Gene function finding through cross-organism ensemble learning

Background: Structured biological information about genes and proteins is a valuable resource to improve discovery and understanding of complex biological processes via machine learning algorithms. Gene Ontology (GO) controlled annotations describe, in a structured form, features and functions of genes and proteins of many organisms. However, such valuable annotations are not always reliable and sometimes are incomplete, especially for rarely studied organisms. Here, we present GeFF (Gene Function Finder), a novel cross-organism ensemble learning method able to reliably predict new GO annotations of a target organism from GO annotations of another source organism evolutionarily related and better studied. Results: Using a supervised method, GeFF predicts unknown annotations from random perturbations of existing annotations. The perturbation consists in randomly deleting a fraction of known annotations in order to produce a reduced annotation set. The key idea is to train a supervised machine learning algorithm with the reduced annotation set to predict, namely to rebuild, the original annotations. The resulting prediction model, in addition to accurately rebuilding the original known annotations for an organism from their perturbed version, also effectively predicts new unknown annotations for the organism. Moreover, the prediction model is also able to discover new unknown annotations in different target organisms without retraining.We combined our novel method with different ensemble learning approaches and compared them to each other and to an equivalent single model technique. We tested the method with five different organisms using their GO annotations: Homo sapiens, Mus musculus, Bos taurus, Gallus gallus and Dictyostelium discoideum. The outcomes demonstrate the effectiveness of the cross-organism ensemble approach, which can be customized with a trade-off between the desired number of predicted new annotations and their precision.A Web application to browse both input annotations used and predicted ones, choosing the ensemble prediction method to use, is publicly available at http://tiny.cc/geff/. Conclusions: Our novel cross-organism ensemble learning method provides reliable predicted novel gene annotations, i.e., functions, ranked according to an associated likelihood value. They are very valuable both to speed the annotation curation, focusing it on the prioritized new annotations predicted, and to complement known annotations available

Protein Bioinformatics Infrastructure for the Integration and Analysis of Multiple High-Throughput “omics” Data

High-throughput “omics” technologies bring new opportunities for biological and biomedical researchers to ask complex questions and gain new scientific insights. However, the voluminous, complex, and context-dependent data being maintained in heterogeneous and distributed environments plus the lack of well-defined data standard and standardized nomenclature imposes a major challenge which requires advanced computational methods and bioinformatics infrastructures for integration, mining, visualization, and comparative analysis to facilitate data-driven hypothesis generation and biological knowledge discovery. In this paper, we present the challenges in high-throughput “omics” data integration and analysis, introduce a protein-centric approach for systems integration of large and heterogeneous high-throughput “omics” data including microarray, mass spectrometry, protein sequence, protein structure, and protein interaction data, and use scientific case study to illustrate how one can use varied “omics” data from different laboratories to make useful connections that could lead to new biological knowledge

Explorative search of distributed bio-data to answer complex biomedical questions

Background The huge amount of biomedical-molecular data increasingly produced is providing scientists with potentially valuable information. Yet, such data quantity makes difficult to find and extract those data that are most reliable and most related to the biomedical questions to be answered, which are increasingly complex and often involve many different biomedical-molecular aspects. Such questions can be addressed only by comprehensively searching and exploring different types of data, which frequently are ordered and provided by different data sources. Search Computing has been proposed for the management and integration of ranked results from heterogeneous search services. Here, we present its novel application to the explorative search of distributed biomedical-molecular data and the integration of the search results to answer complex biomedical questions. Results A set of available bioinformatics search services has been modelled and registered in the Search Computing framework, and a Bioinformatics Search Computing application (Bio-SeCo) using such services has been created and made publicly available at http://www.bioinformatics.deib.polimi.it/bio-seco/seco/. It offers an integrated environment which eases search, exploration and ranking-aware combination of heterogeneous data provided by the available registered services, and supplies global results that can support answering complex multi-topic biomedical questions. Conclusions By using Bio-SeCo, scientists can explore the very large and very heterogeneous biomedical-molecular data available. They can easily make different explorative search attempts, inspect obtained results, select the most appropriate, expand or refine them and move forward and backward in the construction of a global complex biomedical query on multiple distributed sources that could eventually find the most relevant results. Thus, it provides an extremely useful automated support for exploratory integrated bio search, which is fundamental for Life Science data driven knowledge discovery

TargetMine, an Integrated Data Warehouse for Candidate Gene Prioritisation and Target Discovery

Prioritising candidate genes for further experimental characterisation is a non-trivial challenge in drug discovery and biomedical research in general. An integrated approach that combines results from multiple data types is best suited for optimal target selection. We developed TargetMine, a data warehouse for efficient target prioritisation. TargetMine utilises the InterMine framework, with new data models such as protein-DNA interactions integrated in a novel way. It enables complicated searches that are difficult to perform with existing tools and it also offers integration of custom annotations and in-house experimental data. We proposed an objective protocol for target prioritisation using TargetMine and set up a benchmarking procedure to evaluate its performance. The results show that the protocol can identify known disease-associated genes with high precision and coverage. A demonstration version of TargetMine is available at http://targetmine.nibio.go.jp/

Novelty indicator for enhanced prioritization of predicted gene ontology annotations

Biomolecular controlled annotations have become pivotal in computational biology, because they allow scientists to analyze large amounts of biological data to better understand test results, and to infer new knowledge. Yet, biomolecular annotation databases are incomplete by definition, like our knowledge of biology, and might contain errors and inconsistent information. In this context, machine-learning algorithms able to predict and prioritize new annotations are both effective and efficient, especially if compared with time-consuming trials of biological validation. To limit the possibility that these techniques predict obvious and trivial high-level features, and to help prioritize their results, we introduce a new element that can improve accuracy and relevance of the results of an annotation prediction and prioritization pipeline. We propose a novelty indicator able to state the level of “originality” of the annotations predicted for a specific gene to Gene Ontology (GO) terms. This indicator, joint with our previously introduced prediction steps, helps by prioritizing the most novel interesting annotations predicted. We performed an accurate biological functional analysis of the prioritized annotations predicted with high accuracy by our indicator and previously proposed methods. The relevance of our biological findings proves effectiveness and trustworthiness of our indicator and of its prioritization of predicted annotations

Chapter Integrative Systems Biology Resources and Approaches in Disease Analytics

Currently, our analytical competences are struggling to keep-up the pace of in-deep analysis of all generated large-scale data resultant of high-throughput omics platforms. While, a substantial effort was spent on methods enhancement regarding technical aspects across many detection omics platforms, the development of integrative down-stream approaches is still challenging. Systems biology has an immense applicability in the biomedical and pharmacological areas since the main goal of those focuses in the translation of measured outputs into potential markers of a Human ailment and/or to provide new compound leads for drug discovery. This approach would become more straightforward and realistic to use in standard analysis workflows if the collation of all available information of every component of a biological system was ensured into a single database framework, instead of search and fetch a single component at time across a scatter of databases resources. Here, we will describe several database resources, standalone and web-based tools applied in disease analytics workflows based in data-driven integration of outputs of multi-omic detection platforms