Proteomic Biomarkers for the Prediction of Transition to Psychosis in Individuals at Clinical High Risk: A Multi-cohort Model Development Study

Jonah F Byrne^{1

2}, Colm Healy^{1

3}, Melanie Föcking¹, Subash Raj Susai¹, David Mongan^{1

4}, Kieran Wynne⁵, Eleftheria Kodosaki⁶, Meike Heurich⁶, Lieuwe de Haan⁷, Ian B Hickie⁸, Stefan Smesny⁹, Andrew Thompson^{10

11}, Connie Markulev^{10

11}, Alison Ruth Young^{10

12

13}, Miriam R Schäfer^{10

11}, Anita Riecher-Rössler¹⁴, Nilufar Mossaheb¹⁵, Gregor Berger¹⁶, Monika Schlögelhofer¹⁷, Merete Nordentoft^{18

19}, Eric Y H Chen^{20

21}, Swapna Verma^{22

23}, Dorien H Nieman⁷, Scott W Woods²⁴, Barbara A Cornblatt²⁵, William S Stone²⁶, Daniel H Mathalon^{27

28}, Carrie E Bearden²⁹, Kristin S Cadenhead³⁰, Jean Addington³¹, Elaine F Walker^{32

33}, Tyrone D Cannon^{34

35}, Mary Cannon^{1

2

36}, Pat McGorry^{10

11}, Paul Amminger^{10

11}, Gerard Cagney⁵, Barnaby Nelson^{10

11}, Clark Jeffries³⁷, Diana Perkins³⁸, David R Cotter^{1

2

36}

Affiliations

¹ Department of Psychiatry, Royal College of Surgeons in Ireland, University of Medicine and Health Sciences, Dublin, Ireland.
² SFI FutureNeuro Research Centre, Royal College of Surgeons in Ireland, University of Medicine and Health Sciences, Dublin, Ireland.
³ Department of Psychology, Royal College of Surgeons in Ireland, Dublin 2, Ireland.
⁴ Centre for Public Health, Queen's University Belfast, Belfast, UK.
⁵ School of Biomolecular and Biomedical Science, Conway Institute, University College Dublin, Dublin, Ireland.
⁶ School of Pharmacy and Pharmaceutical Sciences, Cardiff University, Wales, UK.
⁷ Department of Psychiatry, Academic Medical Center, Amsterdam, The Netherlands.
⁸ Brain and Mind Centre, The University of Sydney, Sydney, NSW, Australia.
⁹ Department of Psychiatry, Jena University Hospital, Jena, Germany.
¹⁰ Centre for Youth Mental Health, University of Melbourne, Parkville, VIC, Australia.
¹¹ Orygen, The National Centre of Excellence in Youth Mental Health, Melbourne, VIC, Australia.
¹² Institute for Mental and Physical Health and Clinical Translation (IMPACT), Deakin University, Geelong, VIC, Australia.
¹³ School of Health Sciences, University of Manchester, Manchester, UK.
¹⁴ Medical Faculty, University of Basel, Switzerland.
¹⁵ Department of Psychiatry and Psychotherapy, Clinical Division of Social Psychiatry, Medical University of Vienna, Vienna, Austria.
¹⁶ Department of Child and Adolescent Psychiatry and Psychotherapy, Psychiatric Hospital, University of Zurich, Zurich, Switzerland.
¹⁷ BioPsyC-Biopsychosocial Corporation, Non-profit Association for Research Funding Ltd, Vienna, Austria.
¹⁸ Mental Health Center Copenhagen, Research Unit (CORE), Copenhagen, Denmark.
¹⁹ Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
²⁰ Department of Psychiatry, School of Clinical Medicine, LKS Faculty of Medicine, The University of Hong Kong, 2/F New Clinical Building, Queen Mary Hospital, Pok Fu Lam, Hong Kong.
²¹ The State Key Laboratory of Brain and Cognitive Sciences, The University of Hong Kong, Pok Fu Lam, Hong Kong.
²² Office of Education, Duke-NUS Graduate Medical School, Singapore, Singapore.
²³ Department of Psychosis & East Region, Institute of Mental Health, Singapore, Singapore.
²⁴ Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA.
²⁵ Department of Psychiatry, Zucker Hillside Hospital, Long Island, NY, USA.
²⁶ Department of Psychiatry, Harvard Medical School at Beth Israel Deaconess Medical Center and Massachusetts General Hospital, Boston, MA, USA.
²⁷ Department of Psychiatry and Behavioral Sciences, University of California, San Francisco, San Francisco, CA, USA.
²⁸ Mental Health Service 116d, Veterans Affairs San Francisco Health Care System, San Francisco, CA, USA.
²⁹ Semel Institute for Neuroscience and Human Behavior, Departments of Psychiatry and Biobehavioral Sciences and Psychology, University of California, Los Angeles, CA, USA.
³⁰ Department of Psychiatry, University of California, San Diego, CA, USA.
³¹ Department of Psychiatry, Hotchkiss Brain Institute, University of Calgary, Calgary, Canada.
³² Department of Psychology, Emory University, Atlanta, GA, USA.
³³ Department of Psychiatry, Emory University, Atlanta, GA, USA.
³⁴ Department of Psychology, Yale University, New Haven, CT, USA.
³⁵ Department of Psychiatry, Yale University, New Haven, CT, USA.
³⁶ Department of Psychiatry, Beaumont Hospital, Dublin 9, Ireland.
³⁷ Renaissance Computing Institute, University of North Carolina, Chapel Hill, NC, USA.
³⁸ Department of Psychiatry, University of North Carolina, Chapel Hill, NC, USA.

