title: The impact of study design and diagnostic approach in a large multi-centre ADHD study: Part 2: Dimensional measures of psychopathology and intelligence.
abstract: BACKGROUND
  The International Multi-centre ADHD Genetics (IMAGE) project with 11 participating centres from 7 European countries and Israel has collected a large behavioural and genetic database for present and future research. Behavioural data were collected from 1068 probands with ADHD and 1446 unselected siblings. The aim was to describe and analyse questionnaire data and IQ measures from all probands and siblings. In particular, to investigate the influence of age, gender, family status (proband vs. sibling), informant, and centres on sample homogeneity in psychopathological measures.
  
  
  METHODS
  Conners' Questionnaires, Strengths and Difficulties Questionnaires, and Wechsler Intelligence Scores were used to describe the phenotype of the sample. Data were analysed by use of robust statistical multi-way procedures.
  
  
  RESULTS
  Besides main effects of age, gender, informant, and centre, there were considerable interaction effects on questionnaire data. The larger differences between probands and siblings at home than at school may reflect contrast effects in the parents. Furthermore, there were marked gender by status effects on the ADHD symptom ratings with girls scoring one standard deviation higher than boys in the proband sample but lower than boys in the siblings sample. The multi-centre design is another important source of heterogeneity, particularly in the interaction with the family status. To a large extent the centres differed from each other with regard to differences between proband and sibling scores.
  
  
  CONCLUSIONS
  When ADHD probands are diagnosed by use of fixed symptom counts, the severity of the disorder in the proband sample may markedly differ between boys and girls and across age, particularly in samples with a large age range. A multi-centre design carries the risk of considerable phenotypic differences between centres and, consequently, of additional heterogeneity of the sample even if standardized diagnostic procedures are used. These possible sources of variance should be counteracted in genetic analyses either by using age and gender adjusted diagnostic procedures and regional normative data or by adjusting for design artefacts by use of covariate statistics, by eliminating outliers, or by other methods suitable for reducing heterogeneity.
authors.affiliation: Department of Child and Adolescent Psychiatry, University of Zurich, Zurich, Switzerland. u.c.mueller@bluewin.ch
authors.forename: Ueli C
authors.initials: UC
authors.lastname: Müller
authors.forename: Philip
authors.initials: P
authors.lastname: Asherson
authors.forename: Tobias
authors.initials: T
authors.lastname: Banaschewski
authors.forename: Jan K
authors.initials: JK
authors.lastname: Buitelaar
authors.forename: Richard P
authors.initials: RP
authors.lastname: Ebstein
authors.forename: Jaques
authors.initials: J
authors.lastname: Eisenberg
authors.forename: Michael
authors.initials: M
authors.lastname: Gill
authors.forename: Iris
authors.initials: I
authors.lastname: Manor
authors.forename: Ana
authors.initials: A
authors.lastname: Miranda
authors.forename: Robert D
authors.initials: RD
authors.lastname: Oades
authors.forename: Herbert
authors.initials: H
authors.lastname: Roeyers
authors.forename: Aribert
authors.initials: A
authors.lastname: Rothenberger
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Sergeant
authors.forename: Edmund Js
authors.initials: EJ
authors.lastname: Sonuga-Barke
authors.forename: Margaret
authors.initials: M
authors.lastname: Thompson
authors.forename: Stephen V
authors.initials: SV
authors.lastname: Faraone
authors.forename: Hans-Christoph
authors.initials: HC
authors.lastname: Steinhausen
mesh_terms: D000328:Adult; D001289:Attention Deficit Disorder with Hyperactivity / Q000175:diagnosis* / Q000235:genetics*; D002648:Child; D039721:Diagnostic and Statistical Manual of Mental Disorders; D005192:Family Health; D005195:Family Relations; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D007360:Intelligence / Q000235:genetics; D008297:Male; D001523:Mental Disorders / Q000175:diagnosis / Q000453:epidemiology / Q000523:psychology; D015337:Multicenter Studies as Topic; D010641:Phenotype; D011569:Psychiatric Status Rating Scales; D012107:Research Design; D035781:Siblings; D014888:Wechsler Scales / Q000706:statistics & numerical data