Development and Validation of Predictive Model for a Diagnosis of First Episode Psychosis Using the Multinational EU-GEI Case–control Study and Modern Statistical Learning Methods

Author:

Ajnakina Olesya12ORCID,Fadilah Ihsan1,Quattrone Diego3,Arango Celso4,Berardi Domenico5,Bernardo Miguel6,Bobes Julio7,de Haan Lieuwe8,Del-Ben Cristina Marta9,Gayer-Anderson Charlotte10ORCID,Stilo Simona1112,Jongsma Hannah E1314,Lasalvia Antonio15ORCID,Tosato Sarah15ORCID,Llorca Pierre-Michel16,Menezes Paulo Rossi17,Rutten Bart P18,Santos Jose Luis19,Sanjuán Julio20,Selten Jean-Paul21,Szöke Andrei22,Tarricone Ilaria23,D’Andrea Giuseppe5,Tortelli Andrea24,Velthorst Eva2526ORCID,Jones Peter B2728ORCID,Romero Manuel Arrojo29,La Cascia Caterina30,Kirkbride James B31ORCID,van Os Jim123218,O’Donovan Michael33,Morgan Craig10,di Forti Marta3,Murray Robin M1234,Hubbard Kathryn35,Beards Stephanie35,Cristofalo Doriana36,Parellada Mara37,Cuadrado Pedro38,Solano José Juan Rodríguez39,Fraguas David39,Andreu-Bernabeu Álvaro39,Carracedo Angel40,Bernardo Enrique García41,Roldán Laura37,López Gonzalo37,Amoretti Silvia424344,Nacher Juan454647,Garcia-Portilla Paz48,Costas Javier40,Jiménez-López Estela49,Matteis Mario37,Castro Marta Rapado37,González Emiliano37,Martínez Covadonga37,Sánchez Emilio41,Durán-Cutilla Manuel41,Franke Nathalie50,Termorshuizen Fabian5152,van Dam Daniella50,van der Ven Elsje5151,Messchaart Elles18,Leboyer Marion53535454,Schürhoff Franck53535454,Jamain Stéphane555556,Baudin Grégoire5353,Ferchiou Aziz5353,Pignon Baptiste535356,Richard Jean- Romain5555,Charpeaud Thomas565657,Tronche Anne-Marie565657,Frijda Flora58,La Barbera Daniele5858,Marrazzo Giovanna59,Sideli Lucia58,Sartorio Crocettarachele5858,Ferraro Laura58,Seminerio Fabio58,Loureiro Camila Marcelino6060,Shuhama Rosana6060,Ruggeri Mirella36,LaSalvia Antonio36,Bonetto Chiara36,Stahl Daniel1,

Affiliation:

1. Department of Biostatistics and Health Informatics, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, University of London , London , UK

2. Department of Behavioural Science and Health, Institute of Epidemiology and Health Care, University College London , London , UK

3. Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology and Neuroscience, King’s College London , London , UK

4. Child and Adolescent Psychiatry Department, Institute of Psychiatry and Mental Health, Hospital General Universitario Gregorio Marañón, School of Medicine, Universidad Complutense, IiSGM, CIBERSAM , C/Doctor Esquerdo 46, 28007 Madrid , Spain

5. Department of Biomedical and Neuromotor Sciences, Psychiatry Unit, Alma Mater Studiorum Università di Bologna , Viale Pepoli 5, 40126 Bologna , Italy

6. Department of Psychiatry, Barcelona Clinic Schizophrenia Unit, Neuroscience Institute, Hospital Clinic of Barcelona, University of Barcelona, IDIBAPS, CIBERSAM , Barcelona , Spain

7. Faculty of Medicine and Health Sciences, Psychiatry, Universidad de Oviedo, ISPA, INEUROPA . CIBERSAM, Oviedo , Spain

8. Department of Psychiatry, Early Psychosis Section, Amsterdam UMC, University of Amsterdam , Amsterdam , The Netherlands

9. Neuroscience and Behavior Department, Ribeirão Preto Medical School, University of São Paulo , São Paulo , Brazil

10. Department of Health Service and Population Research, Institute of Psychiatry, Psychology and Neuroscience, King’s College London , London , UK

11. Department of Mental Health and Addiction Services, ASP Crotone , Crotone , Italy

12. Department of Psychosis Studies, Institute of Psychiatry, Psychology and Neuroscience, King’s College London , London , UK

