MOTIVATION: Hundreds of resources assign identifiers to biomedical concepts including genes, small molecules, biological processes, diseases, and cell types. Often, these resources overlap by assigning identifiers to the same or related concepts. This creates a data interoperability bottleneck, as integrating data sets and knowledge bases that use identifiers for the same concepts from different resources requires such identifiers to be mapped to each other. However, available mappings are incomplete and fragmented across individual resources, motivating their large-scale integration. RESULTS: We developed SeMRA, a software tool that integrates mappings from multiple sources into a graph data structure. Using graph algorithms, it infers missing mappings implied by available ones while keeping track of provenance and confidence. This allows connecting identifier spaces between which direct mapping was previously not possible. SeMRA implements a customizable workflow that takes a declarative specification as input describing sources to integrate with additional configuration parameters. We used SeMRA to produce the SeMRA Raw Mappings Database, an aggregation of 43.4 million mappings from 127 sources that jointly cover identifiers from 445 ontologies and databases. We also describe benchmarks on specific use cases such as integrating mappings between resources cataloging diseases and cell types. AVAILABILITY AND IMPLEMENTATION: The code is available under the MIT license at https://github.com/biopragmatics/semra. The SeMRA Raw Mappings Database assembled by SeMRA is available at https://doi.org/10.5281/zenodo.11082038.

SUMMARY: We introduce Eliater, a Python package for estimating the effect of perturbation of an upstream molecule on a downstream molecule in a biomolecular network. The estimation takes as input a biomolecular network, observational biomolecular data, and a perturbation of interest, and outputs an estimated quantitative effect of the perturbation. We showcase the functionalities of Eliater in a case study of Escherichia coli transcriptional regulatory network. AVAILABILITY AND IMPLEMENTATION: The code, the documentation, and several case studies are available open source at https://github.com/y0-causal-inference/eliater.

The fast wavelet transform is an essential workhorse in signal processing. Wavelets are local in the spatial- or temporal- and the frequency-domain. This property enables frequency domain analysis while preserving some spatiotemporal information. Until recently, wavelets rarely appeared in the machine learning literature. We provide the PyTorch Wavelet Toolbox to make wavelet methods more accessible to the deep learning community. Our PyTorch Wavelet Toolbox is well documented. A pip package is installable with `pip install ptwt`.

MOTIVATION: Biomedical identifier resources (such as ontologies, taxonomies, and controlled vocabularies) commonly overlap in scope and contain equivalent entries under different identifiers. Maintaining mappings between these entries is crucial for interoperability and the integration of data and knowledge. However, there are substantial gaps in available mappings motivating their semi-automated curation. RESULTS: Biomappings implements a curation workflow for missing mappings which combines automated prediction with human-in-the-loop curation. It supports multiple prediction approaches and provides a web-based user interface for reviewing predicted mappings for correctness, combined with automated consistency checking. Predicted and curated mappings are made available in public, version-controlled resource files on GitHub. Biomappings currently makes available 9274 curated mappings and 40 691 predicted ones, providing previously missing mappings between widely used identifier resources covering small molecules, cell lines, diseases, and other concepts. We demonstrate the value of Biomappings on case studies involving predicting and curating missing mappings among cancer cell lines as well as small molecules tested in clinical trials. We also present how previously missing mappings curated using Biomappings were contributed back to multiple widely used community ontologies. AVAILABILITY AND IMPLEMENTATION: The data and code are available under the CC0 and MIT licenses at https://github.com/biopragmatics/biomappings.

Causal query estimation in biomolecular networks commonly selects a 'valid adjustment set', i.e. a subset of network variables that eliminates the bias of the estimator. A same query may have multiple valid adjustment sets, each with a different variance. When networks are partially observed, current methods use graph-based criteria to find an adjustment set that minimizes asymptotic variance. Unfortunately, many models that share the same graph topology, and therefore same functional dependencies, may differ in the processes that generate the observational data. In these cases, the topology-based criteria fail to distinguish the variances of the adjustment sets. This deficiency can lead to sub-optimal adjustment sets, and to miss-characterization of the effect of the intervention. We propose an approach for deriving 'optimal adjustment sets' that takes into account the nature of the data, bias and finite-sample variance of the estimator, and cost. It empirically learns the data generating processes from historical experimental data, and characterizes the properties of the estimators by simulation. We demonstrate the utility of the proposed approach in four biomolecular Case studies with different topologies and different data generation processes. The implementation and reproducible Case studies are at https://github.com/srtaheri/OptimalAdjustmentSet.

