open access publication

Article, Early Access, 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, 0586-7614, 10.1093/schbul/sbad184

Contributors

Byrne, Jonah F. (Corresponding author) [1] Healy, Colm 0000-0001-7974-1861 [1] [2] Focking, Melanie [1] Susai, Subash Raj 0000-0002-3818-6504 [1] Mongan, David 0000-0001-7931-9636 [1] [3] Wynne, Kieran 0000-0001-5759-5285 [2] Kodosaki, Eleftheria [4] Heurich, Meike [4] de Haan, L. [5] [6] Hickie, Ian 0000-0001-8832-9895 [7] Smesny, Stefan [8] Thompson, Andrew [9] [10] Markulev, Connie [9] [10] Young, Alison Ruth [9] [10] [11] [12] Schaefer, Miriam [9] [10] Riecher-Roessler, Anita 0000-0001-6361-8789 [13] Mossaheb, Nilufar [14] Berger, Gregor 0000-0003-2030-141X [15] Schloegelhofer, Monika [16] Nordentoft, Merete [17] [18] Chen, Eric Y. H. [19] Verma, Swapna [20] [21] Nieman, Dorien H. Woods, Scott W. [22] Cornblatt, B. [23] Stone, William S. 0000-0003-2932-7288 [24] [25] [26] [27] Mathalon, Daniel H. [28] [29] [30] Bearden, Carrie E. [30] [31] Cadenhead, Kristin S. [30] [32] Addington, Jean [33] Walker, Elaine F. [34] Cannon, Tyrone D. [1] [22] Cannon, Mary [1] [35] McGorry, Pat [9] [10] Amminger, Paul [9] [10] Cagney, Gerard 0000-0001-7189-9496 [2] Nelson, Barnaby 0000-0002-6263-2332 [9] [10] Jeffries, Clark [36] [37] Perkins, Diana [36] [37] Cotter, David R. [1] [35]

Affiliations

  1. [1] Beaumont Hosp, RCSI Educ & Res Ctr, Dublin, Ireland
    2. [NORA names: Ireland; Europe, EU; OECD];
  2. [2] Royal Coll Surgeons Ireland, Dept Psychol, Dublin, Ireland
    3. [NORA names: Ireland; Europe, EU; OECD];
  3. [3] Queens Univ Belfast, Ctr Publ Hlth, Belfast, North Ireland
    4. [NORA names: United Kingdom; Europe, Non-EU; OECD];
  4. [4] Cardiff Univ, Sch Pharm & Pharmaceut Sci, Cardiff, Wales
    5. [NORA names: United Kingdom; Europe, Non-EU; OECD];
  5. [5] Acad Med Ctr, Dept Psychiat, Amsterdam, Netherlands
    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 alpha-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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