Abstract
INTRODUCTION: The complexity of COVID-19 requires approaches that extend beyond symptom-based descriptors. Multi-omic data, combining clinical, proteomic, and metabolomic information, offer a more detailed view of disease mechanisms and biomarker discovery. METHODS: As part of a large-scale Quebec initiative, we collected extensive datasets from COVID-19 positive and negative patient samples. Using a multi-view machine learning framework with ensemble methods, we integrated thousands of features across clinical, proteomic, and metabolomic domains to classify COVID-19 status. We further applied a novel feature relevance methodology to identify condensed signatures. RESULTS: Our models achieved a balanced accuracy of 89% ± 5% despite the high-dimensional nature of the data. Feature selection yielded 12- and 50-feature signatures that improved classification accuracy by at least 3% compared to the full feature set. These signatures were both accurate and interpretable. DISCUSSION: This work demonstrates that multi-omic integration, combined with advanced machine learning, enables the extraction of robust COVID-19 signatures from complex datasets. The condensed biomarker sets provide a practical path toward improved diagnosis and precision medicine, representing a significant advancement in COVID-19 biomarker discovery.