Learning the Consensus of Multiple Correspondences between Data Structures

En aquesta tesi presentem un marc de treball per aprendre el consens donades múltiples correspondències. S'assumeix que les diferents parts involucrades han generat aquestes correspondències per separat, i el nostre sistema actua com un mecanisme que calibra diferents característiques i considera diferents paràmetres per aprendre les millors assignacions i així, conformar una correspondència amb la major precisió possible a costa d'un cost computacional raonable. Aquest marc de treball de consens és presentat en una forma gradual, començant pels desenvolupaments més bàsics que utilitzaven exclusivament conceptes ben definits o únicament un parell de correspondències, fins al model final que és capaç de considerar múltiples correspondències, amb la capacitat d'aprendre automàticament alguns paràmetres de ponderació. Cada pas d'aquest marc de treball és avaluat fent servir bases de dades de naturalesa variada per demostrar efectivament que és possible tractar diferents escenaris de matching. Addicionalment, dos avanços suplementaris relacionats amb correspondències es presenten en aquest treball. En primer lloc, una nova mètrica de distància per correspondències s'ha desenvolupat, la qual va derivar en una nova estratègia per a la cerca de mitjanes ponderades. En segon lloc, un marc de treball específicament dissenyat per a generar correspondències al camp del registre d'imatges s'ha modelat, on es considera que una de les imatges és una imatge completa, i l'altra és una mostra petita d'aquesta. La conclusió presenta noves percepcions de com el nostre marc de treball de consens pot ser millorada, i com els dos desenvolupaments paral·lels poden convergir amb el marc de treball de consens.En esta tesis presentamos un marco de trabajo para aprender el consenso dadas múltiples correspondencias. Se asume que las distintas partes involucradas han generado dichas correspondencias por separado, y nuestro sistema actúa como un mecanismo que calibra distintas características y considera diferentes parámetros para aprender las mejores asignaciones y así, conformar una correspondencia con la mayor precisión posible a expensas de un costo computacional razonable. El marco de trabajo de consenso es presentado en una forma gradual, comenzando por los acercamientos más básicos que utilizaban exclusivamente conceptos bien definidos o únicamente un par de correspondencias, hasta el modelo final que es capaz de considerar múltiples correspondencias, con la capacidad de aprender automáticamente algunos parámetros de ponderación. Cada paso de este marco de trabajo es evaluado usando bases de datos de naturaleza variada para demostrar efectivamente que es posible tratar diferentes escenarios de matching. Adicionalmente, dos avances suplementarios relacionados con correspondencias son presentados en este trabajo. En primer lugar, una nueva métrica de distancia para correspondencias ha sido desarrollada, la cual derivó en una nueva estrategia para la búsqueda de medias ponderadas. En segundo lugar, un marco de trabajo específicamente diseñado para generar correspondencias en el campo del registro de imágenes ha sido establecida, donde se considera que una de las imágenes es una imagen completa, y la otra es una muestra pequeña de ésta. La conclusión presenta nuevas percepciones de cómo nuestro marco de trabajo de consenso puede ser mejorada, y cómo los dos desarrollos paralelos pueden converger con éste.In this work, we present a framework to learn the consensus given multiple correspondences. It is assumed that the several parties involved have generated separately these correspondences, and our system acts as a mechanism that gauges several characteristics and considers different parameters to learn the best mappings and thus, conform a correspondence with the highest possible accuracy at the expense of a reasonable computational cost. The consensus framework is presented in a gradual form, starting from the most basic approaches that used exclusively well-known concepts or only two correspondences, until the final model which is able to consider multiple correspondences, with the capability of automatically learning some weighting parameters. Each step of the framework is evaluated using databases of varied nature to effectively demonstrate that it is capable to address different matching scenarios. In addition, two supplementary advances related on correspondences are presented in this work. Firstly, a new distance metric for correspondences has been developed, which lead to a new strategy for the weighted mean correspondence search. Secondly, a framework specifically designed for correspondence generation in the image registration field has been established, where it is considered that one of the images is a full image, and the other one is a small sample of it. The conclusion presents insights of how our consensus framework can be enhanced, and how these two parallel developments can converge with it

