The multiclass ARKA framework for developing improved q-RASAR models for environmental toxicity endpoints†

The continuous quest for the quick, accurate, and efficient methods for filling the gaps in the toxicity data of commercial chemicals is the need of the hour. Thus, it has become essential to develop simple and improved modeling strategies that aim to generate more accurate predictions. Recently, quantitative Read-Across Structure–Activity Relationship (q-RASAR) modeling has been reported to enhance the external predictivity of QSAR models. However, the cross-validation metrics of some q-RASAR models show compromised values compared to those of the corresponding QSAR models. We report here an improved q-RASAR workflow coupled with the Arithmetic Residuals in K-groups Analysis (ARKA) framework. This improved workflow (ARKA-RASAR) considers two important aspects: the contribution of different QSAR descriptors to different experimental response ranges, and the identification of similarity among close congeners based on both the selected QSAR descriptors and the contribution of different QSAR descriptors to different experimental response ranges. A simple, free, and user-friendly Java-based tool, Multiclass ARKA-v1.0, has been developed to compute the multiclass ARKA descriptors. In this study, five different toxicity datasets previously used for the development of QSAR and q-RASAR models were considered. We developed hybrid ARKA models that consist of a combination of QSAR descriptors and ARKA descriptors. These hybrid feature spaces were used to compute RASAR descriptors and develop ARKA-RASAR models. We used the same modeling strategies used to develop the previously reported QSAR and q-RASAR models for a fair comparison. Additionally, these modeling algorithms are straightforward, reproducible, and transferable. A multi-criteria decision-making statistical approach, the Sum of Ranking Differences (SRD), indicated that the ARKA-RASAR models are the best-performing models, considering training, test, and cross-validation statistics. The least significant difference procedure ensured that the SRD values were significantly different for most models, presenting an unbiased workflow. True external validation using a set of pesticide metabolites and predicting their early-stage acute fish toxicity using relevant ARKA-RASAR models was also carried out and yielded encouraging results. The promising results and the ease of computation of ARKA and RASAR descriptors using our tools suggest that the ARKA-RASAR modeling framework may be a potential choice for developing highly robust and predictive models for filling the gaps in environmental toxicity data.