Insights into Heart Failure Metabolite Markers through Explainable Machine Learning

Understanding molecular traits through metabolomics offers an avenue to tailor cardiovascular prevention, diagnosis and treatment strategies more effectively. This study focuses on the application of machine learning (ML) and explainable artificial intelligence (XAI) algorithms to detect discriminant molecular signatures in heart failure (HF). In this study, we aim to uncover metabolites with significant predictive value by analyzing targeted metabolomics data through ML models and XAI methodologies. After robust quality control procedures, we analyzed 55 metabolites from 124 plasma samples, including 53 HF patients and 71 controls, comparing Logistic Regression (Logit) models with Support Vector Machine (SVM) and eXtreme Gradient Boosting (XGB), all achieving high accuracy in predicting group labels: 84.20% ( σ =5.46), 85.73% ( σ =6.25), and 84.80% ( σ =7.84), respectively. Permutation-based variable importance and Local Interpretable Model-agnostic Explanations (LIME) were used for group-level and individual-level explainability, respectively, complemented by H-Friedman statistics for variable interactions, yielding reliable, explainable insights of the ML models. Metabolites well-known for their association with heart failure, such as glucose and cholesterol, but also more recently described association such C18:1 carnitine, were reaffirmed in our analysis. The novel discovery of lignoceric acid (C24:0 fatty acid) as a critical discriminator, was confirmed in a replication cohort, underscoring its potential as a metabolite marker. Furthermore, our study highlights the utility of 2-way variable interaction analysis in unveiling a network of metabolite interactions essential for accurate disease prediction. The results demonstrate our approach’s efficacy in identifying key metabolites and their interactions, illustrating the power of ML and XAI in advancing personalized healthcare solutions.

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