SUMMARY: Knowledge graphs are increasingly being used to integrate heterogeneous biomedical knowledge and data. General-purpose graph database management systems such as Neo4j are often used to host and search knowledge graphs, but such tools come with overhead and leave biomedical-specific standards compliance and reasoning to the user. Interoperability across biomedical knowledge bases and reasoning systems necessitates the use of standards such as those adopted by the Biomedical Data Translator consortium. We present PloverDB, a comprehensive software platform for hosting and efficiently serving biomedical knowledge graphs as standards-compliant web application programming interfaces. In addition to fundamental back-end knowledge reasoning tasks, PloverDB automatically handles entity resolution, exposure of standardized metadata and test data, and multiplexing of knowledge graphs, all in a single platform designed specifically for efficient query answering and ease of deployment. PloverDB increases data accessibility and utility by allowing data providers to quickly serve their biomedical knowledge graphs as standards-compliant web services. AVAILABILITY AND IMPLEMENTATION: PloverDB's source code and technical documentation are publicly available under an MIT License at github:RTXteam/PloverDB, archived on Zenodo at doi:10.5281/zenodo.15454600.

MOTIVATION: With the rapidly growing volume of knowledge and data in biomedical databases, improved methods for knowledge-graph-based computational reasoning are needed in order to answer translational questions. Previous efforts to solve such challenging computational reasoning problems have contributed tools and approaches, but progress has been hindered by the lack of an expressive analysis workflow language for translational reasoning and by the lack of a reasoning engine-supporting that language-that federates semantically integrated knowledge-bases. RESULTS: We introduce ARAX, a new reasoning system for translational biomedicine that provides a web browser user interface and an application programming interface (API). ARAX enables users to encode translational biomedical questions and to integrate knowledge across sources to answer the user's query and facilitate exploration of results. For ARAX, we developed new approaches to query planning, knowledge-gathering, reasoning and result ranking and dynamically integrate knowledge providers for answering biomedical questions. To illustrate ARAX's application and utility in specific disease contexts, we present several use-case examples. AVAILABILITY AND IMPLEMENTATION: The source code and technical documentation for building the ARAX server-side software and its built-in knowledge database are freely available online (https://github.com/RTXteam/RTX). We provide a hosted ARAX service with a web browser interface at arax.rtx.ai and a web API endpoint at arax.rtx.ai/api/arax/v1.3/ui/. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

BACKGROUND: Biomedical translational science is increasingly using computational reasoning on repositories of structured knowledge (such as UMLS, SemMedDB, ChEMBL, Reactome, DrugBank, and SMPDB in order to facilitate discovery of new therapeutic targets and modalities. The NCATS Biomedical Data Translator project is working to federate autonomous reasoning agents and knowledge providers within a distributed system for answering translational questions. Within that project and the broader field, there is a need for a framework that can efficiently and reproducibly build an integrated, standards-compliant, and comprehensive biomedical knowledge graph that can be downloaded in standard serialized form or queried via a public application programming interface (API). RESULTS: To create a knowledge provider system within the Translator project, we have developed RTX-KG2, an open-source software system for building-and hosting a web API for querying-a biomedical knowledge graph that uses an Extract-Transform-Load approach to integrate 70 knowledge sources (including the aforementioned core six sources) into a knowledge graph with provenance information including (where available) citations. The semantic layer and schema for RTX-KG2 follow the standard Biolink model to maximize interoperability. RTX-KG2 is currently being used by multiple Translator reasoning agents, both in its downloadable form and via its SmartAPI-registered interface. Serializations of RTX-KG2 are available for download in both the pre-canonicalized form and in canonicalized form (in which synonyms are merged). The current canonicalized version (KG2.7.3) of RTX-KG2 contains 6.4M nodes and 39.3M edges with a hierarchy of 77 relationship types from Biolink. CONCLUSION: RTX-KG2 is the first knowledge graph that integrates UMLS, SemMedDB, ChEMBL, DrugBank, Reactome, SMPDB, and 64 additional knowledge sources within a knowledge graph that conforms to the Biolink standard for its semantic layer and schema. RTX-KG2 is publicly available for querying via its API at arax.rtx.ai/api/rtxkg2/v1.2/openapi.json . The code to build RTX-KG2 is publicly available at github:RTXteam/RTX-KG2 .

Supervised and Unsupervised ML algorithms are widely used over graphs. They use the structural properties of the data to deliver effective results. It is known that the same information can be represented under various graph structures. Thus, these algorithms may be effective on some structural variations of the data and ineffective on others. One would like to have an algorithm that is effective and generalizes to all structural variations of a data graph. We define the concept of structural generalizability for algorithms over graphs. We focus on the problem of similarity search, which is a popular task and the building block of many ML algorithms on graphs, and propose a structurally generalizable similarity search algorithm. As this algorithm may require users to specify features in a rather complex language, we modify this algorithm so that it requires only simple guidance from the user. Our extensive empirical study show that our algorithms are structurally generalizable while being efficient and more effective than current algorithms.