background
High prevalence of mental disorders among foster children highlight the need to examine the mental health of children placed out of home. We examined the properties of the Strengths and Difficulties Questionnaire (SDQ) in screening school-aged foster children for mental disorders.
Methods
Foster parents and teachers of 279 foster children completed the SDQ and the diagnostic interview Developmental and Well-Being Assessment (DAWBA). Using the diagnoses derived from the DAWBA as the standard, we examined the performance of the SDQ scales as dimensional measures of mental health problems using receiver operating characteristic (ROC) analyses. Recommended cut-off scores were derived from ROC coordinates. The SDQ predictive algorithms were also examined.
Results
ROC analyses supported the screening properties of the SDQ Total difficulties and Impact scores (AUC = 0.80–0.83). Logistic regression analyses showed that the prevalence of mental disorders increased linearly with higher SDQ Total difficulties scores (X2 = 121.47, df = 13, p<.001) and Impact scores (X2 = 69.93, df = 6, p<.001). Our results indicated that there is an additive value of combining the scores from the Total difficulties and Impact scales, where scores above cut-off on any of the two scales predicted disorders with high sensitivity (89.1%), but moderate specificity (62.1%). Scores above cut-off on both scales yielded somewhat lower sensitivity (73.4%), but higher specificity (81.1%). The SDQ multi-informant algorithm showed low discriminative ability for the main diagnostic categories, with an exception being the SDQ Conduct subscale, which accurately predicted the absence of behavioural disorders (LHR− = 0.00).
Conclusions
The results support the use of the SDQ Total difficulties and Impact scales when screening foster children for mental health problems. Cut-off values for both scales are suggested. The SDQ multi-informant algorithms are not recommended for mental health screening of foster children in Norway.
doi:10.1371/journal.pone.0102134
PMCID: PMC4090209  PMID: 25006669
7.  Mental disorders in foster children: a study of prevalence, comorbidity and risk factors 
Background
The aim of this study is to examine the prevalence of mental disorders in 6- to 12-year-old foster children and assess comorbidity and risk factors.
Methods
Information on mental health was collected from foster parents and from teachers using Developmental and Well-Being Assessment (DAWBA) Web-based diagnostic interview. Child welfare services provided information about care conditions prior to placement and about the child’s placement history.
Results
Diagnostic information was obtained about 279 (70.5%) of 396 eligible foster children. In total, 50.9% of the children met the criteria for one or more DSM-IV disorders. The most common disorders were grouped into 3 main diagnostic groups: Emotional disorders (24.0%), ADHD (19.0%), and Behavioural disorders (21.5%). The comorbidity rates among these 3 main groups were high: 30.4% had disorders in 2 of these 3 diagnostic groups, and 13.0% had disorders in all 3 groups. In addition, Reactive attachment disorder (RAD) was diagnosed in 19.4% of the children, of whom 58.5% had comorbid disorders in the main diagnostic groups. Exposure to violence, serious neglect, and the number of prior placements increased the risk for mental disorders.
Conclusions
Foster children in Norway have a high prevalence of mental disorders, compared to the general child population in Norway and to other societies. The finding that 1 in 2 foster children presented with a mental disorder with high rates of comorbidity highlight the need for skilled assessment and qualified service provision for foster children and families.
doi:10.1186/1753-2000-7-39
PMCID: PMC3922948  PMID: 24256809
8.  Agreement on Web-based Diagnoses and Severity of Mental Health Problems in Norwegian Child and Adolescent Mental Health Services 
Objective:
This study examined the agreement between diagnoses and severity ratings assigned by clinicians using a structured web-based interview within a child and adolescent mental health outpatient setting.
Method:
Information on 100 youths was obtained from multiple informants through a web-based Development and Well-Being Assessment (DAWBA). Based on this information, four experienced clinicians independently diagnosed (according to the International Classification of Diseases Revision 10) and rated the severity of mental health problems according to the Health of the Nation Outcome Scales for Children and Adolescents (HoNOSCA) and the Children’s Global Assessment Scale (C-GAS).
Results:
Agreement for diagnosis was κ=0.69-0.82. Intra-class correlation for single measures was 0.78 for HoNOSCA and 0.74 for C-GAS, and 0.93 and 0.92, respectively for average measures.
Conclusions:
Agreement was good to excellent for all diagnostic categories. Agreement for severity was moderate, but improved to substantial when the average of the ratings given by all clinicians was considered. Therefore, we conclude that experienced clinicians can assign reliable diagnoses and assess severity based on DAWBA data collected online.
doi:10.2174/1745017901208010016
PMCID: PMC3343321  PMID: 22582083
Web-based; telepsychiatry; DAWBA; HoNOSCA; C-GAS.
9.  Cross-national differences in questionnaires do not necessarily reflect comparable differences in disorder prevalence 
Purpose
To examine whether the widely used Strengths and Difficulties Questionnaire (SDQ) can validly be used to compare the prevalence of child mental health problems cross nationally.
