Müller, U.C., Asherson, P., Banaschewski, T., Buitelaar, J. K., Ebstein, R. P., Eisenberg, J., Gill, M., Manor, I., Miranda, A., Oades, R. D., Roeyers, H., Rothenberger, A., Sergeant, J. A., Sonuga-Barke, E. J. S., Thompson, M., Faraone, S. V., & Steinhausen, H-C.,

The impact of study design and diagnostic approach in a large multi-centre ADHD study: Part 2: Dimensional measures of psychopathology and intelligence. BMC Psychiatry, 11, 55.,
[Request a copy]

Introduction: The International Multi-centre ADHD-Genetics (IMAGE) project with 11 participating centres from 7 European countries & Israel has collected a large behavioural & genetic database for present & future research. Behavioural data were collected from 1068 probands with ADHD & 1446 unselected siblings.

Methods: Dimensional questionnaire data & IQ measures from all probands & siblings were analyzed with respect to effects of age, gender, family status, informant, & centres. Conners' Questionnaires, SDQs, & Wechsler Intelligence Scores were used to describe the phenotype of the sample. Data were analyzed by use of robust statistical multi-way procedures.

1 - Besides main effects of age, gender, informant, & centre, there were remarkable interaction effects on questionnaire data.

2 - The larger differences between probands & siblings at home than at school reflected contrast effects in the parents.

3 - Furthermore, there were marked gender by status effects in the ADHD scales with girls scoring one standard deviation higher than boys in the proband sample but lower than boys in the siblings sample. Most probably, these findings resulted from an artefact of the recruiting procedures using DSM-IV criteria with fixed symptom counts independent of age & gender.

4 - The largest mean score differences between centres in ADHD scores, in some comorbidity scores, and in IQ measures were about one standard deviation even if national normative sample data were used for IQ.


a) When ADHDs are diagnosed by use of fixed symptom counts, the disease severity in the probands sample may markedly differ between boys and girls and across age, particularly in samples with a large age range.

b) A multi-centre design carries the risk of remarkable phenotypic centre differences &, consequently, additional heterogeneity of the sample even if standardized diagnostic procedures are used.

c) In genetic analyses these possible sources of variance should be considered 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 to reduce heterogeneity.