Gene2DisCo : gene to disease using disease commonalities

OBJECTIVE: Finding the human genes co-causing complex diseases, also known as "disease-genes", is one of the emerging and challenging tasks in biomedicine. This process, termed gene prioritization (GP), is characterized by a scarcity of known disease-genes for most diseases, and by a vast amount of heterogeneous data, usually encoded into networks describing different types of functional relationships between genes. In addition, different diseases may share common profiles (e.g. genetic or therapeutic profiles), and exploiting disease commonalities may significantly enhance the performance of GP methods. This work aims to provide a systematic comparison of several disease similarity measures, and to embed disease similarities and heterogeneous data into a flexible framework for gene prioritization which specifically handles the lack of known disease-genes. METHODS: We present a novel network-based method, Gene2DisCo, based on generalized linear models (GLMs) to effectively prioritize genes by exploiting data regarding disease-genes, gene interaction networks and disease similarities. The scarcity of disease-genes is addressed by applying an efficient negative selection procedure, together with imbalance-aware GLMs. Gene2DisCo is a flexible framework, in the sense it is not dependent upon specific types of data, and/or upon specific disease ontologies. RESULTS: On a benchmark dataset composed of nine human networks and 708 medical subject headings (MeSH) diseases, Gene2DisCo largely outperformed the best benchmark algorithm, kernelized score functions, in terms of both area under the ROC curve (0.94 against 0.86) and precision at given recall levels (for recall levels from 0.1 to 1 with steps 0.1). Furthermore, we enriched and extended the benchmark data to the whole human genome and provided the top-ranked unannotated candidate genes even for MeSH disease terms without known annotations

A multilayer network approach for guiding drug repositioning in neglected diseases

Drug development for neglected diseases has been historically hampered due to lack of market incentives. The advent of public domain resources containing chemical information from high throughput screenings is changing the landscape of drug discovery for these diseases. In this work we took advantage of data from extensively studied organisms like human, mouse, E. coli and yeast, among others, to develop a novel integrative network model to prioritize and identify candidate drug targets in neglected pathogen proteomes, and bioactive drug-like molecules. We modeled genomic (proteins) and chemical (bioactive compounds) data as a multilayer weighted network graph that takes advantage of bioactivity data across 221 species, chemical similarities between 1.7 105 compounds and several functional relations among 1.67 105 proteins. These relations comprised orthology, sharing of protein domains, and shared participation in defined biochemical pathways. We showcase the application of this network graph to the problem of prioritization of new candidate targets, based on the information available in the graph for known compound-target associations. We validated this strategy by performing a cross validation procedure for known mouse and Trypanosoma cruzi targets and showed that our approach outperforms classic alignment-based approaches. Moreover, our model provides additional flexibility as two different network definitions could be considered, finding in both cases qualitatively different but sensible candidate targets. We also showcase the application of the network to suggest targets for orphan compounds that are active against Plasmodium falciparum in high-throughput screens. In this case our approach provided a reduced prioritization list of target proteins for the query molecules and showed the ability to propose new testable hypotheses for each compound. Moreover, we found that some predictions highlighted by our network model were supported by independent experimental validations as found post-facto in the literature.Fil: Berenstein, Ariel José. Fundación Instituto Leloir; Argentina. Universidad de Buenos Aires. Facultad de Ingeniería. Departamento de Física; ArgentinaFil: Magariños, María Paula. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Investigaciones Biotecnológicas. Instituto de Investigaciones Biotecnológicas "Dr. Raúl Alfonsín" (sede Chascomús). Universidad Nacional de San Martín. Instituto de Investigaciones Biotecnológicas. Instituto de Investigaciones Biotecnológicas "Dr. Raúl Alfonsín" (sede Chascomús); ArgentinaFil: Chernomoretz, Ariel. Fundación Instituto Leloir; Argentina. Universidad de Buenos Aires. Facultad de Ingeniería. Departamento de Física; ArgentinaFil: Fernandez Aguero, Maria Jose. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Investigaciones Biotecnológicas. Instituto de Investigaciones Biotecnológicas "Dr. Raúl Alfonsín" (sede Chascomús). Universidad Nacional de San Martín. Instituto de Investigaciones Biotecnológicas. Instituto de Investigaciones Biotecnológicas "Dr. Raúl Alfonsín" (sede Chascomús); Argentin

