Attention deficit hyperactivity disorder symptoms and brain morphology: examining confounding bias
- Erasmus MC, Netherlands
- 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
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.
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.
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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Attention deficit hyperactivity disorder symptoms and brain morphology: examining confounding bias
eLife 11:e78002.
https://doi.org/10.7554/eLife.78002
Further reading
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- Epidemiology and Global Health
Background:
The role of circulating metabolites on child development is understudied. We investigated associations between children’s serum metabolome and early childhood development (ECD).
Methods:
Untargeted metabolomics was performed on serum samples of 5004 children aged 6–59 months, a subset of participants from the Brazilian National Survey on Child Nutrition (ENANI-2019). ECD was assessed using the Survey of Well-being of Young Children’s milestones questionnaire. The graded response model was used to estimate developmental age. Developmental quotient (DQ) was calculated as the developmental age divided by chronological age. Partial least square regression selected metabolites with a variable importance projection ≥1. The interaction between significant metabolites and the child’s age was tested.
Results:
Twenty-eight top-ranked metabolites were included in linear regression models adjusted for the child’s nutritional status, diet quality, and infant age. Cresol sulfate (β=–0.07; adjusted-p <0.001), hippuric acid (β=–0.06; adjusted-p <0.001), phenylacetylglutamine (β=–0.06; adjusted-p <0.001), and trimethylamine-N-oxide (β=–0.05; adjusted-p=0.002) showed inverse associations with DQ. We observed opposite directions in the association of DQ for creatinine (for children aged –1 SD: β=–0.05; pP=0.01;+1 SD: β=0.05; p=0.02) and methylhistidine (–1 SD: β = - 0.04; p=0.04;+1 SD: β=0.04; p=0.03).
Conclusions:
Serum biomarkers, including dietary and microbial-derived metabolites involved in the gut-brain axis, may potentially be used to track children at risk for developmental delays.
Funding:
Supported by the Brazilian Ministry of Health and the Brazilian National Research Council.
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- Epidemiology and Global Health
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