PMID: 38243809
PMCID: PMC11059811
DOI: 10.1093/schbul/sbad184

Proteomic Biomarkers for the Prediction of Transition to Psychosis in Individuals at Clinical High Risk: A Multi-cohort Model Development Study

Jonah F Byrne et al. Schizophr Bull. 2024.

. 2024 Apr 30;50(3):579-588.

doi: 10.1093/schbul/sbad184.

Authors

Affiliations

¹ Department of Psychiatry, Royal College of Surgeons in Ireland, University of Medicine and Health Sciences, Dublin, Ireland.
² SFI FutureNeuro Research Centre, Royal College of Surgeons in Ireland, University of Medicine and Health Sciences, Dublin, Ireland.
³ Department of Psychology, Royal College of Surgeons in Ireland, Dublin 2, Ireland.
⁴ Centre for Public Health, Queen's University Belfast, Belfast, UK.
⁵ School of Biomolecular and Biomedical Science, Conway Institute, University College Dublin, Dublin, Ireland.
⁶ School of Pharmacy and Pharmaceutical Sciences, Cardiff University, Wales, UK.
⁷ Department of Psychiatry, Academic Medical Center, Amsterdam, The Netherlands.
⁸ Brain and Mind Centre, The University of Sydney, Sydney, NSW, Australia.
⁹ Department of Psychiatry, Jena University Hospital, Jena, Germany.
¹⁰ Centre for Youth Mental Health, University of Melbourne, Parkville, VIC, Australia.
¹¹ Orygen, The National Centre of Excellence in Youth Mental Health, Melbourne, VIC, Australia.
¹² Institute for Mental and Physical Health and Clinical Translation (IMPACT), Deakin University, Geelong, VIC, Australia.
¹³ School of Health Sciences, University of Manchester, Manchester, UK.
¹⁴ Medical Faculty, University of Basel, Switzerland.
¹⁵ Department of Psychiatry and Psychotherapy, Clinical Division of Social Psychiatry, Medical University of Vienna, Vienna, Austria.
¹⁶ Department of Child and Adolescent Psychiatry and Psychotherapy, Psychiatric Hospital, University of Zurich, Zurich, Switzerland.
¹⁷ BioPsyC-Biopsychosocial Corporation, Non-profit Association for Research Funding Ltd, Vienna, Austria.
¹⁸ Mental Health Center Copenhagen, Research Unit (CORE), Copenhagen, Denmark.
¹⁹ Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
²⁰ Department of Psychiatry, School of Clinical Medicine, LKS Faculty of Medicine, The University of Hong Kong, 2/F New Clinical Building, Queen Mary Hospital, Pok Fu Lam, Hong Kong.
²¹ The State Key Laboratory of Brain and Cognitive Sciences, The University of Hong Kong, Pok Fu Lam, Hong Kong.
²² Office of Education, Duke-NUS Graduate Medical School, Singapore, Singapore.
²³ Department of Psychosis & East Region, Institute of Mental Health, Singapore, Singapore.
²⁴ Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA.
²⁵ Department of Psychiatry, Zucker Hillside Hospital, Long Island, NY, USA.
²⁶ Department of Psychiatry, Harvard Medical School at Beth Israel Deaconess Medical Center and Massachusetts General Hospital, Boston, MA, USA.
²⁷ Department of Psychiatry and Behavioral Sciences, University of California, San Francisco, San Francisco, CA, USA.
²⁸ Mental Health Service 116d, Veterans Affairs San Francisco Health Care System, San Francisco, CA, USA.