Functional Analysis of Human Long Non-coding RNAs and Their Associations with Diseases

Within this study, we sought to leverage knowledge from well-characterized protein coding genes to characterize the lesser known long non-coding RNA (lncRNA) genes using computational methods to find functional annotations and disease associations. Functional genome annotation is an essential step to a systems-level view of the human genome. With this knowledge, we can gain a deeper understanding of how humans develop and function, and a better understanding of human disease. LncRNAs are transcripts greater than 200 nucleotides, which do not code for proteins. LncRNAs have been found to regulate development, tissue and cell differentiation, and organ formation. Their dysregulation has been linked to several diseases including autism spectrum disorder (ASD) and cancer. While a great deal of research has been dedicated to protein-coding genes, the relatively recently discovered lncRNA genes have yet to be characterized. LncRNA function is tied closely to when and where they are expressed. Co-expression network analysis offer a means of functional annotation of uncharacterized genes through a guilt by association approach. We have constructed two co-expression networks using known disease-associated protein-coding genes and lncRNA genes. Through clustering of the networks, gene set enrichment analysis, and centrality measures, we found enrichment for disease association and functions as well as identified high-confidence lncRNA disease gene targets. We present a novel approach to the identification of disease state associations by demonstrating genes that are associated with the same disease states share patterns that can be discerned from transcriptomes of healthy tissues. Using a machine learning algorithm, we built a model to classify ASD versus non-ASD genes using their expression profiles from healthy developing human brain tissues. Feature selection during the model-building process also identified critical temporospatial points for the determination of ASD genes. We constructed a webserver tool for the prioritization of genes for ASD association. The webserver tool has a database containing prioritization and co-expression information for nearly every gene in the human genome

Learning node labels with multi-category Hopfield networks

In several real-world node label prediction problems on graphs, in fields ranging from computational biology to World Wide Web analysis, nodes can be partitioned into categories different from the classes to be predicted, on the basis of their characteristics or their common properties. Such partitions may provide further information about node classification that classical machine learning algorithms do not take into account. We introduce a novel family of parametric Hopfield networks (m-category Hopfield networks) and a novel algorithm (Hopfield multi-category \u2014 HoMCat ), designed to appropriately exploit the presence of property-based partitions of nodes into multiple categories. Moreover, the proposed model adopts a cost-sensitive learning strategy to prevent the remarkable decay in performance usually observed when instance labels are unbalanced, that is, when one class of labels is highly underrepresented than the other one. We validate the proposed model on both synthetic and real-world data, in the context of multi-species function prediction, where the classes to be predicted are the Gene Ontology terms and the categories the different species in the multi-species protein network. We carried out an intensive experimental validation, which on the one hand compares HoMCat with several state-of-the-art graph-based algorithms, and on the other hand reveals that exploiting meaningful prior partitions of input data can substantially improve classification performances

