Plasma Proteomic Profiles Predict Subsequent Obstructive Sleep Apnea Diagnosis in Adults With Metabolic Dysfunction‐Associated Steatotic Liver Disease

ABSTRACT

Early detection of obstructive sleep apnea (OSA) in adults with metabolic dysfunction associated steatotic liver disease (MASLD) remains a clinical challenge. Plasma proteomics provides a non‐invasive tool for identifying individuals at elevated risk prior to symptom onset. We quantified 2911 plasma proteins in 17 375 OSA‐free MASLD subjects from the UK Biobank (UKB). Participants were split into training and validation sets. Cox regression and Light Gradient Boosting Machine (LightGBM) with forward feature selection were used to identify and rank predictive proteins. Model performance was assessed by area under the receiver operating characteristic curve (AUC) in the validation set, and shapley additive explanations (SHAP) values were used to interpret feature contributions. Among 17 375 MASLD participants, 541 (3.1%) developed subsequent clinical diagnosis of OSA. Seven core proteins (FABP4, PON3, RTN4R, KIAA0319, CFC1, TFRC, CST3) were identified and combined into a protein risk score (ProRS). The ProRS stratified high‐ and low‐risk individuals with C‐index 0.727 and 10‐year AUC 0.727, outperforming the clinical risk score (C‐index 0.548). Integration with clinical factors further improved discrimination (C‐index 0.765, 10‐year AUC 0.765) and net benefit. The plasma protein‐based ProRS predicts future OSA in MASLD and enhances risk stratification beyond clinical variables, supporting its potential for early, non‐invasive screening and targeted intervention.