MOTIVATION: Predicting gene-disease associations (GDAs) can be framed as a ranking problem where genes are ranked for a query disease based on features such as phenotypic similarity. By describing phenotypes using phenotype ontologies, ontology-based semantic similarity measures can be used. However, traditional semantic similarity measures use only the ontology taxonomy. Recent methods based on ontology embeddings compare phenotypes in latent space; these methods can use all ontology axioms as well as a supervised signal, but are inherently transductive, i.e. query entities must already be known at the time of learning embeddings, and therefore these methods do not generalize to novel diseases (sets of phenotypes) at inference time. RESULTS: We developed INDIGENA, an inductive disease-gene association method for ranking genes based on a set of phenotypes. Our method first uses a graph projection to map axioms from phenotype ontologies to a graph structure, and then uses graph embeddings to create latent representations of phenotypes. We use an explicit aggregation strategy to combine phenotype embeddings into representations of genes or diseases, allowing us to generalize to novel sets of phenotypes. We also develop a method to make the phenotype embeddings and the similarity measure task-specific by including a supervised signal from known GDAs. We apply our method to mouse models of human disease and demonstrate that we can significantly improve over the inductive semantic similarity baseline measures, and reach a performance similar to transductive methods for predicting GDAs while being more general. AVAILABILITY AND IMPLEMENTATION: https://github.com/bio-ontology-research-group/indigena.

Ontologies are widely used for representing domain knowledge and meta data, playing an increasingly important role in Information Systems, the Semantic Web, Bioinformatics and many other domains. However, logical reasoning that ontologies can directly support are quite limited in learning, approximation and prediction. One straightforward solution is to integrate statistical analysis and machine learning. To this end, automatically learning vector representation for knowledge of an ontology i.e.,ontology embeddinghas been widely investigated. Numerous papers have been published on ontology embedding, but a lack of systematic reviews hinders researchers from gaining a comprehensive understanding of this field. To bridge this gap, we write this survey paper, which first introduces different kinds of semantics of ontologies and formally defines ontology embedding as well as its property of faithfulness. Based on this, it systematically categorizes and analyses a relatively complete set of over 80 papers, according to the ontologies they aim at and their technical solutions including geometric modeling, sequence modeling and graph propagation. This survey also introduces the applications of ontology embedding in ontology engineering, machine learning augmentation and life sciences, presents a new library mOWL and discusses the challenges and future directions.

MOTIVATION: Whole-exome and genome sequencing have become common tools in diagnosing patients with rare diseases. Despite their success, this approach leaves many patients undiagnosed. A common argument is that more disease variants still await discovery, or the novelty of disease phenotypes results from a combination of variants in multiple disease-related genes. Interpreting the phenotypic consequences of genomic variants relies on information about gene functions, gene expression, physiology, and other genomic features. Phenotype-based methods to identify variants involved in genetic diseases combine molecular features with prior knowledge about the phenotypic consequences of altering gene functions. While phenotype-based methods have been successfully applied to prioritizing variants, such methods are based on known gene-disease or gene-phenotype associations as training data and are applicable to genes that have phenotypes associated, thereby limiting their scope. In addition, phenotypes are not assigned uniformly by different clinicians, and phenotype-based methods need to account for this variability. RESULTS: We developed an Embedding-based Phenotype Variant Predictor (EmbedPVP), a computational method to prioritize variants involved in genetic diseases by combining genomic information and clinical phenotypes. EmbedPVP leverages a large amount of background knowledge from human and model organisms about molecular mechanisms through which abnormal phenotypes may arise. Specifically, EmbedPVP incorporates phenotypes linked to genes, functions of gene products, and the anatomical site of gene expression, and systematically relates them to their phenotypic effects through neuro-symbolic, knowledge-enhanced machine learning. We demonstrate EmbedPVP's efficacy on a large set of synthetic genomes and genomes matched with clinical information. AVAILABILITY AND IMPLEMENTATION: EmbedPVP and all evaluation experiments are freely available at https://github.com/bio-ontology-research-group/EmbedPVP.

Automated protein function prediction is a crucial and widely studied problem in bioinformatics. Computationally, protein function is a multilabel classification problem where only positive samples are defined and there is a large number of unlabeled annotations. Most existing methods rely on the assumption that the unlabeled set of protein function annotations are negatives, inducing the false negative issue, where potential positive samples are trained as negatives. We introduce a novel approach named PU-GO, wherein we address function prediction as a positive-unlabeled ranking problem. We apply empirical risk minimization, i.e. we minimize the classification risk of a classifier where class priors are obtained from the Gene Ontology hierarchical structure. We show that our approach is more robust than other state-of-the-art methods on similarity-based and time-based benchmark datasets. AVAILABILITY AND IMPLEMENTATION: Data and code are available at https://github.com/bio-ontology-research-group/PU-GO.

MOTIVATION: Ontologies contain formal and structured information about a domain and are widely used in bioinformatics for annotation and integration of data. Several methods use ontologies to provide background knowledge in machine learning tasks, which is of particular importance in bioinformatics. These methods rely on a set of common primitives that are not readily available in a software library; a library providing these primitives would facilitate the use of current machine learning methods with ontologies and the development of novel methods for other ontology-based biomedical applications. RESULTS: We developed mOWL, a Python library for machine learning with ontologies formalized in the Web Ontology Language (OWL). mOWL implements ontology embedding methods that map information contained in formal knowledge bases and ontologies into vector spaces while preserving some of the properties and relations in ontologies, as well as methods to use these embeddings for similarity computation, deductive inference and zero-shot learning. We demonstrate mOWL on the knowledge-based prediction of protein-protein interactions using the gene ontology and gene-disease associations using phenotype ontologies. AVAILABILITY AND IMPLEMENTATION: mOWL is freely available on https://github.com/bio-ontology-research-group/mowl and as a Python package in PyPi. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.