Justin Reese

J. Harry Caufield, Harshad Hegde, Vincent Emonet et al. · berkeley

Creating knowledge bases and ontologies is a time consuming task that relies on a manual curation. AI/NLP approaches can assist expert curators in populating these knowledge bases, but current approaches rely on extensive training data, and are not able to populate arbitrary complex nested knowledge schemas. Here we present Structured Prompt Interrogation and Recursive Extraction of Semantics (SPIRES), a Knowledge Extraction approach that relies on the ability of Large Language Models (LLMs) to perform zero-shot learning (ZSL) and general-purpose query answering from flexible prompts and return information conforming to a specified schema. Given a detailed, user-defined knowledge schema and an input text, SPIRES recursively performs prompt interrogation against GPT-3+ to obtain a set of responses matching the provided schema. SPIRES uses existing ontologies and vocabularies to provide identifiers for all matched elements. We present examples of use of SPIRES in different domains, including extraction of food recipes, multi-species cellular signaling pathways, disease treatments, multi-step drug mechanisms, and chemical to disease causation graphs. Current SPIRES accuracy is comparable to the mid-range of existing Relation Extraction (RE) methods, but has the advantage of easy customization, flexibility, and, crucially, the ability to perform new tasks in the absence of any training data. This method supports a general strategy of leveraging the language interpreting capabilities of LLMs to assemble knowledge bases, assisting manual knowledge curation and acquisition while supporting validation with publicly-available databases and ontologies external to the LLM. SPIRES is available as part of the open source OntoGPT package: https://github.com/ monarch-initiative/ontogpt.

Tiffany J. Callahan, Ignacio J. Tripodi, Adrianne L. Stefanski et al. · berkeley, harvard

Translational research requires data at multiple scales of biological organization. Advancements in sequencing and multi-omics technologies have increased the availability of these data, but researchers face significant integration challenges. Knowledge graphs (KGs) are used to model complex phenomena, and methods exist to construct them automatically. However, tackling complex biomedical integration problems requires flexibility in the way knowledge is modeled. Moreover, existing KG construction methods provide robust tooling at the cost of fixed or limited choices among knowledge representation models. PheKnowLator (Phenotype Knowledge Translator) is a semantic ecosystem for automating the FAIR (Findable, Accessible, Interoperable, and Reusable) construction of ontologically grounded KGs with fully customizable knowledge representation. The ecosystem includes KG construction resources (e.g., data preparation APIs), analysis tools (e.g., SPARQL endpoints and abstraction algorithms), and benchmarks (e.g., prebuilt KGs and embeddings). We evaluated the ecosystem by systematically comparing it to existing open-source KG construction methods and by analyzing its computational performance when used to construct 12 large-scale KGs. With flexible knowledge representation, PheKnowLator enables fully customizable KGs without compromising performance or usability.

J Harry Caufield, Tim Putman, Kevin Schaper et al. · berkeley

Knowledge graphs (KGs) are a powerful approach for integrating heterogeneous data and making inferences in biology and many other domains, but a coherent solution for constructing, exchanging, and facilitating the downstream use of knowledge graphs is lacking. Here we present KG-Hub, a platform that enables standardized construction, exchange, and reuse of knowledge graphs. Features include a simple, modular extract-transform-load (ETL) pattern for producing graphs compliant with Biolink Model (a high-level data model for standardizing biological data), easy integration of any OBO (Open Biological and Biomedical Ontologies) ontology, cached downloads of upstream data sources, versioned and automatically updated builds with stable URLs, web-browsable storage of KG artifacts on cloud infrastructure, and easy reuse of transformed subgraphs across projects. Current KG-Hub projects span use cases including COVID-19 research, drug repurposing, microbial-environmental interactions, and rare disease research. KG-Hub is equipped with tooling to easily analyze and manipulate knowledge graphs. KG-Hub is also tightly integrated with graph machine learning (ML) tools which allow automated graph machine learning, including node embeddings and training of models for link prediction and node classification.

Elena Casiraghi, Rachel Wong, Margaret Hall et al.

Healthcare datasets obtained from Electronic Health Records have proven to be extremely useful to assess associations between patients' predictors and outcomes of interest. However, these datasets often suffer from missing values in a high proportion of cases and the simple removal of these cases may introduce severe bias. For these reasons, several multiple imputation algorithms have been proposed to attempt to recover the missing information. Each algorithm presents strengths and weaknesses, and there is currently no consensus on which multiple imputation algorithms works best in a given scenario. Furthermore, the selection of each algorithm parameters and data-related modelling choices are also both crucial and challenging. In this paper, we propose a novel framework to numerically evaluate strategies for handling missing data in the context of statistical analysis, with a particular focus on multiple imputation techniques. We demonstrate the feasibility of our approach on a large cohort of type-2 diabetes patients provided by the National COVID Cohort Collaborative (N3C) Enclave, where we explored the influence of various patient characteristics on outcomes related to COVID-19. Our analysis included classic multiple imputation techniques as well as simple complete-case Inverse Probability Weighted models. The experiments presented here show that our approach could effectively highlight the most valid and performant missing-data handling strategy for our case study. Moreover, our methodology allowed us to gain an understanding of the behavior of the different models and of how it changed as we modified their parameters. Our method is general and can be applied to different research fields and on datasets containing heterogeneous types.

