Machine Learning-Based Identification of Diagnostic Biomarkers for Korean Male Sarcopenia Through Integrative DNA Methylation and Methylation Risk Score: From the Korean Genomic Epidemiology Study (KoGES).

Abstract

Sarcopenia, characterized by a progressive decline in muscle mass, strength, and function, is primarily attributable to aging. DNA methylation, influenced by both genetic predispositions and environmental exposures, plays a significant role in sarcopenia occurrence. This study employed machine learning (ML) methods to identify differentially methylated probes (DMPs) capable of diagnosing sarcopenia in middle-aged individuals. We also investigated the relationship between muscle strength, muscle mass, age, and sarcopenia risk as reflected in methylation profiles. Data from 509 male participants in the urban cohort of the Korean Genome Epidemiology Study_Health Examinee study were categorized into quartile groups based on the sarcopenia criteria for appendicular skeletal muscle index (ASMI) and handgrip strength (HG). To identify diagnostic biomarkers for sarcopenia, we used recursive feature elimination with cross validation (RFECV), to pinpoint DMPs significantly associated with sarcopenia. An ensemble model, leveraging majority voting, was utilized for evaluation. Furthermore, a methylation risk score (MRS) was calculated, and its correlation with muscle strength, function, and age was assessed using likelihood ratio analysis and multinomial logistic regression. Participants were classified into two groups based on quartile thresholds: sarcopenia (n = 37) with ASMI and HG in the lowest quartile, and normal ranges (n = 48) in the highest. In total, 238 DMPs were identified and eight probes were selected using RFECV. These DMPs were used to build an ensemble model with robust diagnostic capabilities for sarcopenia, as evidenced by an area under the receiver operating characteristic curve of 0.94. Based on eight probes, the MRS was calculated and then validated by analyzing age, HG, and ASMI among the control group (n = 424). Age was positively correlated with high MRS (coefficient, 1.2494; odds ratio [OR], 3.4882), whereas ASMI and HG were negatively correlated with high MRS (ASMI coefficient, -0.4275; OR, 0.6521; HG coefficient, -0.3116; OR, 0.7323). Overall, this study identified key epigenetic markers of sarcopenia in Korean males and developed a ML model with high diagnostic accuracy for sarcopenia. The MRS also revealed significant correlations between these markers and age, HG, and ASMI. These findings suggest that both diagnostic models and the MRS can play an important role in managing sarcopenia in middle-aged populations.