13. Centre for Transcultural Psychiatry Veldzicht , Balkbrug , The Netherlands

14. University Centre for Psychiatry, University Medical Centre Groningen , Groningen , The Netherlands

15. Section of Psychiatry, Department of Neuroscience, Biomedicine and Movement Sciences, University of Verona , Piazzale L.A. Scuro 10, 37134 Verona , Italy

16. Université Clermont Auvergne, CMP-B CHU, CNRS, Clermont Auvergne INP, Institut Pascal , F-63000 Clermont-Ferrand , France

17. Department of Preventative Medicine, Faculdade de Medicina FMUSP, University of São Paulo , São Paulo , Brazil

18. Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience, South Limburg Mental Health Research and Teaching Network, Maastricht University Medical Centre , P.O. Box 616, 6200 MD Maastricht , The Netherlands

19. Department of Psychiatry, Servicio de Psiquiatría Hospital “Virgen de la Luz” , Cuenca , Spain

20. Department of Psychiatry, Hospital Clínico Universitario de Valencia, INCLIVA, CIBERSAM, School of Medicine, Universidad de Valencia , Valencia , Spain

21. Rivierduinen Institute for Mental Health Care , Sandifortdreef 19, 2333 ZZ Leiden , The Netherlands

22. University of Paris Est Creteil, INSERM, IMRB, AP-HP, Hôpitaux Universitaires « H. Mondor », DMU IMPACT , Fondation FondaMental, F-94010 Creteil , France

23. Department of Medical and Surgical Sciences, Bologna University , Bologna , Italy

24. Etablissement Public de Santé Maison Blanche , Paris , France

25. Department of Psychiatry, Early Psychosis Section, Academic Medical Centre, University of Amsterdam , Amsterdam , The Netherlands

26. Department of Psychiatry, Icahn School of Medicine at Mount Sinai , New York, NY , USA

27. Department of Psychiatry, University of Cambridge, Herchel Smith Building for Brain and Mind Sciences , Forvie Site, Robinson Way, Cambridge, CB2 0SZ , UK

28. CAMEO Early Intervention Service, Cambridgeshire and Peterborough NHS Foundation Trust , Cambridge, CB21 5EF , UK

29. Department of Psychiatry, Psychiatric Genetic Group, Instituto de Investigación Sanitaria de Santiago de Compostela, Complejo Hospitalario s , Santiago de Compostela , Spain

30. Department of Experimental Biomedicine and Clinical Neuroscience, University of Palermo , Via G. La Loggia 1, 90129 Palermo , Italy

31. Psylife Group, Division of Psychiatry, University College London , 6th Floor, Maple House, 149 Tottenham Court Road, London, W1T 7NF , UK

32. Department of Psychiatry, Brain Centre Rudolf Magnus, Utrecht University Medical centre , Utrecht , The Netherlands

33. Division of Psychological Medicine and Clinical Neurosciences, MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University , Cardiff CF24 4HQ , UK

34. Department of Psychiatry, Experimental Biomedicine and Clinical Neuroscience, University of Palermo , Palermo , Italy

35. Department of Health Service and Population Research, Institute of Psychiatry, King’s College London , De Crespigny Park, Denmark Hill, London, SE5 8AF , United Kingdom

36. Section of Psychiatry, Department of Neuroscience, Biomedicine and Movement, University of Verona , Piazzale L.A. Scuro 10, 37134 Verona , Italy

37. Department of Child and Adolescent Psychiatry, Hospital General Universitario Gregorio Marañón, School of Medicine, Universidad Complutense, IiSGM (CIBERSAM) , C/Doctor Esquerdo 46, 28007 Madrid , Spain

38. Villa de Vallecas Mental Health Department, Villa de Vallecas Mental Health Centre, Hospital Universitario Infanta Leonor/ Hospital Virgen de la Torre , C/San Claudio 154, 28038 Madrid , Spain

39. Puente de Vallecas Mental Health Department, Hospital Universitario Infanta Leonor/ Hospital Virgen de la Torre, Centro de Salud Mental Puente de Vallecas , C/Peña Gorbea 4, 28018 Madrid , Spain

40. Fundación Pública Galega de Medicina Xenómica, Hospital Clínico Universitario, Choupana s/n , 15782 Santiago de Compostela , Spain

41. Department of Psychiatry, Hospital General Universitario Gregorio Marañón, School of Medicine, Universidad Complutense, IiSGM (CIBERSAM) , C/Doctor Esquerdo 46, 28007 Madrid , Spain