Tudor Groza, Harry Caufield, Dylan Gration et al.

Objective: Clinical deep phenotyping and phenotype annotation play a critical role in both the diagnosis of patients with rare disorders as well as in building computationally-tractable knowledge in the rare disorders field. These processes rely on using ontology concepts, often from the Human Phenotype Ontology, in conjunction with a phenotype concept recognition task (supported usually by machine learning methods) to curate patient profiles or existing scientific literature. With the significant shift in the use of large language models (LLMs) for most NLP tasks, we examine the performance of the latest Generative Pre-trained Transformer (GPT) models underpinning ChatGPT as a foundation for the tasks of clinical phenotyping and phenotype annotation. Materials and Methods: The experimental setup of the study included seven prompts of various levels of specificity, two GPT models (gpt-3.5-turbo and gpt-4.0) and two established gold standard corpora for phenotype recognition, one consisting of publication abstracts and the other clinical observations. Results: Our results show that, with an appropriate setup, these models can achieve state of the art performance. The best run, using few-shot learning, achieved 0.58 macro F1 score on publication abstracts and 0.75 macro F1 score on clinical observations, the former being comparable with the state of the art, while the latter surpassing the current best in class tool. Conclusion: While the results are promising, the non-deterministic nature of the outcomes, the high cost and the lack of concordance between different runs using the same prompt and input make the use of these LLMs challenging for this particular task.

Tiffany J. Callahan, Adrianne L. Stefanski, Jordan M. Wyrwa et al.

Background: Common data models solve many challenges of standardizing electronic health record (EHR) data, but are unable to semantically integrate all the resources needed for deep phenotyping. Open Biological and Biomedical Ontology (OBO) Foundry ontologies provide computable representations of biological knowledge and enable the integration of heterogeneous data. However, mapping EHR data to OBO ontologies requires significant manual curation and domain expertise. Objective: We introduce OMOP2OBO, an algorithm for mapping Observational Medical Outcomes Partnership (OMOP) vocabularies to OBO ontologies. Results: Using OMOP2OBO, we produced mappings for 92,367 conditions, 8611 drug ingredients, and 10,673 measurement results, which covered 68-99% of concepts used in clinical practice when examined across 24 hospitals. When used to phenotype rare disease patients, the mappings helped systematically identify undiagnosed patients who might benefit from genetic testing. Conclusions: By aligning OMOP vocabularies to OBO ontologies our algorithm presents new opportunities to advance EHR-based deep phenotyping.

Nicolas Matentzoglu, J. Harry Caufield, Harshad B. Hegde et al.

Aligning terminological resources, including ontologies, controlled vocabularies, taxonomies, and value sets is a critical part of data integration in many domains such as healthcare, chemistry, and biomedical research. Entity mapping is the process of determining correspondences between entities across these resources, such as gene identifiers, disease concepts, or chemical entity identifiers. Many tools have been developed to compute such mappings based on common structural features and lexical information such as labels and synonyms. Lexical approaches in particular often provide very high recall, but low precision, due to lexical ambiguity. As a consequence of this, mapping efforts often resort to a labor intensive manual mapping refinement through a human curator. Large Language Models (LLMs), such as the ones employed by ChatGPT, have generalizable abilities to perform a wide range of tasks, including question-answering and information extraction. Here we present MapperGPT, an approach that uses LLMs to review and refine mapping relationships as a post-processing step, in concert with existing high-recall methods that are based on lexical and structural heuristics. We evaluated MapperGPT on a series of alignment tasks from different domains, including anatomy, developmental biology, and renal diseases. We devised a collection of tasks that are designed to be particularly challenging for lexical methods. We show that when used in combination with high-recall methods, MapperGPT can provide a substantial improvement in accuracy, beating state-of-the-art (SOTA) methods such as LogMap.

Emanuele Cavalleri, Alberto Cabri, Mauricio Soto-Gomez et al.

The "RNA world" represents a novel frontier for the study of fundamental biological processes and human diseases and is paving the way for the development of new drugs tailored to the patient's biomolecular characteristics. Although scientific data about coding and non-coding RNA molecules are continuously produced and available from public repositories, they are scattered across different databases and a centralized, uniform, and semantically consistent representation of the "RNA world" is still lacking. We propose RNA-KG, a knowledge graph encompassing biological knowledge about RNAs gathered from more than 50 public databases, integrating functional relationships with genes, proteins, and chemicals and ontologically grounded biomedical concepts. To develop RNA-KG, we first identified, pre-processed, and characterized each data source; next, we built a meta-graph that provides an ontological description of the KG by representing all the bio-molecular entities and medical concepts of interest in this domain, as well as the types of interactions connecting them. Finally, we leveraged an instance-based semantically abstracted knowledge model to specify the ontological alignment according to which RNA-KG was generated. RNA-KG can be downloaded in different formats and also queried by a SPARQL endpoint. A thorough topological analysis of the resulting heterogeneous graph provides further insights into the characteristics of the "RNA world". RNA-KG can be both directly explored and visualized, and/or analyzed by applying computational methods to infer bio-medical knowledge from its heterogeneous nodes and edges. The resource can be easily updated with new experimental data, and specific views of the overall KG can be extracted according to the bio-medical problem to be studied.

