The normative modeling framework for computational psychiatry

Saige Rutherford*, Seyed Mostafa Kia, Thomas Wolfers, Charlotte Fraza, Mariam Zabihi, Richard Dinga, Pierre Berthet, Amanda Worker, Serena Verdi, Henricus G. Ruhe, Christian F. Beckmann, Andre F. Marquand

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

42 Citations (Scopus)


Normative modeling is an emerging and innovative framework for mapping individual differences at the level of a single subject or observation in relation to a reference model. It involves charting centiles of variation across a population in terms of mappings between biology and behavior, which can then be used to make statistical inferences at the level of the individual. The fields of computational psychiatry and clinical neuroscience have been slow to transition away from patient versus ‘healthy’ control analytic approaches, probably owing to a lack of tools designed to properly model biological heterogeneity of mental disorders. Normative modeling provides a solution to address this issue and moves analysis away from case–control comparisons that rely on potentially noisy clinical labels. Here we define a standardized protocol to guide users through, from start to finish, normative modeling analysis using the Predictive Clinical Neuroscience toolkit (PCNtoolkit). We describe the input data selection process, provide intuition behind the various modeling choices and conclude by demonstrating several examples of downstream analyses that the normative model may facilitate, such as stratification of high-risk individuals, subtyping and behavioral predictive modeling. The protocol takes ~1–3 h to complete.

Original languageEnglish
Pages (from-to)1711-1734
Number of pages24
JournalNature Protocols
Issue number7
Publication statusPublished - Jul 2022


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