Scalable statistical learning for relation prediction on structured data

Relation prediction seeks to predict unknown but potentially true relations by revealing missing relations in available data, by predicting future events based on historical data, and by making predicted relations retrievable by query. The approach developed in this thesis can be used for a wide variety of purposes, including to predict likely new friends on social networks, attractive points of interest for an individual visiting an unfamiliar city, and associations between genes and particular diseases. In recent years, relation prediction has attracted significant interest in both research and application domains, partially due to the increasing volume of published structured data and background knowledge. In the Linked Open Data initiative of the Semantic Web, for instance, entities are uniquely identified such that the published information can be integrated into applications and services, and the rapid increase in the availability of such structured data creates excellent opportunities as well as challenges for relation prediction. This thesis focuses on the prediction of potential relations by exploiting regularities in data using statistical relational learning algorithms and applying these methods to relational knowledge bases, in particular in Linked Open Data in particular. We review representative statistical relational learning approaches, e.g., Inductive Logic Programming and Probabilistic Relational Models. While logic-based reasoning can infer and include new relations via deduction by using ontologies, machine learning can be exploited to predict new relations (with some degree of certainty) via induction, purely based on the data. Because the application of machine learning approaches to relation prediction usually requires handling large datasets, we also discuss the scalability of machine learning as a solution to relation prediction, as well as the significant challenge posed by incomplete relational data (such as social network data, which is often much more extensive for some users than others). The main contribution of this thesis is to develop a learning framework called the Statistical Unit Node Set (SUNS) and to propose a multivariate prediction approach used in the framework. We argue that multivariate prediction approaches are most suitable for dealing with large, sparse data matrices. According to the characteristics and intended application of the data, the approach can be extended in different ways. We discuss and test two extensions of the approach--kernelization and a probabilistic method of handling complex n-ary relationships--in empirical studies based on real-world data sets. Additionally, this thesis contributes to the field of relation prediction by applying the SUNS framework to various domains. We focus on three applications: 1. In social network analysis, we present a combined approach of inductive and deductive reasoning for recommending movies to users. 2. In the life sciences, we address the disease gene prioritization problem. 3. In the recommendation system, we describe and investigate the back-end of a mobile app called BOTTARI, which provides personalized location-based recommendations of restaurants.Die Beziehungsvorhersage strebt an, unbekannte aber potenziell wahre Beziehungen vorherzusagen, indem fehlende Relationen in verfügbaren Daten aufgedeckt, zukünftige Ereignisse auf der Grundlage historischer Daten prognostiziert und vorhergesagte Relationen durch Anfragen abrufbar gemacht werden. Der in dieser Arbeit entwickelte Ansatz lässt sich für eine Vielzahl von Zwecken einschließlich der Vorhersage wahrscheinlicher neuer Freunde in sozialen Netzen, der Empfehlung attraktiver Sehenswürdigkeiten für Touristen in fremden Städten und der Priorisierung möglicher Assoziationen zwischen Genen und bestimmten Krankheiten, verwenden. In den letzten Jahren hat die Beziehungsvorhersage sowohl in Forschungs- als auch in Anwendungsbereichen eine enorme Aufmerksamkeit erregt, aufgrund des Zuwachses veröffentlichter strukturierter Daten und von Hintergrundwissen. In der Linked Open Data-Initiative des Semantischen Web werden beispielsweise Entitäten eindeutig identifiziert, sodass die veröffentlichten Informationen in Anwendungen und Dienste integriert werden können. Diese rapide Erhöhung der Verfügbarkeit strukturierter Daten bietet hervorragende Gelegenheiten sowie Herausforderungen für die Beziehungsvorhersage. Diese Arbeit fokussiert sich auf die Vorhersage potenzieller Beziehungen durch Ausnutzung von Regelmäßigkeiten in Daten unter der Verwendung statistischer relationaler Lernalgorithmen und durch Einsatz dieser Methoden in relationale Wissensbasen, insbesondere in den Linked Open Daten. Wir geben einen Überblick über repräsentative statistische relationale Lernansätze, z.B. die Induktive Logikprogrammierung und Probabilistische Relationale Modelle. Während das logikbasierte Reasoning neue Beziehungen unter der Nutzung von Ontologien ableiten und diese einbeziehen kann, kann maschinelles Lernen neue Beziehungen (mit gewisser Wahrscheinlichkeit) durch Induktion ausschließlich auf der Basis der vorliegenden Daten vorhersagen. Da die Verarbeitung von massiven Datenmengen in der Regel erforderlich ist, wenn maschinelle Lernmethoden in die Beziehungsvorhersage eingesetzt werden, diskutieren wir auch die Skalierbarkeit des maschinellen Lernens sowie die erhebliche Herausforderung, die sich aus unvollständigen relationalen Daten ergibt (z. B. Daten aus sozialen Netzen, die oft für manche Benutzer wesentlich umfangreicher sind als für Anderen). Der Hauptbeitrag der vorliegenden Arbeit besteht darin, ein Lernframework namens Statistical Unit Node Set (SUNS) zu entwickeln und einen im Framework angewendeten multivariaten Prädiktionsansatz einzubringen. Wir argumentieren, dass multivariate Vorhersageansätze am besten für die Bearbeitung von großen und dünnbesetzten Datenmatrizen geeignet sind. Je nach den Eigenschaften und der beabsichtigten Anwendung der Daten kann der Ansatz auf verschiedene Weise erweitert werden. In empirischen Studien werden zwei Erweiterungen des Ansatzes--ein kernelisierter Ansatz sowie ein probabilistischer Ansatz zur Behandlung komplexer n-stelliger Beziehungen-- diskutiert und auf realen Datensätzen untersucht. Ein weiterer Beitrag dieser Arbeit ist die Anwendung des SUNS Frameworks auf verschiedene Bereiche. Wir konzentrieren uns auf drei Anwendungen: 1. In der Analyse sozialer Netze stellen wir einen kombinierten Ansatz von induktivem und deduktivem Reasoning vor, um Benutzern Filme zu empfehlen. 2. In den Biowissenschaften befassen wir uns mit dem Problem der Priorisierung von Krankheitsgenen. 3. In den Empfehlungssystemen beschreiben und untersuchen wir das Backend einer mobilen App "BOTTARI", das personalisierte ortsbezogene Empfehlungen von Restaurants bietet