In this paper, we introduce ChemicalX, a PyTorch-based deep learning library designed for providing a range of state of the art models to solve the drug pair scoring task. The primary objective of the library is to make deep drug pair scoring models accessible to machine learning researchers and practitioners in a streamlined framework. The design of ChemicalX reuses existing high level model training utilities, geometric deep learning, and deep chemistry layers from the PyTorch ecosystem. Our system provides neural network layers, custom pair scoring architectures, data loaders, and batch iterators for end users. We showcase these features with example code snippets and case studies to highlight the characteristics of ChemicalX. A range of experiments on real world drug-drug interaction, polypharmacy side effect, and combination synergy prediction tasks demonstrate that the models available in ChemicalX are effective at solving the pair scoring task. Finally, we show that ChemicalX could be used to train and score machine learning models on large drug pair datasets with hundreds of thousands of compounds on commodity hardware.

Drug discovery and development is a complex and costly process. Machine learning approaches are being investigated to help improve the effectiveness and speed of multiple stages of the drug discovery pipeline. Of these, those that use Knowledge Graphs (KG) have promise in many tasks, including drug repurposing, drug toxicity prediction and target gene-disease prioritization. In a drug discovery KG, crucial elements including genes, diseases and drugs are represented as entities, while relationships between them indicate an interaction. However, to construct high-quality KGs, suitable data are required. In this review, we detail publicly available sources suitable for use in constructing drug discovery focused KGs. We aim to help guide machine learning and KG practitioners who are interested in applying new techniques to the drug discovery field, but who may be unfamiliar with the relevant data sources. The datasets are selected via strict criteria, categorized according to the primary type of information contained within and are considered based upon what information could be extracted to build a KG. We then present a comparative analysis of existing public drug discovery KGs and an evaluation of selected motivating case studies from the literature. Additionally, we raise numerous and unique challenges and issues associated with the domain and its datasets, while also highlighting key future research directions. We hope this review will motivate KGs use in solving key and emerging questions in the drug discovery domain.

MOTIVATION: The majority of biomedical knowledge is stored in structured databases or as unstructured text in scientific publications. This vast amount of information has led to numerous machine learning-based biological applications using either text through natural language processing (NLP) or structured data through knowledge graph embedding models. However, representations based on a single modality are inherently limited. RESULTS: To generate better representations of biological knowledge, we propose STonKGs, a Sophisticated Transformer trained on biomedical text and Knowledge Graphs (KGs). This multimodal Transformer uses combined input sequences of structured information from KGs and unstructured text data from biomedical literature to learn joint representations in a shared embedding space. First, we pre-trained STonKGs on a knowledge base assembled by the Integrated Network and Dynamical Reasoning Assembler consisting of millions of text-triple pairs extracted from biomedical literature by multiple NLP systems. Then, we benchmarked STonKGs against three baseline models trained on either one of the modalities (i.e. text or KG) across eight different classification tasks, each corresponding to a different biological application. Our results demonstrate that STonKGs outperforms both baselines, especially on the more challenging tasks with respect to the number of classes, improving upon the F1-score of the best baseline by up to 0.084 (i.e. from 0.881 to 0.965). Finally, our pre-trained model as well as the model architecture can be adapted to various other transfer learning applications. AVAILABILITY AND IMPLEMENTATION: We make the source code and the Python package of STonKGs available at GitHub (https://github.com/stonkgs/stonkgs) and PyPI (https://pypi.org/project/stonkgs/). The pre-trained STonKGs models and the task-specific classification models are respectively available at https://huggingface.co/stonkgs/stonkgs-150k and https://zenodo.org/communities/stonkgs. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

MOTIVATION: Estimating causal queries, such as changes in protein abundance in response to a perturbation, is a fundamental task in the analysis of biomolecular pathways. The estimation requires experimental measurements on the pathway components. However, in practice many pathway components are left unobserved (latent) because they are either unknown, or difficult to measure. Latent variable models (LVMs) are well-suited for such estimation. Unfortunately, LVM-based estimation of causal queries can be inaccurate when parameters of the latent variables are not uniquely identified, or when the number of latent variables is misspecified. This has limited the use of LVMs for causal inference in biomolecular pathways. RESULTS: In this article, we propose a general and practical approach for LVM-based estimation of causal queries. We prove that, despite the challenges above, LVM-based estimators of causal queries are accurate if the queries are identifiable according to Pearl's do-calculus and describe an algorithm for its estimation. We illustrate the breadth and the practical utility of this approach for estimating causal queries in four synthetic and two experimental case studies, where structures of biomolecular pathways challenge the existing methods for causal query estimation. AVAILABILITY AND IMPLEMENTATION: The code and the data documenting all the case studies are available at https://github.com/srtaheri/LVMwithDoCalculus. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

