Multi-omics integration predicts 17 disease incidences in the UK Biobank.

[IMPORTANCE] Traditional clinical predictors for disease risks have limitations in capturing underlying disease complexity. Multi-omics technologies, such as metabolomics and proteomics, offer deeper molecular perspectives that could enhance risk prediction, but large-scale studies integrating the two omics are scarce.

[OBJECTIVES] The primary objective is to systematically evaluate whether adding metabolomics and/or proteomics data to traditional clinical predictors improves risk prediction for 17 common incident diseases. A secondary objective is to identify key disease-related omics features.

[DATA SOURCES AND PARTICIPANTS] Our study incorporated 23,776 UK Biobank participants who had complete baseline omics data for 159 NMR-based metabolites and 2,923 Olink affinity-based proteins.

[MAIN OUTCOMES AND MEASURES] We evaluated the model prediction of 17 incident diseases by fitting Cox proportional hazard models and obtaining Harrell's C-index. Feature importance scores were calculated to identify key molecules contributing to each disease risk prediction.

[RESULTS] Adding omics data significantly improved risk prediction for all 17 diseases compared to models with clinical predictors alone (p-value < 2E-4). Proteomics-only models generally demonstrated superior predictive performance over metabolomics-only models for 14 of the 17 endpoints. We also identified key proteins, including established biomarkers like KLK3 (PSA) for prostate cancer and CRYBB2 for cataracts.

[CONCLUSION AND RELEVANCE] Integration of Olink proteomics, and to a lesser extent Nightingale metabolomics, substantially improves risk prediction for a wide range of common diseases beyond established clinical factors. These findings highlight the clinical utility of proteomics for enhancing individual risk prediction and provide molecular insights into disease mechanisms, which may potentially guide future therapeutic development.