In silico profiling of systemic effects of drugs to predict unexpected interactions.

Identifying unexpected drug interactions is an essential step in drug development. Most studies focus on predicting whether a drug pair interacts or is effective on a certain disease without considering the mechanism of action (MoA). Here, we introduce a novel method to infer effects and interactions of drug pairs with MoA based on the profiling of systemic effects of drugs. By investigating propagated drug effects from the molecular and phenotypic networks, we constructed profiles of 5,441 approved and investigational drugs for 3,833 phenotypes. Our analysis indicates that highly connected phenotypes between drug profiles represent the potential effects of drug pairs and the drug pairs with strong potential effects are more likely to interact. When applied to drug interactions with verified effects, both therapeutic and adverse effects have been successfully identified with high specificity and sensitivity. Finally, tracing drug interactions in molecular and phenotypic networks allows us to understand the MoA.

Predicting the Absorption Potential of Chemical Compounds Through a Deep Learning Approach.

The human colorectal carcinoma cell line (Caco-2) is a commonly used in-vitro test that predicts the absorption potential of orally administered drugs. In-silico prediction methods, based on the Caco-2 assay data, may increase the effectiveness of the high-throughput screening of new drug candidates. However, previously developed in-silico models that predict the Caco-2 cellular permeability of chemical compounds use handcrafted features that may be dataset-specific and induce over-fitting problems. Deep Neural Network (DNN) generates high-level features based on non-linear transformations for raw features, which provides high discriminant power and, therefore, creates a good generalized model. We present a DNN-based binary Caco-2 permeability classifier. Our model was constructed based on 663 chemical compounds with in-vitro Caco-2 apparent permeability data. Two hundred nine molecular descriptors are used for generating the high-level features during DNN model generation. Dropout regularization is applied to solve the over-fitting problem and the non-linear activation. The Rectified Linear Unit (ReLU) is adopted to reduce the vanishing gradient problem. The results demonstrate that the high-level features generated by the DNN are more robust than handcrafted features for predicting the cellular permeability of structurally diverse chemical compounds in Caco-2 cell lines.

An Approach to Reducing Information Loss and Achieving Diversity of Sensitive Attributes in k-anonymity Methods.

Electronic Health Records (EHRs) enable the sharing of patients' medical data. Since EHRs include patients' private data, access by researchers is restricted. Therefore k-anonymity is necessary to keep patients' private data safe without damaging useful medical information. However, k-anonymity cannot prevent sensitive attribute disclosure. An alternative, l-diversity, has been proposed as a solution to this problem and is defined as: each Q-block (ie, each set of rows corresponding to the same value for identifiers) contains at least l well-represented values for each sensitive attribute. While l-diversity protects against sensitive attribute disclosure, it is limited in that it focuses only on diversifying sensitive attributes. The aim of the study is to develop a k-anonymity method that not only minimizes information loss but also achieves diversity of the sensitive attribute. This paper proposes a new privacy protection method that uses conditional entropy and mutual information. This method considers both information loss as well as diversity of sensitive attributes. Conditional entropy can measure the information loss by generalization, and mutual information is used to achieve the diversity of sensitive attributes. This method can offer appropriate Q-blocks for generalization. We used the adult database from the UCI Machine Learning Repository and found that the proposed method can greatly reduce information loss compared with a recent l-diversity study. It can also achieve the diversity of sensitive attributes by counting the number of Q-blocks that have leaks of diversity. This study provides a privacy protection method that can improve data utility and protect against sensitive attribute disclosure. The method is viable and should be of interest for further privacy protection in EHR applications.