Definition of early age at onset in bipolar disorder according to distinctive neurodevelopmental pathways: Insights from the FACE-BD study

Filippo Corponi, Antoine Lefrere, Marion Leboyer, Frank Bellivier, Ophelia Godin, Josephine Loftus, Philippe Courtet, Caroline Dubertret, Emmanuel Haffen, Pierre Michel Llorca, Paul Roux, Mircea Polosan, Raymund Schwan, Ludovic Samalin, Emilie Olié, Bruno Etain, Peggy Seriès, Raoul Belzeaux*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract / Description of output

Converging evidence suggests that a subgroup of bipolar disorder (BD) with an early age at onset (AAO) may develop from aberrant neurodevelopment. However, the definition of early AAO remains unprecise. We thus tested which age cut-off for early AAO best corresponds to distinguishable neurodevelopmental pathways.

We analyzed data from the FondaMental Advanced Center of Expertise-Bipolar Disorder cohort, a naturalistic sample of 4421 patients. First, a supervised learning framework was applied in binary classification experiments using neurodevelopmental history to predict early AAO, defined either with Gaussian mixture models (GMM) clustering or with each of the different cut-offs in the range 14 to 25 years. Second, an unsupervised learning approach was used to find clusters based on neurodevelopmental factors and to examine the overlap between such data-driven groups and definitions of early AAO used for supervised learning.

A young cut-off, i.e. 14 up to 16 years, induced higher separability [mean nested cross-validation test AUROC = 0.7327 (± 0.0169) for ⩽16 years]. Predictive performance deteriorated increasing the cut-off or setting early AAO with GMM. Similarly, defining early AAO below 17 years was associated with a higher degree of overlap with data-driven clusters (Normalized Mutual Information = 0.41 for ⩽17 years) relatively to other definitions.

Early AAO best captures distinctive neurodevelopmental patterns when defined as ⩽17 years. GMM-based definition of early AAO falls short of mapping to highly distinguishable neurodevelopmental pathways. These results should be used to improve patients' stratification in future studies of BD pathophysiology and biomarkers.
Original languageEnglish
Pages (from-to)6724-6732
Number of pages9
JournalPsychological Medicine
Issue number14
Early online date28 Feb 2023
Publication statusPublished - 1 Oct 2023

Keywords / Materials (for Non-textual outputs)

  • age at onset
  • bipolar disorder
  • machine learning
  • neurodevelopment


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