Harry Caufield, Carlo Kroll, Shawn T O'Neil et al.

Effective data-driven biomedical discovery requires data curation: a time-consuming process of finding, organizing, distilling, integrating, interpreting, annotating, and validating diverse information into a structured form suitable for databases and knowledge bases. Accurate and efficient curation of these digital assets is critical to ensuring that they are FAIR, trustworthy, and sustainable. Unfortunately, expert curators face significant time and resource constraints. The rapid pace of new information being published daily is exceeding their capacity for curation. Generative AI, exemplified by instruction-tuned large language models (LLMs), has opened up new possibilities for assisting human-driven curation. The design philosophy of agents combines the emerging abilities of generative AI with more precise methods. A curator's tasks can be aided by agents for performing reasoning, searching ontologies, and integrating knowledge across external sources, all efforts otherwise requiring extensive manual effort. Our LLM-driven annotation tool, CurateGPT, melds the power of generative AI together with trusted knowledge bases and literature sources. CurateGPT streamlines the curation process, enhancing collaboration and efficiency in common workflows. Compared to direct interaction with an LLM, CurateGPT's agents enable access to information beyond that in the LLM's training data and they provide direct links to the data supporting each claim. This helps curators, researchers, and engineers scale up curation efforts to keep pace with the ever-increasing volume of scientific data.

Christopher J. Mungall, Adnan Malik, Daniel R. Korn et al.

Accurately classifying chemical structures is essential for cheminformatics and bioinformatics, including tasks such as identifying bioactive compounds of interest, screening molecules for toxicity to humans, finding non-organic compounds with desirable material properties, or organizing large chemical libraries for drug discovery or environmental monitoring. However, manual classification is labor-intensive and difficult to scale to large chemical databases. Existing automated approaches either rely on manually constructed classification rules, or are deep learning methods that lack explainability. This work presents an approach that uses generative artificial intelligence to automatically write chemical classifier programs for classes in the Chemical Entities of Biological Interest (ChEBI) database. These programs can be used for efficient deterministic run-time classification of SMILES structures, with natural language explanations. The programs themselves constitute an explainable computable ontological model of chemical class nomenclature, which we call the ChEBI Chemical Class Program Ontology (C3PO). We validated our approach against the ChEBI database, and compared our results against deep learning models and a naive SMARTS pattern based classifier. C3PO outperforms the naive classifier, but does not reach the performance of state of the art deep learning methods. However, C3PO has a number of strengths that complement deep learning methods, including explainability and reduced data dependence. C3PO can be used alongside deep learning classifiers to provide an explanation of the classification, where both methods agree. The programs can be used as part of the ontology development process, and iteratively refined by expert human curators.

Luca Cappelletti, Tommaso Fontana, Elena Casiraghi et al.

Graph Representation Learning (GRL) methods opened new avenues for addressing complex, real-world problems represented by graphs. However, many graphs used in these applications comprise millions of nodes and billions of edges and are beyond the capabilities of current methods and software implementations. We present GRAPE, a software resource for graph processing and embedding that can scale with big graphs by using specialized and smart data structures, algorithms, and a fast parallel implementation of random walk-based methods. Compared with state-of-the-art software resources, GRAPE shows an improvement of orders of magnitude in empirical space and time complexity, as well as a competitive edge and node label prediction performance. GRAPE comprises about 1.7 million well-documented lines of Python and Rust code and provides 69 node embedding methods, 25 inference models, a collection of efficient graph processing utilities and over 80,000 graphs from the literature and other sources. Standardized interfaces allow seamless integration of third-party libraries, while ready-to-use and modular pipelines permit an easy-to-use evaluation of GRL methods, therefore also positioning GRAPE as a software resource to perform a fair comparison between methods and libraries for graph processing and embedding.

Mauricio Soto-Gomez, Peter Robinson, Carlos Cano et al.

Many real-world problems are naturally modeled as heterogeneous graphs, where nodes and edges represent multiple types of entities and relations. Existing learning models for heterogeneous graph representation usually depend on the computation of specific and user-defined heterogeneous paths, or in the application of large and often not scalable deep neural network architectures. We propose Het-node2vec, an extension of the node2vec algorithm, designed for embedding heterogeneous graphs. Het-node2vec addresses the challenge of capturing the topological and structural characteristics of graphs and the semantic information underlying the different types of nodes and edges of heterogeneous graphs, by introducing a simple stochastic node and edge type switching strategy in second order random walk processes. The proposed approach also introduces an ''attention mechanism'' to focus the random walks on specific node and edge types, thus allowing more accurate embeddings and more focused predictions on specific node and edge types of interest. Empirical results on benchmark datasets show that Hetnode2vec achieves comparable or superior performance with respect to state-of-the-art methods for heterogeneous graphs in node label and edge prediction tasks.