The heterogeneity in recently published knowledge graph embedding models' implementations, training, and evaluation has made fair and thorough comparisons difficult. To assess the reproducibility of previously published results, we re-implemented and evaluated 21 models in the PyKEEN software package. In this paper, we outline which results could be reproduced with their reported hyper-parameters, which could only be reproduced with alternate hyper-parameters, and which could not be reproduced at all, as well as provide insight as to why this might be the case. We then performed a large-scale benchmarking on four datasets with several thousands of experiments and 24,804 GPU hours of computation time. We present insights gained as to best practices, best configurations for each model, and where improvements could be made over previously published best configurations. Our results highlight that the combination of model architecture, training approach, loss function, and the explicit modeling of inverse relations is crucial for a model's performance and is not only determined by its architecture. We provide evidence that several architectures can obtain results competitive to the state of the art when configured carefully. We have made all code, experimental configurations, results, and analyses available at https://github.com/pykeen/pykeen and https://github.com/pykeen/benchmarking.

The majority of clinical trials fail due to low efficacy of investigated drugs, often resulting from a poor choice of target protein. Existing computational approaches aim to support target selection either via genetic evidence or by putting potential targets into the context of a disease specific network reconstruction. The purpose of this work was to investigate whether network representation learning techniques could be used to allow for a machine learning based prioritization of putative targets. We propose a novel target prioritization approach, GuiltyTargets, which relies on attributed network representation learning of a genome-wide protein-protein interaction network annotated with disease-specific differential gene expression and uses positive-unlabeled (PU) machine learning for candidate ranking. We evaluated our approach on 12 datasets from six diseases of different type (cancer, metabolic, neurodegenerative) within a 10 times repeated 5-fold stratified cross-validation and achieved AUROC values between 0.92 - 0.97, significantly outperforming previous approaches that relied on manually engineered topological features. Moreover, we showed that GuiltyTargets allows for target repositioning across related disease areas. An application of GuiltyTargets to Alzheimer's disease resulted in a number of highly ranked candidates that are currently discussed as targets in the literature. Interestingly, one (COMT) is also the target of an approved drug (Tolcapone) for Parkinson's disease, highlighting the potential for target repositioning with our method. The GuiltyTargets Python package is available on PyPI and all code used for analysis can be found under the MIT License at https://github.com/GuiltyTargets. Attributed network representation learning techniques provide an interesting approach to effectively leverage the existing knowledge about the molecular mechanisms in different diseases. In this work, the combination with positive-unlabeled learning for target prioritization demonstrated a clear superiority compared to classical feature engineering approaches. Our work highlights the potential of attributed network representation learning for target prioritization. Given the overarching relevance of networks in computational biology we believe that attributed network representation learning techniques could have a broader impact in the future.

SUMMARY: As machine learning and artificial intelligence increasingly attain a larger number of applications in the biomedical domain, at their core, their utility depends on the data used to train them. Due to the complexity and high dimensionality of biomedical data, there is a need for approaches that combine prior knowledge around known biological interactions with patient data. Here, we present CLinical Embedding of Patients (CLEP), a novel approach that generates new patient representations by leveraging both prior knowledge and patient-level data. First, given a patient-level dataset and a knowledge graph containing relations across features that can be mapped to the dataset, CLEP incorporates patients into the knowledge graph as new nodes connected to their most characteristic features. Next, CLEP employs knowledge graph embedding models to generate new patient representations that can ultimately be used for a variety of downstream tasks, ranging from clustering to classification. We demonstrate how using new patient representations generated by CLEP significantly improves performance in classifying between patients and healthy controls for a variety of machine learning models, as compared to the use of the original transcriptomics data. Furthermore, we also show how incorporating patients into a knowledge graph can foster the interpretation and identification of biological features characteristic of a specific disease or patient subgroup. Finally, we released CLEP as an open source Python package together with examples and documentation. AVAILABILITY AND IMPLEMENTATION: CLEP is available to the bioinformatics community as an open source Python package at https://github.com/hybrid-kg/clep under the Apache 2.0 License. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

