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The normative modeling framework for computational psychiatry

Nature Protocols volume 17, pages 1711–1734 (2022)Cite this article

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Abstract

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.

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Fig. 1: Conceptual overview of normative modeling.
Fig. 2: Practical overview of normative modeling framework.
Fig. 3: Overview of resources for running a normative modeling analysis.
Fig. 4: Visualization of normative model evaluation metrics.

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Data availability

All data used in this protocol are available on GitHub (https://github.com/predictive-clinical-neuroscience/PCNtoolkit-demo/tree/main/tutorials/BLR_protocol) and Zenodo86 (https://zenodo.org/record/5592153#.YjL7PY_P2UI) in csv. files. We also include a template csv. file to help format user’s own data into the correct form for running the protocol using their own dataset.

Code availability

All code is available on GitHub (https://github.com/predictive-clinical-neuroscience/PCNtoolkit-demo/tree/main/tutorials/BLR_protocol) in the format of Python notebooks that can be run in the cloud (for free) using Google Colab (https://colab.research.google.com/github/predictive-clinical-neuroscience/PCNtoolkit-demo/blob/main/tutorials/BLR_protocol/BLR_normativemodel_protocol.ipynb). We have also shared the GitHub repository on Zenodo (https://zenodo.org/record/5592153#.YjL7PY_P2UI) to create a citable DOI for this software that also allows versions that are necessary as additional code and tutorials may be added over time86.

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Acknowledgements

This research was supported by grants from the European Research Council (ERC, grant ‘MENTALPRECISION’ 10100118 and ‘BRAINMINT’ 802998), the Wellcome Trust under an Innovator award (‘BRAINCHART’, 215698/Z/19/Z) and a Strategic Award (098369/Z/12/Z), the Dutch Organisation for Scientific Research (VIDI grant 016.156.415). T.W. also gratefully acknowledges the Niels Stensen Fellowship as well as the European Union’s Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie Grant agreement no. 895011.

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Author notes

  1. These authors contributed equally to this work: Henricus G. Ruhe, Christian F. Beckmann, Andre F. Marquand.

Authors and Affiliations

  1. Donders Institute for Brain, Cognition, and Behavior, Radboud University, Nijmegen, the Netherlands

    Saige Rutherford, Seyed Mostafa Kia, Charlotte Fraza, Mariam Zabihi, Richard Dinga, Henricus G. Ruhe, Christian F. Beckmann & Andre F. Marquand

  2. Department of Cognitive Neuroscience, Radboud University Medical Center, Nijmegen, the Netherlands

    Saige Rutherford, Seyed Mostafa Kia, Charlotte Fraza, Mariam Zabihi, Richard Dinga, Christian F. Beckmann & Andre F. Marquand

  3. Department of Psychiatry, University of Michigan, Ann Arbor, MI, USA

    Saige Rutherford

  4. Department of Psychiatry, Utrecht University Medical Center, Utrecht, the Netherlands

    Seyed Mostafa Kia

  5. Department of Psychology, University of Oslo, Oslo, Norway

    Thomas Wolfers & Pierre Berthet

  6. Norwegian Center for Mental Disorders Research, University of Oslo, Oslo, Norway

    Thomas Wolfers & Pierre Berthet

  7. Department of Psychological Medicine, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London, UK

    Amanda Worker & Andre F. Marquand

  8. Centre for Medical Image Computing, Medical Physics and Biomedical Engineering, University College London, London, UK

    Serena Verdi

  9. Dementia Research Centre, UCL Queen Square Institute of Neurology, London, UK

    Serena Verdi

  10. Department of Psychiatry, Radboud University Medical Center, Nijmegen, the Netherlands

    Henricus G. Ruhe

  11. Centre for Functional MRI of the Brain, University of Oxford, Oxford, UK

    Christian F. Beckmann

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Contributions

Conceptualization: S.R., S.M.K., T.W., C.F., M.Z., R.D., P.B., A.W., S.V., H.G.R., C.F.B. and A.F.M. Methodology: S.R., S.M.K., T.W., C.F., M.Z., R.D. and A.F.M. Data curation: S.R. and A.F.M. Writing—original draft: S.R. Writing—reviewing and editing: S.R., S.M.K., T.W., C.F., M.Z., R.D., P.B., A.W., S.V., H.G.R., C.F.B. and A.F.M. Visualization: S.R. Supervision: H.R., C.F.B. and A.F.M. Funding acquisition: H.R., C.F.B. and A.F.M.

Corresponding author

Correspondence to Saige Rutherford.

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Competing interests

C.F.B. is director and shareholder of SBGNeuro Ltd. H.G.R. received speaker’s honorarium from Lundbeck and Janssen. The other authors report no conflicts of interest.

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Nature Protocols thanks Linden Parkes and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Key references using this protocol

Marquand, A. F. et al. Mol. Psychiatry 24, 1415–1424 (2019): https://doi.org/10.1038/s41380-019-0441-1

Zabihi, M. et al. Transl. Psychiatry 10, 384 (2020): https://doi.org/10.1038/s41398-020-01057-0

Wolfers, T. JAMA Psychiatry 75, 1146–1155 (2018): https://doi.org/10.1001/jamapsychiatry.2018.2467

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Rutherford, S., Kia, S.M., Wolfers, T. et al. The normative modeling framework for computational psychiatry. Nat Protoc 17, 1711–1734 (2022). https://doi.org/10.1038/s41596-022-00696-5

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