Addressing heterogeneous treatment effects in acute care syndromes: principles and practical considerations

BACKGROUND: Critical care medicine has historically relied on syndromic diagnoses such as sepsis, acute respiratory distress syndrome (ARDS) and acute kidney injury to guide research and treatment. While this approach has advanced clinical practice, the growing recognition of patient heterogeneity presents significant challenges for treatment optimisation and trial interpretation. Understanding heterogeneous treatment effects (HTE) has emerged as a crucial methodological frontier, particularly for complex critical care syndromes where patient responses to interventions vary substantially. FINDINGS: There are three major methodological frameworks for analysing HTE: (1) Risk-based analyses, guided by the Predictive Approaches to Treatment effect Heterogeneity statement, provide an accessible framework for examining treatment effect variation across baseline risk strata but may overlook important effect modifiers. (2) Clustering techniques have successfully identified distinct phenotypes in both ARDS and sepsis, though external validation remains challenging. (3) Effect-based methods employing new methods offer sophisticated capabilities for identifying treatment effect modifiers but require careful consideration to model specification. CONCLUSION: This review examines these methodological approaches through both theoretical framework and practical application. Considerations on the applicability of HTE are also provided. We conclude that while HTE methods offer promising tools for personalising critical care interventions, their successful implementation requires careful consideration of both methodological rigour and practical feasibility.