Scalable statistical learning for relation prediction on structured data

Relation prediction seeks to predict unknown but potentially true relations by revealing missing relations in available data, by predicting future events based on historical data, and by making predicted relations retrievable by query. The approach developed in this thesis can be used for a wide variety of purposes, including to predict likely new friends on social networks, attractive points of interest for an individual visiting an unfamiliar city, and associations between genes and particular diseases. In recent years, relation prediction has attracted significant interest in both research and application domains, partially due to the increasing volume of published structured data and background knowledge. In the Linked Open Data initiative of the Semantic Web, for instance, entities are uniquely identified such that the published information can be integrated into applications and services, and the rapid increase in the availability of such structured data creates excellent opportunities as well as challenges for relation prediction. This thesis focuses on the prediction of potential relations by exploiting regularities in data using statistical relational learning algorithms and applying these methods to relational knowledge bases, in particular in Linked Open Data in particular. We review representative statistical relational learning approaches, e.g., Inductive Logic Programming and Probabilistic Relational Models. While logic-based reasoning can infer and include new relations via deduction by using ontologies, machine learning can be exploited to predict new relations (with some degree of certainty) via induction, purely based on the data. Because the application of machine learning approaches to relation prediction usually requires handling large datasets, we also discuss the scalability of machine learning as a solution to relation prediction, as well as the significant challenge posed by incomplete relational data (such as social network data, which is often much more extensive for some users than others). The main contribution of this thesis is to develop a learning framework called the Statistical Unit Node Set (SUNS) and to propose a multivariate prediction approach used in the framework. We argue that multivariate prediction approaches are most suitable for dealing with large, sparse data matrices. According to the characteristics and intended application of the data, the approach can be extended in different ways. We discuss and test two extensions of the approach--kernelization and a probabilistic method of handling complex n-ary relationships--in empirical studies based on real-world data sets. Additionally, this thesis contributes to the field of relation prediction by applying the SUNS framework to various domains. We focus on three applications: 1. In social network analysis, we present a combined approach of inductive and deductive reasoning for recommending movies to users. 2. In the life sciences, we address the disease gene prioritization problem. 3. In the recommendation system, we describe and investigate the back-end of a mobile app called BOTTARI, which provides personalized location-based recommendations of restaurants.Die Beziehungsvorhersage strebt an, unbekannte aber potenziell wahre Beziehungen vorherzusagen, indem fehlende Relationen in verfügbaren Daten aufgedeckt, zukünftige Ereignisse auf der Grundlage historischer Daten prognostiziert und vorhergesagte Relationen durch Anfragen abrufbar gemacht werden. Der in dieser Arbeit entwickelte Ansatz lässt sich für eine Vielzahl von Zwecken einschließlich der Vorhersage wahrscheinlicher neuer Freunde in sozialen Netzen, der Empfehlung attraktiver Sehenswürdigkeiten für Touristen in fremden Städten und der Priorisierung möglicher Assoziationen zwischen Genen und bestimmten Krankheiten, verwenden. In den letzten Jahren hat die Beziehungsvorhersage sowohl in Forschungs- als auch in Anwendungsbereichen eine enorme Aufmerksamkeit erregt, aufgrund des Zuwachses veröffentlichter strukturierter Daten und von Hintergrundwissen. In der Linked Open Data-Initiative des Semantischen Web werden beispielsweise Entitäten eindeutig identifiziert, sodass die veröffentlichten Informationen in Anwendungen und Dienste integriert werden können. Diese rapide Erhöhung der Verfügbarkeit strukturierter Daten bietet hervorragende Gelegenheiten sowie Herausforderungen für die Beziehungsvorhersage. Diese Arbeit fokussiert sich auf die Vorhersage potenzieller Beziehungen durch Ausnutzung von Regelmäßigkeiten in Daten unter der Verwendung statistischer relationaler Lernalgorithmen und durch Einsatz dieser Methoden in relationale Wissensbasen, insbesondere in den Linked Open Daten. Wir geben einen Überblick über repräsentative statistische relationale Lernansätze, z.B. die Induktive Logikprogrammierung und Probabilistische Relationale Modelle. Während das logikbasierte Reasoning neue Beziehungen unter der Nutzung von Ontologien ableiten und diese einbeziehen kann, kann maschinelles Lernen neue Beziehungen (mit gewisser Wahrscheinlichkeit) durch Induktion ausschließlich auf der Basis der vorliegenden Daten vorhersagen. Da die Verarbeitung von massiven Datenmengen in der Regel erforderlich ist, wenn maschinelle Lernmethoden in die Beziehungsvorhersage eingesetzt werden, diskutieren wir auch die Skalierbarkeit des maschinellen Lernens sowie die erhebliche Herausforderung, die sich aus unvollständigen relationalen Daten ergibt (z. B. Daten aus sozialen Netzen, die oft für manche Benutzer wesentlich umfangreicher sind als für Anderen). Der Hauptbeitrag der vorliegenden Arbeit besteht darin, ein Lernframework namens Statistical Unit Node Set (SUNS) zu entwickeln und einen im Framework angewendeten multivariaten Prädiktionsansatz einzubringen. Wir argumentieren, dass multivariate Vorhersageansätze am besten für die Bearbeitung von großen und dünnbesetzten Datenmatrizen geeignet sind. Je nach den Eigenschaften und der beabsichtigten Anwendung der Daten kann der Ansatz auf verschiedene Weise erweitert werden. In empirischen Studien werden zwei Erweiterungen des Ansatzes--ein kernelisierter Ansatz sowie ein probabilistischer Ansatz zur Behandlung komplexer n-stelliger Beziehungen-- diskutiert und auf realen Datensätzen untersucht. Ein weiterer Beitrag dieser Arbeit ist die Anwendung des SUNS Frameworks auf verschiedene Bereiche. Wir konzentrieren uns auf drei Anwendungen: 1. In der Analyse sozialer Netze stellen wir einen kombinierten Ansatz von induktivem und deduktivem Reasoning vor, um Benutzern Filme zu empfehlen. 2. In den Biowissenschaften befassen wir uns mit dem Problem der Priorisierung von Krankheitsgenen. 3. In den Empfehlungssystemen beschreiben und untersuchen wir das Backend einer mobilen App "BOTTARI", das personalisierte ortsbezogene Empfehlungen von Restaurants bietet