MOTIVATION: A large variety of molecular interactions occurs between biomolecular components in cells. When a molecular interaction results in a regulatory effect, exerted by one component onto a downstream component, a so-called 'causal interaction' takes place. Causal interactions constitute the building blocks in our understanding of larger regulatory networks in cells. These causal interactions and the biological processes they enable (e.g. gene regulation) need to be described with a careful appreciation of the underlying molecular reactions. A proper description of this information enables archiving, sharing and reuse by humans and for automated computational processing. Various representations of causal relationships between biological components are currently used in a variety of resources. RESULTS: Here, we propose a checklist that accommodates current representations, called the Minimum Information about a Molecular Interaction CAusal STatement (MI2CAST). This checklist defines both the required core information, as well as a comprehensive set of other contextual details valuable to the end user and relevant for reusing and reproducing causal molecular interaction information. The MI2CAST checklist can be used as reporting guidelines when annotating and curating causal statements, while fostering uniformity and interoperability of the data across resources. AVAILABILITY AND IMPLEMENTATION: The checklist together with examples is accessible at https://github.com/MI2CAST/MI2CAST. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Recently, knowledge graph embeddings (KGEs) have received significant attention, and several software libraries have been developed for training and evaluation. While each of them addresses specific needs, we report on a community effort to a re-design and re-implementation of PyKEEN, one of the early KGE libraries. PyKEEN 1.0 enables users to compose knowledge graph embedding models based on a wide range of interaction models, training approaches, loss functions, and permits the explicit modeling of inverse relations. It allows users to measure each component's influence individually on the model's performance. Besides, an automatic memory optimization has been realized in order to optimally exploit the provided hardware. Through the integration of Optuna, extensive hyper-parameter optimization (HPO) functionalities are provided.

Counterfactual inference is a useful tool for comparing outcomes of interventions on complex systems. It requires us to represent the system in form of a structural causal model, complete with a causal diagram, probabilistic assumptions on exogenous variables, and functional assignments. Specifying such models can be extremely difficult in practice. The process requires substantial domain expertise, and does not scale easily to large systems, multiple systems, or novel system modifications. At the same time, many application domains, such as molecular biology, are rich in structured causal knowledge that is qualitative in nature. This article proposes a general approach for querying a causal biological knowledge graph, and converting the qualitative result into a quantitative structural causal model that can learn from data to answer the question. We demonstrate the feasibility, accuracy and versatility of this approach using two case studies in systems biology. The first demonstrates the appropriateness of the underlying assumptions and the accuracy of the results. The second demonstrates the versatility of the approach by querying a knowledge base for the molecular determinants of a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-induced cytokine storm, and performing counterfactual inference to estimate the causal effect of medical countermeasures for severely ill patients.

BACKGROUND: During the last decade, there has been a surge towards computational drug repositioning owing to constantly increasing -omics data in the biomedical research field. While numerous existing methods focus on the integration of heterogeneous data to propose candidate drugs, it is still challenging to substantiate their results with mechanistic insights of these candidate drugs. Therefore, there is a need for more innovative and efficient methods which can enable better integration of data and knowledge for drug repositioning. RESULTS: Here, we present a customizable workflow (PS4DR) which not only integrates high-throughput data such as genome-wide association study (GWAS) data and gene expression signatures from disease and drug perturbations but also takes pathway knowledge into consideration to predict drug candidates for repositioning. We have collected and integrated publicly available GWAS data and gene expression signatures for several diseases and hundreds of FDA-approved drugs or those under clinical trial in this study. Additionally, different pathway databases were used for mechanistic knowledge integration in the workflow. Using this systematic consolidation of data and knowledge, the workflow computes pathway signatures that assist in the prediction of new indications for approved and investigational drugs. CONCLUSION: We showcase PS4DR with applications demonstrating how this tool can be used for repositioning and identifying new drugs as well as proposing drugs that can simulate disease dysregulations. We were able to validate our workflow by demonstrating its capability to predict FDA-approved drugs for their known indications for several diseases. Further, PS4DR returned many potential drug candidates for repositioning that were backed up by epidemiological evidence extracted from scientific literature. Source code is freely available at https://github.com/ps4dr/ps4dr.

