Abstract To identify causation, model-free inference methods, such as Granger Causality, have been widely used due to their flexibility. However, they have difficulty distinguishing synchrony and indirect effects from direct causation, leading to false predictions. To overcome this, model-based inference methods that test the reproducibility of data with a specific mechanistic model to infer causality were developed. However, they can only be applied to systems described by a specific model, greatly limiting their applicability. Here, we address this limitation by deriving an easily testable condition for a general monotonic ODE model to reproduce time-series data. We built a user-friendly computational package, General ODE-Based Inference (GOBI), which is applicable to nearly any monotonic system with positive and negative regulations described by ODE. GOBI successfully inferred positive and negative regulations in various networks at both the molecular and population levels, unlike existing model-free methods. Thus, this accurate and broadly applicable inference method is a powerful tool for understanding complex dynamical systems.
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