Predicting anatomic therapeutic chemical classification codes using tiered learning

BACKGROUND: The low success rate and high cost of drug discovery requires the development of new paradigms to identify molecules of therapeutic value. The Anatomical Therapeutic Chemical (ATC) Code System is a World Health Organization (WHO) proposed classification that assigns multi-level codes to compounds based on their therapeutic, pharmacological and chemical characteristics as well as the in-vivo sites(s) of activity. The ability to predict ATC codes of compounds can assist in creation of high-quality chemical libraries for drug screening and in applications such as drug repositioning. We propose a machine learning architecture called tiered learning for prediction of ATC codes that relies on the prediction results of the higher levels of the ATC code to simplify the predictions of the lower levels. RESULTS: The proposed approach was validated using a number of compounds in both cross-validation and test setting. The validation experiments compared chemical descriptors, initialization methods and classification algorithms. The prediction accuracy obtained with tiered learning was found to be either comparable or better than that of established methods. Additionally, the experiments demonstrated the generalizability of the tiered learning architecture, in that its use was found to improve prediction rates for a majority of machine learning algorithms when compared to their stand-alone application. CONCLUSION: The basis of our approach lies in the observation that anatomical-therapeutic biological activity of certain types typically precludes activities of many other types. Thus, there exists a characteristic distribution of the ATC codes, which can be leveraged to limit the search-space of possible codes that can be ascribed at a particular level once the codes at the preceding levels are known. Tiered learning utilizes this observation to constrain the learning space for ATC codes at a particular level based on the ATC code at higher levels. This simplifies the prediction and allows for improved accuracy.