The Tip of the Iceberg: Pathway Biology Must Anchor the Next Generation of Critical Care Trials.

Heterogeneity of treatment effect has yielded decades of negative critical care trials. Syndromic diagnoses like sepsis and acute respiratory distress syndrome mask distinct molecular programs that respond differently to the same intervention, and single biomarkers lack the resolution to capture this complexity. Recent evidence now demonstrates that each step of the enrichment pipeline, from real-time bedside endotyping to prospective endotype-matched therapy, is clinically operational. However, current approaches rely on limited biomarker panels that capture only surface-level biology. Pathway biology, examining coordinated dysregulation of molecular networks rather than isolated analytes, offers the deeper resolution needed to match patients to targeted therapies. We propose a translational pipeline integrating multiomics, pathway analysis, machine learning, and point-of-care assays to advance critical care toward pathway-focused predictive enrichment.