April 2, 2024

Synergy detection: A practical guide to statistical assessment of potential drug combinations

Puntos clave

Combination treatments aim to improve response, reduce resistance, and lower adverse events.
Effect sizes and confidence intervals were quantified using the Biochemically Intuitive Generalized Loewe methodology.
The methodology allows for proper statistical evaluation under different null models to detect interactions effectively and accurately during experiments across therapeutic areas and applications requiring drug discovery and combination assessment—while minimizing false coverage rates in results interpretation and presentation across multiple tests, models, and theoretical forecasts and protocols for statistical detection of synergistic effects in drug design and screening effort improvement.

Resumen

Abstract Combination treatments have been of increasing importance in drug development across therapeutic areas to improve treatment response, minimize the development of resistance, and/or minimize adverse events. Pre‐clinical in‐vitro combination experiments aim to explore the potential of such drug combinations during drug discovery by comparing the observed effect of the combination with the expected treatment effect under the assumption of no interaction (i.e., null model). This tutorial will address important design aspects of such experiments to allow proper statistical evaluation. Additionally, it will highlight the Biochemically Intuitive Generalized Loewe methodology (BIGL R package available on CRAN) to statistically detect deviations from the expectation under different null models. A clear advantage of the methodology is the quantification of the effect sizes, together with confidence interval while controlling the directional false coverage rate. Finally, a case study will showcase the workflow in analyzing combination experiments.

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