Methods
We used data on 29,225 5- to 16-year olds in eight population-based studies from seven countries: Bangladesh, Brazil, Britain, India, Norway, Russia and Yemen. Parents completed the SDQ in all eight studies, teachers in seven studies and youth in five studies. We used these SDQ data to calculate three different sorts of “caseness indicators” based on (1) SDQ symptoms, (2) SDQ symptoms plus impact and (3) an overall respondent judgement of ‘definite’ or ‘severe’ difficulties. Respondents also completed structured diagnostic interviews including extensive open-ended questions (the Development and Well-Being Assessment, DAWBA). Diagnostic ratings were all carried out or supervised by the DAWBA’s creator, working in conjunction with experienced local professionals.
Results
As judged by the DAWBA, the prevalence of any mental disorder ranged from 2.2% in India to 17.1% in Russia. The nine SDQ caseness indicators (three indicators times three informants) explained 8–56% of the cross-national variation in disorder prevalence. This was insufficient to make meaningful prevalence estimates since populations with a similar measured prevalence of disorder on the DAWBA showed large variations across the various SDQ caseness indicators.
Conclusions
The relationship between SDQ caseness indicators and disorder rates varies substantially between populations: cross-national differences in SDQ indicators do not necessarily reflect comparable differences in disorder rates. More generally, considerable caution is required when interpreting cross-cultural comparisons of mental health, particularly when these rely on brief questionnaires.
Electronic supplementary material
The online version of this article (doi:10.1007/s00127-011-0440-2) contains supplementary material, which is available to authorized users.
doi:10.1007/s00127-011-0440-2
PMCID: PMC3405234  PMID: 22033632
Cross cultural; Questionnaire; Prevalence; Reporting bias
10.  The strengths and difficulties questionnaire as a screening instrument for norwegian child and adolescent mental health services, application of UK scoring algorithms 
Background
The use of screening instruments can reduce waiting lists and increase treatment capacity. The aim of this study was to examine the usefulness of the Strengths and Difficulties Questionnaire (SDQ) with the original UK scoring algorithms, when used as a screening instrument to detect mental health disorders among patients in the Norwegian Child and Adolescent Mental Health Services (CAMHS) North Study.
Methods
A total of 286 outpatients, aged 5 to 18 years, from the CAMHS North Study were assigned diagnoses based on a Development and Well-Being Assessment (DAWBA). The main diagnostic groups (emotional, hyperactivity, conduct and other disorders) were then compared to the SDQ scoring algorithms using two dichotomisation levels: 'possible' and 'probable' levels. Sensitivity, specificity, positive predictive value, negative predictive value, positive likelihood ratio, negative likelihood ratio, and diagnostic odds ratio (ORD) were calculated.
Results
Sensitivity for the diagnostic categories included was 0.47-0.85 ('probable' dichotomisation level) and 0.81-1.00 ('possible' dichotomisation level). Specificity was 0.52-0.87 ('probable' level) and 0.24-0.58 ('possible' level). The discriminative ability, as measured by ORD, was in the interval for potentially useful tests for hyperactivity disorders and conduct disorders when dichotomised on the 'possible' level.
Conclusions
The usefulness of the SDQ UK-based scoring algorithms in detecting mental health disorders among patients in the CAMHS North Study is only partly supported in the present study. They seem best suited to identify children and adolescents who do not require further psychiatric evaluation, although this as well is problematic from a clinical point of view.
doi:10.1186/1753-2000-5-32
PMCID: PMC3207884  PMID: 21992589
11.  Prevalence of the ADHD phenotype in 7- to 9-year-old children: effects of informant, gender and non-participation 
Purpose
To estimate the prevalence of the ADHD phenotype based on parent and teacher reports in a general population sample of 7- to 9-year-old Norwegian children and evaluate the effect of parent attrition, gender and informant on the prevalence estimate.
Methods
The population consisted of all children (N = 9,430) attending 2nd–4th grade in the City of Bergen, Norway. The 18 symptoms of ADHD corresponding to the SNAP-IV and DSM-IV were included in the Bergen Child Study questionnaire to teachers and parents. Teacher information was available for 9,137 children (97%) and information from both informants was available for the 6,237 children (66%) whose parents agreed to participate in the study.
Results
The prevalence of the ADHD phenotype based on the combination of parent and teacher reports was 5.2% among participants. Teacher ratings of non-participants had a doubled rate of ADHD high scorers with an OR of 2.1 (95% CI, 1.9–2.4). The non-participant ADHD high scorers had more inattentive and fewer hyperactive/impulsive symptoms as compared to participating ADHD high scorers. Teachers reported high scores of hyperactivity/impulsivity and the combined symptom constellation much more frequently in boys than girls, while the difference between genders was less marked according to parent reports.
Conclusions
The ADHD phenotype was twice as prevalent among non-participants as among participants. Reported prevalences in population studies are therefore likely to be underestimates, if such attrition bias is not accounted for. Choice of informant, criteria for symptom count, definitions of subtypes and gender differences influence the prevalence estimates of the ADHD phenotype.
doi:10.1007/s00127-011-0379-3
PMCID: PMC3328684  PMID: 21499807
Attention-deficit/hyperactivity disorder; Child psychiatry; Epidemiology; Attrition; Gender

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