On Two Novel Parameters for Validation of Predictive QSAR Models.

Validation is a crucial aspect of quantitative structure-activity relationship (QSAR) modeling. The present paper shows that traditionally used validation parameters (leave-one-out Q2 for internal validation and predictive R2 for external validation) may be supplemented with two novel parameters rm 2 and Rp 2 for a stricter test of validation. The parameter rm 2 (overall) penalizes a model for large differences between observed and predicted values of the compounds of the whole set (considering both training and test sets) while the parameter Rp 2 penalizes model R2 for large differences between determination coefficient of nonrandom model and square of mean correlation coefficient of random models in case of a randomization test. Two other variants of rm 2 parameter, rm 2 (LOO) and rm 2 (test), penalize a model more strictly than Q2 and R2 pred respectively. Three different data sets of moderate to large size have been used to develop multiple models in order to indicate the suitability of the novel parameters in QSAR studies. The results show that in many cases the developed models could satisfy the requirements of conventional parameters (Q2 and R2 pred) but fail to achieve the required values for the novel parameters rm 2 and Rp 2. Moreover, these parameters also help in identifying the best models from among a set of comparable models. Thus, a test for these two parameters is suggested to be a more stringent requirement than the traditional validation parameters to decide acceptability of a predictive QSAR model, especially when a regulatory decision is involved. [ABSTRACT FROM AUTHOR]