SUMMARY: Knowledge graph embeddings (KGEs) have received significant attention in other domains due to their ability to predict links and create dense representations for graphs' nodes and edges. However, the software ecosystem for their application to bioinformatics remains limited and inaccessible for users without expertise in programing and machine learning. Therefore, we developed BioKEEN (Biological KnowlEdge EmbeddiNgs) and PyKEEN (Python KnowlEdge EmbeddiNgs) to facilitate their easy use through an interactive command line interface. Finally, we present a case study in which we used a novel biological pathway mapping resource to predict links that represent pathway crosstalks and hierarchies. AVAILABILITY AND IMPLEMENTATION: BioKEEN and PyKEEN are open source Python packages publicly available under the MIT License at https://github.com/SmartDataAnalytics/BioKEEN and https://github.com/SmartDataAnalytics/PyKEEN. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

BACKGROUND: The complexity of representing biological systems is compounded by an ever-expanding body of knowledge emerging from multi-omics experiments. A number of pathway databases have facilitated pathway-centric approaches that assist in the interpretation of molecular signatures yielded by these experiments. However, the lack of interoperability between pathway databases has hindered the ability to harmonize these resources and to exploit their consolidated knowledge. Such a unification of pathway knowledge is imperative in enhancing the comprehension and modeling of biological abstractions. RESULTS: Here, we present PathMe, a Python package that transforms pathway knowledge from three major pathway databases into a unified abstraction using Biological Expression Language as the pivotal, integrative schema. PathMe is complemented by a novel web application (freely available at https://pathme.scai.fraunhofer.de/ ) which allows users to comprehensively explore pathway crosstalk and compare areas of consensus and discrepancies. CONCLUSIONS: This work has harmonized three major pathway databases and transformed them into a unified schema in order to gain a holistic picture of pathway knowledge. We demonstrate the utility of the PathMe framework in: i) integrating pathway landscapes at the database level, ii) comparing the degree of consensus at the pathway level, and iii) exploring pathway crosstalk and investigating consensus at the molecular level.

BACKGROUND: Literature derived knowledge assemblies have been used as an effective way of representing biological phenomenon and understanding disease etiology in systems biology. These include canonical pathway databases such as KEGG, Reactome and WikiPathways and disease specific network inventories such as causal biological networks database, PD map and NeuroMMSig. The represented knowledge in these resources delineates qualitative information focusing mainly on the causal relationships between biological entities. Genes, the major constituents of knowledge representations, tend to express differentially in different conditions such as cell types, brain regions and disease stages. A classical approach of interpreting a knowledge assembly is to explore gene expression patterns of the individual genes. However, an approach that enables quantification of the overall impact of differentially expressed genes in the corresponding network is still lacking. RESULTS: Using the concept of heat diffusion, we have devised an algorithm that is able to calculate the magnitude of regulation of a biological network using expression datasets. We have demonstrated that molecular mechanisms specific to Alzheimer (AD) and Parkinson Disease (PD) regulate with different intensities across spatial and temporal resolutions. Our approach depicts that the mitochondrial dysfunction in PD is severe in cortex and advanced stages of PD patients. Similarly, we have shown that the intensity of aggregation of neurofibrillary tangles (NFTs) in AD increases as the disease progresses. This finding is in concordance with previous studies that explain the burden of NFTs in stages of AD. CONCLUSIONS: This study is one of the first attempts that enable quantification of mechanisms represented as biological networks. We have been able to quantify the magnitude of regulation of a biological network and illustrate that the magnitudes are different across spatial and temporal resolution.

Summary: While cause-and-effect knowledge assembly models encoded in Biological Expression Language are able to support generation of mechanistic hypotheses, they are static and limited in their ability to encode temporality. Here, we present BEL2ABM, a software for producing continuous, dynamic, executable agent-based models from BEL templates. Availability and implementation: The tool has been developed in Java and NetLogo. Code, data and documentation are available under the Apache 2.0 License at https://github.com/pybel/bel2abm. Supplementary information: Supplementary data are available at Bioinformatics online.

Summary: Biological Expression Language (BEL) assembles knowledge networks from biological relations across multiple modes and scales. Here, we present PyBEL; a software package for parsing, validating, converting, storing, querying, and visualizing networks encoded in BEL. Availability and implementation: PyBEL is implemented in platform-independent, universal Python code. Its source is distributed under the Apache 2.0 License at https://github.com/pybel. Contact: [email protected]. Supplementary information: Supplementary data are available at Bioinformatics online.

We consider the problem of determining multiple steady states for positive real values in models of biological networks. Investigating the potential for these in models of the mitogen-activated protein kinases (MAPK) network has consumed considerable effort using special insights into the structure of corresponding models. Here we apply combinations of symbolic computation methods for mixed equality/inequality systems, specifically virtual substitution, lazy real triangularization and cylindrical algebraic decomposition. We determine multistationarity of an 11-dimensional MAPK network when numeric values are known for all but potentially one parameter. More precisely, our considered model has 11 equations in 11 variables and 19 parameters, 3 of which are of interest for symbolic treatment, and furthermore positivity conditions on all variables and parameters.