Explainable artificial intelligence in high-throughput drug repositioning for subgroup stratifications with interventionable potential

• Published in: Journal of biomedical informatics 2021-06, Vol.118, p.103792-103792, Article 103792
• Main Authors: Al-Taie, Zainab, Liu, Danlu, Mitchem, Jonathan B, Papageorgiou, Christos, Kaifi, Jussuf T., Warren, Wesley C., Shyu, Chi-Ren
• Format: Article
• Language: English
• Subjects: Data mining; Drug repositioning; Explainable AI; Network analysis; Subgroup stratifications
• ISSN: 1532-0464; 1532-0480
• DOI: 10.1016/j.jbi.2021.103792

[Display omitted] •Patient stratification is an essential part of precision medicine implementation.•Computational drug repositioning (DR) is valuable and efficient to streamline the identification of subgroup treatment.•We developed an explainable AI approach for subgroup discovery and DR.•Contrast pattern mining and heterogeneous network analysis were used.•Our approach identifies disease subtypes and recommends drugs for the subgroups. Enabling precision medicine requires developing robust patient stratification methods as well as drugs tailored to homogeneous subgroups of patients from a heterogeneous population. Developing de novo drugs is expensive and time consuming with an ultimately low FDA approval rate. These limitations make developing new drugs for a small portion of a disease population unfeasible. Therefore, drug repositioning is an essential alternative for developing new drugs for a disease subpopulation. This shows the importance of developing data-driven approaches that find druggable homogeneous subgroups within the disease population and reposition the drugs for these subgroups. In this study, we developed an explainable AI approach for patient stratification and drug repositioning. Contrast pattern mining and network analysis were used to discover homogeneous subgroups within a disease population. For each subgroup, a biomedical network analysis was done to find the drugs that are most relevant to a given subgroup of patients. The set of candidate drugs for each subgroup was ranked using an aggregated drug score assigned to each drug. The proposed method represents a human-in-the-loop framework, where medical experts use the data-driven results to generate hypotheses and obtain insights into potential therapeutic candidates for patients who belong to a subgroup. Colorectal cancer (CRC) was used as a case study. Patients' phenotypic and genotypic data was utilized with a heterogeneous knowledge base because it gives a multi-view perspective for finding new indications for drugs outside of their original use. Our analysis of the top candidate drugs for the subgroups identified by medical experts showed that most of these drugs are cancer-related, and most of them have the potential to be a CRC regimen based on studies in the literature.