42. Department of Psychiatry, Hospital Clinic, IDIBAPS, Universidad de Barcelona , C/Villarroel 170, 08036 Barcelona , Spain

43. Department of Psychiatry, Hospital Universitari Vall d’Hebron; Group of Psychiatry, Mental Health and Addictions, Psychiatric Genetics Unit, Vall d’Hebron Research Institute (VHIR) , Barcelona , Spain

44. Biomedical Network Research Centre on Mental Health (CIBERSAM) , Barcelona , Spain

45. Neurobiology Unit, Program in Neurosciences and Interdisciplinary Research Structure for Biotechnology and Biomedicine (BIOTECMED), Universitat de València , Burjassot , Spain

46. Biomedical Research Networking Centre in Mental Health (CIBERSAM) , Madrid , Spain

47. Biomedical Research Institute INCLIVA , Valencia , Spain

48. Department of Medicine, Psychiatry Area, School of Medicine, Universidad de Oviedo, Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM) , C/Julián Clavería s/n, 33006 Oviedo , Spain

49. Department of Psychiatry, Servicio de Psiquiatría Hospital “Virgen de la Luz,” C/Hermandad de Donantes de Sangre , 16002 Cuenca , Spain

50. Department of Psychiatry, Early Psychosis Section, Academic Medical Centre, University of Amsterdam , Meibergdreef 5, 1105 AZ Amsterdam , The Netherlands

51. Rivierduinen Centre for Mental Health, Leiden , Sandifortdreef 19, 2333 ZZ Leiden , The Netherlands

52. Rivierduinen Centre for Mental Health , Leiden, Sandifortdreef 19, 2333 ZZ Leiden , The Netherlands

53. AP-HP, Groupe Hospitalier “Mondor,” Pôle de Psychiatrie , 51 Avenue de Maréchal de Lattre de Tassigny, 94010 Créteil , France

54. Faculté de Médecine, Université Paris-Est , 51 Avenue de Maréchal de Lattre de Tassigny, 94010 Créteil , France

55. INSERM, U955, Equipe 15, 51 Avenue de Maréchal de Lattre de Tassigny , 94010 Créteil , France

56. Fondation Fondamental , 40 Rue de Mesly, 94000 Créteil , France

57. Université Clermont Auvergne , EA 7280, Clermont-Ferrand, 63000 , France

58. Department of Experimental Biomedicine and Clinical Neuroscience, Section of Psychiatry, University of Palermo , Via G. La Loggia n.1, 90129 Palermo , Italy

59. Unit of Psychiatry, “P. Giaccone” General Hospital , Via G. La Loggia n.1, 90129 Palermo , Italy

60. Departamento de Neurociências e Ciencias do Comportamento, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo , Av. Bandeirantes, 3900 - Monte Alegre- CEP 14049-900, Ribeirão Preto, SP , Brasil

Abstract

Abstract Background and Hypothesis It is argued that availability of diagnostic models will facilitate a more rapid identification of individuals who are at a higher risk of first episode psychosis (FEP). Therefore, we developed, evaluated, and validated a diagnostic risk estimation model to classify individual with FEP and controls across six countries. Study Design We used data from a large multi-center study encompassing 2627 phenotypically well-defined participants (aged 18–64 years) recruited from six countries spanning 17 research sites, as part of the European Network of National Schizophrenia Networks Studying Gene-Environment Interactions study. To build the diagnostic model and identify which of important factors for estimating an individual risk of FEP, we applied a binary logistic model with regularization by the least absolute shrinkage and selection operator. The model was validated employing the internal-external cross-validation approach. The model performance was assessed with the area under the receiver operating characteristic curve (AUROC), calibration, sensitivity, and specificity. Study Results Having included preselected 22 predictor variables, the model was able to discriminate adults with FEP and controls with high accuracy across all six countries (rangesAUROC = 0.84–0.86). Specificity (range = 73.9–78.0%) and sensitivity (range = 75.6–79.3%) were equally good, cumulatively indicating an excellent model accuracy; though, calibration slope for the diagnostic model showed a presence of some overfitting when applied specifically to participants from France, the UK, and The Netherlands. Conclusions The new FEP model achieved a good discrimination and good calibration across six countries with different ethnic contributions supporting its robustness and good generalizability.

Funder

National Institute for Health Research

Publisher

Oxford University Press (OUP)

Subject

Psychiatry and Mental health

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