In the context of using big data to improve healthcare and life sciences and with a specific focus on drug discovery, we consider the problem of formulating biomedical mechanism-of-action (MOA) hypotheses that can explain how specific drugs treat specific diseases. Our aim is to enable scalable mining and interpretation of MOA hypotheses enabling drug discovery and repurposing on large-scale biomedical knowledge graphs (KGs).The approach that we introduce to address this problem centers on expert-guided generation of candidate MOA hypotheses in the form of regular-path KG patterns between the KG nodes for the entities of interest, such as drugs and diseases. We call those patterns that represent promising candidate MOAs functional path patterns (FPPs), and call the proposed approach FPP-Hunter. The results of a drug-disease case study that we have conducted with the biomedical KG ROBOKOP suggest that the proposed approach has the potential to address scalability challenges in forming promising MOA hypotheses using large-scale KGs, in drug repurposing and potentially beyond.

Knowledge graphs (KGs) represent the connections and relationships between real-world entities. We propose a link prediction framework on KGs named Enrichment-Driven GrAph Reasoner (EDGAR) that infers new edges by mining entity-local rules. This approach is based on enrichment analysis, a well-established statistical method used to calculate mechanisms common to a set of differentially expressed genes. EDGAR’s inference results are inherently explainable and rankable, equipped with p-values for statistical significance of each enrichment-based rule. We demonstrate its effectiveness on a large-scale biomedical KG, ROBOKOP, focusing on drug repurposing for Alzheimer disease (AD) as a case study. Initially, we extracted 14 known drugs from the KG and identified 20 contextual biomarkers through enrichment analysis, shedding light on functional pathways relevant to the shared efficacy of drugs for AD. Subsequently, using the top 1,000 enrichment results, our enrichment-driven system identified 1,246 additional drug candidates for AD treatment. We validated the top 10 candidates using medical literature evidence. EDGAR is deployed within ROBOKOP, along with a web user interface. This is the first work to use enrichment analysis for either large graph completion or drug repurposing.

Knowledge graphs have been growing in popularity in recent years, due to their successful use in many data-analytics and knowledge-discovery tasks. As the sizes of domain graphs continue to grow, they can become too large to be processed efficiently by downstream applications. It is thus indispensable in many cases to aim to address the efficiency issue by reducing knowledge-graph sizes via summarization. At the same time, to provide quality results, that is, to be effective, on the graph summaries, many downstream analytics and knowledge-discovery tasks require the summaries to retain as much information from the original graph as possible. It turns out that state-of-the-art data-reduction approaches may generate task-specific or lossy summaries, which may present challenges for the effectiveness of downstream analytics in some cases. As a result, it is important to study trade-offs between the performance and accuracy of graph summarizations for analytics and knowledge discovery.In this paper, in the scope of knowledge-graph size reduction via summarization, we consider the trade-off between the performance and accuracy of one type of knowledge-graph analytics, inference-rule mining, on the summarized graphs as compared with the original graphs. Toward addressing the tradeoff challenge, we introduce a domain- and task-independent knowledge-graph summarization approach called GAME for generating reduced abstract knowledge graphs from a given graph. Our preliminary experimental results suggest that our GAME approach can preserve as much information from the given (original) graph as possible for the purpose of rule mining, while potentially significantly improving the rule-mining efficiency. We anticipate that the knowledge-graph reduction provided by the proposed GAME approach can enable efficient, yet effective, results for diverse applications and use cases.

Recently, knowledge graphs have seen a significant increase in popularity in a wide variety of domains, as they provide a basis for many data-analytics and knowledge-discovery approaches. At the same time, many knowledge graphs are not immediately usable due to their format, unreadable or missing data, and inaccessibility. These issues present barriers to the exploration and use of knowledge graphs for big data analytics and knowledge discovery. In this paper we present a workflow for domain- and task-sensitive curation of large-scale knowledge graphs, and detail our experience with implementing this workflow with the biomedical knowledge graph called Drug Repurposing Knowledge Graph (DRKG). The workflow aims to address usability-related issues of real-life knowledge graphs, by performing data setup and curation that align with the needs of specific tasks and domains. Recognizing that domain experts and anticipated users of a knowledge graph provide invaluable expertise regarding the desired graph format, the proposed workflow involves them as humans-in-the-loop. We present the processes required to execute the workflow, detail our experience in the biomedical domain with the use case of DRKG, and discuss the challenges and lessons learned throughout the experience. We anticipate that the proposed workflow and experiences will be applicable to other domains, and that our workflow will enable and encourage exploration and wider use of large-scale knowledge graphs, thereby improving big data analytics.

Knowledge-graph (KG) embeddings have emerged as a promise in addressing challenges faced by modern biomedical research, including the growing gap between therapeutic needs and available treatments. The popularity of KG embeddings in graph analytics is on the rise, due at least partially to the presumed semanticity of the learned embeddings. Unfortunately, the ability of a node neighborhood picked up by an embedding to capture the node's semantics may depend on the characteristics of the data. One of the reasons for this problem is that KG nodes can be promiscuous, that is, associated with a number of different relationships that are not unique or indicative of the properties of the nodes.

Drug discovery is an important process used by biomedical experts to identify potential treatments for diseases. In its traditional form, the process requires significant expert time and manual effort. By encoding a wealth of information about relationships between drugs and diseases, modern large-scale biomedical knowledge graphs provide excellent opportunities to accelerate drug discovery, by automating aspects of the process. One opportunity is to use explainable fact-checking tools to generate explanations for hypothesized drug-disease treatment relationships in a given knowledge graph, with a reliability score assigned to each explanation. The explanations and their scores can then be used by experts to determine which drug-disease pairs to consider for clinical trials.In our collaboration with a biomedical team, we have found that existing explainable fact-checking tools are not necessarily helpful in drug discovery, as their explanation formats and evaluation metrics do not match well the requirements of scientific discovery in the biomedical domain. To address these challenges in using fact-checking tools in drug discovery, we introduce a scalable automated approach for generating explanations that are modeled after existing biomedical concepts and supplemented with data-supported evaluation metrics. Our explanations are based on knowledge-graph patterns, which are readily understood by biomedical experts. Our experimental results suggest that our proposed metrics are accurate and useful on largescale biomedical knowledge graphs, and our explanations are understandable and reasonable to experts doing drug discovery.