²⁹ Semel Institute for Neuroscience and Human Behavior, Departments of Psychiatry and Biobehavioral Sciences and Psychology, University of California, Los Angeles, CA, USA.
³⁰ Department of Psychiatry, University of California, San Diego, CA, USA.
³¹ Department of Psychiatry, Hotchkiss Brain Institute, University of Calgary, Calgary, Canada.
³² Department of Psychology, Emory University, Atlanta, GA, USA.
³³ Department of Psychiatry, Emory University, Atlanta, GA, USA.
³⁴ Department of Psychology, Yale University, New Haven, CT, USA.
³⁵ Department of Psychiatry, Yale University, New Haven, CT, USA.
³⁶ Department of Psychiatry, Beaumont Hospital, Dublin 9, Ireland.
³⁷ Renaissance Computing Institute, University of North Carolina, Chapel Hill, NC, USA.
³⁸ Department of Psychiatry, University of North Carolina, Chapel Hill, NC, USA.

PMID: 38243809
PMCID: PMC11059811
DOI: 10.1093/schbul/sbad184

Abstract

Psychosis risk prediction is one of the leading challenges in psychiatry. Previous investigations have suggested that plasma proteomic data may be useful in accurately predicting transition to psychosis in individuals at clinical high risk (CHR). We hypothesized that an a priori-specified proteomic prediction model would have strong predictive accuracy for psychosis risk and aimed to replicate longitudinal associations between plasma proteins and transition to psychosis. This study used plasma samples from participants in 3 CHR cohorts: the North American Prodrome Longitudinal Studies 2 and 3, and the NEURAPRO randomized control trial (total n = 754). Plasma proteomic data were quantified using mass spectrometry. The primary outcome was transition to psychosis over the study follow-up period. Logistic regression models were internally validated, and optimism-corrected performance metrics derived with a bootstrap procedure. In the overall sample of CHR participants (age: 18.5, SD: 3.9; 51.9% male), 20.4% (n = 154) developed psychosis within 4.4 years. The a priori-specified model showed poor risk-prediction accuracy for the development of psychosis (C-statistic: 0.51 [95% CI: 0.50, 0.59], calibration slope: 0.45). At a group level, Complement C8B, C4B, C5, and leucine-rich α-2 glycoprotein 1 (LRG1) were associated with transition to psychosis but did not surpass correction for multiple comparisons. This study did not confirm the findings from a previous proteomic prediction model of transition from CHR to psychosis. Certain complement proteins may be weakly associated with transition at a group level. Previous findings, derived from small samples, should be interpreted with caution.

Keywords: coagulation; complement; high risk; immune; model; prediction; proteome; psychosis.

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References

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Proteomic Biomarkers for the Prediction of Transition to Psychosis in Individuals at Clinical High Risk: A Multi-cohort Model Development Study

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Proteomic Biomarkers for the Prediction of Transition to Psychosis in Individuals at Clinical High Risk: A Multi-cohort Model Development Study

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