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We show that both thresholding methods improve significantly the performance of RF. We tested the use of GHOST with four different classifiers in combination with two molecular descriptors, and we found that most classifiers benefit from threshold optimization. GHOST also outperformed other strategies, including random undersampling and conformal prediction. Finally, we show that our thresholding procedures can be effectively applied to real-world drug discovery projects, where the imbalance and characteristics of the data vary greatly be