Attention deficit hyperactivity disorder symptoms and brain morphology: examining confounding bias

  1. Lorenza Dall'Aglio
  2. Hannah H Kim
  3. Sander Lamballais
  4. Jeremy Labrecque
  5. Ryan L Muetzel
  6. Henning Tiemeier  Is a corresponding author
  1. Erasmus MC, Netherlands
  2. Harvard TH Chan School of Public Health, United States

Abstract

Background: Associations between attention-deficit/hyperactivity disorder (ADHD) and brain morphology have been reported, although with several inconsistencies. These may partly stem from confounding bias, which could distort associations and limit generalizability. We examined how associations between brain morphology and ADHD symptoms change with adjustments for potential confounders typically overlooked in the literature (aim 1), and for IQ and head motion, which are typically corrected for but play ambiguous roles (aim 2).

Methods: Participants were 10-year-old children from the Adolescent Brain Cognitive Development (N=7,722) and Generation R (N=2,531) studies. Cortical area, volume, and thickness were measured with MRI and ADHD symptoms with the Child Behavior Checklist. Surface-based cross-sectional analyses were run.

Results: ADHD symptoms related to widespread cortical regions when solely adjusting for demographic factors. Additional adjustments for socioeconomic and maternal behavioral confounders (aim 1) generally attenuated associations, as cluster sizes halved and effect sizes substantially reduced. Cluster sizes further changed when including IQ and head motion (aim 2), however, we argue that adjustments might have introduced bias.

Conclusions: Careful confounder selection and control can help identify more robust and specific regions of associations for ADHD symptoms, across two cohorts. We provided guidance to minimizing confounding bias in psychiatric neuroimaging.

Funding: Authors are supported by an NWO-VICI grant (NWO-ZonMW: 016.VICI.170.200 to HT) for HT, LDA, SL, and the Sophia Foundation S18-20, and Erasmus University and Erasmus MC Fellowship for RLM.

Data availability

All datasets for this article are not automatically publicly available due to legal and informed consent restrictions. Reasonable requests to access the datasets should be directed to the Director of the Generation R Study, Vincent Jaddoe (generationr@erasmusmc.nl), in accordance with the local, national, and European Union regulations. Data for The ABCD Study is already open and available in the NIMH Data Archive (NDA) (nda.nih.gov) to eligible researchers within NIH-verified institutions. Data can be accessed following a data request to the NIH data access committee (https://nda.nih.gov/), which should include information on the planned topic of study. The request is valid for one year. Data use should be in line with the NDA Data Use Certification. The code used for this study is publicly available athttps://github.com/LorenzaDA/ADHD_brainmorphology_confounding

Article and author information

Author details

  1. Lorenza Dall'Aglio

    Department of Child and Adolescent Psychiatry, Erasmus MC, Rotterdam, Netherlands
    Competing interests
    The authors declare that no competing interests exist.
  2. Hannah H Kim

    Department of Social and Behavioral Sciences, Harvard TH Chan School of Public Health, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Sander Lamballais

    Department of Clinical Genetics, Erasmus MC, Rotterdam, Netherlands
    Competing interests
    The authors declare that no competing interests exist.
  4. Jeremy Labrecque

    Department of Epidemiology, Erasmus MC, Rotterdam, Netherlands
    Competing interests
    The authors declare that no competing interests exist.
  5. Ryan L Muetzel

    Department of Child and Adolescent Psychiatry, Erasmus MC, Rotterdam, Netherlands
    Competing interests
    The authors declare that no competing interests exist.
  6. Henning Tiemeier

    Department of Social and Behavioral Sciences, Harvard TH Chan School of Public Health, Boston, United States
    For correspondence
    tiemeier@hsph.harvard.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-4395-1397

Funding

Nederlandse Organisatie voor Wetenschappelijk Onderzoek (NWO-ZonMW: 016.VICI.170.200)

  • Henning Tiemeier

Nederlandse Organisatie voor Wetenschappelijk Onderzoek (NWO-ZonMW: 016.VICI.170.200)

  • Lorenza Dall'Aglio

Nederlandse Organisatie voor Wetenschappelijk Onderzoek (NWO-ZonMW: 016.VICI.170.200)

  • Sander Lamballais

Erasmus Medisch Centrum (Sophia Foundation S18-20)

  • Ryan L Muetzel

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Juan Helen Zhou, National University of Singapore, Singapore

Ethics

Human subjects: Research protocols for the ABCD study were approved by the institutional review board of the University of California, San Diego (#160091), and the institutional review boards of the 21 data collection sites, while the design of the Generation R study was approved by the Medical Ethics Committee of the Erasmus MC (METC-2012-165). For both studies, written informed consent and assent from the primary caregiver or child were obtained.

Version history

  1. Received: February 18, 2022
  2. Preprint posted: May 3, 2022 (view preprint)
  3. Accepted: November 6, 2022
  4. Accepted Manuscript published: November 9, 2022 (version 1)
  5. Version of Record published: November 29, 2022 (version 2)

Copyright

© 2022, Dall'Aglio et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Lorenza Dall'Aglio
  2. Hannah H Kim
  3. Sander Lamballais
  4. Jeremy Labrecque
  5. Ryan L Muetzel
  6. Henning Tiemeier
(2022)
Attention deficit hyperactivity disorder symptoms and brain morphology: examining confounding bias
eLife 11:e78002.
https://doi.org/10.7554/eLife.78002

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https://doi.org/10.7554/eLife.78002

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