Connectivity modelling for a species-driven nature recovery network in Oxfordshire

The development of England’s new Nature Recovery Network has been piloted in several counties in the country, but few have systematically mapped connectivity based on species dispersal. This study proposes and evaluates a novel modelling framework that integrates various layers of species information into a spatial conservation prioritization analysis. It aims to strategically identify optimal zones for nature recovery that can maximize species connectivity in Oxfordshire, using bats as a focal species. The framework was able to not only identify key landscape corridors but also stepping stone habitats for bats and emphasized how well-placed, small-scale green and blue infrastructure, such as hedgerows and ponds, can be just as effective as larger reserves. It also found that the current coverage of protected areas may not adequately be protecting woodland habitat needed for connectivity. Next steps for Oxfordshire’s NRN should scale up the application of this connectivity framework to address these areas of priority in the landscape

Computational solutions for omics data

High-throughput experimental technologies are generating increasingly massive and complex genomic data sets. The sheer enormity and heterogeneity of these data threaten to make the arising problems computationally infeasible. Fortunately, powerful algorithmic techniques lead to software that can answer important biomedical questions in practice. In this Review, we sample the algorithmic landscape, focusing on state-of-the-art techniques, the understanding of which will aid the bench biologist in analysing omics data. We spotlight specific examples that have facilitated and enriched analyses of sequence, transcriptomic and network data sets.National Institutes of Health (U.S.) (Grant GM081871