open access publication

Article, 2024

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

Schizophrenia Bulletin, ISSN 0586-7614, 1745-1701, Volume 50, 3, Pages 579-588, 10.1093/schbul/sbad184

Contributors

Byrne, Jonah F 0000-0002-7046-0630 (Corresponding author) [1] Healy, Colm 0000-0001-7974-1861 [1] Föcking, Melanie 0000-0002-6299-2952 [1] Susai, Subash Raj 0000-0002-3818-6504 [1] Mongan, David 0000-0001-7931-9636 [1] [2] Wynne, Kieran J 0000-0001-5759-5285 [3] Kodosaki, Eleftheria 0000-0003-1086-6409 [4] Heurich, Meike 0000-0003-0105-2702 [4] de Haan, Lieuwe [5] Hickie, Ian Bernard 0000-0001-8832-9895 [6] Smesny, Stefan [7] Thompson, Andrew [8] [9] Markulev, Connie [8] [9] Young, Alison Ruth [8] [10] [11] Schäfer, Miriam R [8] [9] Riecher-Rössler, Anita 0000-0001-6361-8789 [12] Mossaheb, Nilufar 0000-0002-7339-7219 [13] Berger, Gregor Emanuel 0000-0003-2030-141X [14] Schlögelhofer, Monika [15] Nordentoft, Merethe 0000-0003-4895-7023 [16] [17] Chen, Eric Yu Hai 0000-0002-5247-3593 [18] [19] Verma, Swapna Kamal 0000-0003-1098-0842 [20] [21] Nieman, Dorien H 0000-0002-9846-4254 [5] Woods, Scott W [22] Cornblatt, Barbara A [23] Stone, William Seth 0000-0003-2932-7288 [24] Mathalon, Daniel H 0000-0001-6090-4974 [25] [26] Bearden, Carrie Elyse 0000-0002-8516-923X [27] Cadenhead, Kristin Suzanne 0000-0002-5952-4605 [28] Addington, Jean [29] Walker, Elaine F [30] Cannon, Tyronne D [22] Cannon, Mary D 0000-0002-0910-299X [1] [31] Mcgorry, Patrick Denistoon 0000-0002-3789-6168 [8] [9] Amminger, Paul G [8] [9] Cagney, Gerard 0000-0001-7189-9496 [3] Nelson, Barnaby [8] [9] Jeffries, Clark Debs [32] Perkins, Diana [33] Cotter, David R 0000-0003-4308-0648 [1] [31]

Affiliations

  1. [1] Royal College of Surgeons in Ireland
    2. [NORA names: Ireland; Europe, EU; OECD];
  2. [2] Queen's University Belfast
    3. [NORA names: United Kingdom; Europe, Non-EU; OECD];
  3. [3] University College Dublin
    4. [NORA names: Ireland; Europe, EU; OECD];
  4. [4] Cardiff University
    5. [NORA names: United Kingdom; Europe, Non-EU; OECD];
  5. [5] Academic Medical Center
    6. [NORA names: Netherlands; Europe, EU; OECD];

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

C4b, C5, C8B, CHR participants, NEURAPRO, North American Prodrome Longitudinal Study 2, Study 2, accuracy, associated with transition to psychosis, associated with transitions, association, biomarkers, bootstrap, bootstrap procedure, caution, clinical high risk, clinical high-risk cohort, cohort, comparison, complement, complement proteins, controlled trials, correction, data, development, development of psychosis, development studies, findings, glycoprotein 1, group, group level, high risk, individuals, investigation, levels, logistic regression models, longitudinal Study 2, longitudinal associations, mass spectrometry, metrics, model, model development studies, multi-cohort, multiple comparisons, outcomes, participants, performance metrics, period, plasma, plasma proteins, plasma proteomics data, plasma samples, predicting transition to psychosis, prediction, prediction accuracy, prediction model, prediction of transition, primary outcome, procedure, protein, proteomic biomarkers, proteomic data, psychiatry, psychosis, psychosis risk, randomized controlled trials, regression models, risk, risk prediction, risk prediction accuracy, samples, spectrometry, study, study follow-up period, transition, transition to psychosis, trials, years

Funders

  • Science Foundation Ireland
  • National Health and Medical Research Council
  • National Institute of Mental Health
  • European Commission

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