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Understanding molecular traits through metabolomics offers an avenue to tailor cardiovascular prevention, diagnosis and treatment strategies… (see more) 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). We aim to uncover metabolites with significant predictive value by analyzing targeted metabolomics data through ML and XAI algorithms. After quality control, we analyzed 55 metabolites from 124 plasma samples, including 53 HF patients and 71 controls, comparing Ridge Logistic Regression, Support Vector Machine and eXtreme Gradient Boosting models. All achieved high accuracy in predicting group labels: 84.0% [95% CI: 75.3 — 92.7], 85.73 [95% CI: 78.6 — 92.9], and 84.8% [95% CI: 76.1 – 93.5], 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 HF, such as glucose and cholesterol, and more recently described, the 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.
2024-12-31
Computational and Structural Biotechnology Journal (published)
Studies combining metabolomics and genetics, known as metabolite genome-wide association studies (mGWAS), have provided valuable insights in… (see more)to our understanding of the genetic control of metabolite levels. However, the biological interpretation of these associations remains challenging due to a lack of existing tools to annotate mGWAS gene-metabolite pairs beyond the use of conservative statistical significance threshold. Here, we computed the shortest reactional distance (SRD) based on the curated knowledge of the KEGG database to explore its utility in enhancing the biological interpretation of results from three independent mGWAS, including a case study on sickle cell disease patients. Results show that, in reported mGWAS pairs, there is an excess of small SRD values and that SRD values and p-values significantly correlate, even beyond the standard conservative thresholds. The added-value of SRD annotation is shown for identification of potential false negative hits, exemplified by the finding of gene-metabolite associations with SRD ≤1 that did not reach standard genome-wide significance cut-off. The wider use of this statistic as an mGWAS annotation would prevent the exclusion of biologically relevant associations and can also identify errors or gaps in current metabolic pathway databases. Our findings highlight the SRD metric as an objective, quantitative and easy-to-compute annotation for gene-metabolite pairs that can be used to integrate statistical evidence to biological networks.