PPIcons: identification of protein-protein interaction sites in selected organisms

The physico-chemical properties of interaction interfaces have a crucial role in characterization of protein–protein interactions (PPI). In silico prediction of participating amino acids helps to identify interface residues for further experimental verification using mutational analysis, or inhibition studies by screening library of ligands against given protein. Given the unbound structure of a protein and the fact that it forms a complex with another known protein, the objective of this work is to identify the residues that are involved in the interaction. We attempt to predict interaction sites in protein complexes using local composition of amino acids together with their physico-chemical characteristics. The local sequence segments (LSS) are dissected from the protein sequences using a sliding window of 21 amino acids. The list of LSSs is passed to the support vector machine (SVM) predictor, which identifies interacting residue pairs considering their inter-atom distances. We have analyzed three different model organisms of Escherichia coli, Saccharomyces Cerevisiae and Homo sapiens, where the numbers of considered hetero-complexes are equal to 40, 123 and 33 respectively. Moreover, the unified multi-organism PPI meta-predictor is also developed under the current work by combining the training databases of above organisms. The PPIcons interface residues prediction method is measured by the area under ROC curve (AUC) equal to 0.82, 0.75, 0.72 and 0.76 for the aforementioned organisms and the meta-predictor respectively. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s00894-013-1886-9) contains supplementary material, which is available to authorized users

PROTEIN FUNCTION, DIVERISTY AND FUNCTIONAL INTERPLAY

Functional annotations of novel or unknown proteins is one of the central problems in post-genomics bioinformatics research. With the vast expansion of genomic and proteomic data and technologies over the last decade, development of automated function prediction (AFP) methods for large-scale identification of protein function has be-come imperative in many aspects. In this research, we address two important divergences from the “one protein – one function” concept on which all existing AFP methods are developed

An Ensemble Model of QSAR Tools for Regulatory Risk Assessment

Quantitative structure activity relationships (QSARs) are theoretical models that relate a quantitative measure of chemical structure to a physical property or a biological effect. QSAR predictions can be used for chemical risk assessment for protection of human and environmental health, which makes them interesting to regulators, especially in the absence of experimental data. For compatibility with regulatory use, QSAR models should be transparent, reproducible and optimized to minimize the number of false negatives. In silico QSAR tools are gaining wide acceptance as a faster alternative to otherwise time-consuming clinical and animal testing methods. However, different QSAR tools often make conflicting predictions for a given chemical and may also vary in their predictive performance across different chemical datasets. In a regulatory context, conflicting predictions raise interpretation, validation and adequacy concerns. To address these concerns, ensemble learning techniques in the machine learning paradigm can be used to integrate predictions from multiple tools. By leveraging various underlying QSAR algorithms and training datasets, the resulting consensus prediction should yield better overall predictive ability. We present a novel ensemble QSAR model using Bayesian classification. The model allows for varying a cut-off parameter that allows for a selection in the desirable trade-off between model sensitivity and specificity. The predictive performance of the ensemble model is compared with four in silico tools (Toxtree, Lazar, OECD Toolbox, and Danish QSAR) to predict carcinogenicity for a dataset of air toxins (332 chemicals) and a subset of the gold carcinogenic potency database (480 chemicals). Leave-one-out cross validation results show that the ensemble model achieves the best trade-off between sensitivity and specificity (accuracy: 83.8 % and 80.4 %, and balanced accuracy: 80.6 % and 80.8 %) and highest inter-rater agreement [kappa (κ): 0.63 and 0.62] for both the datasets. The ROC curves demonstrate the utility of the cut-off feature in the predictive ability of the ensemble model. This feature provides an additional control to the regulators in grading a chemical based on the severity of the toxic endpoint under study

Development and Validation of a Computational Model Ensemble for the Early Detection of BCRP/ABCG2 Substrates during the Drug Design Stage

Breast Cancer Resistance Protein (BCRP) is an ATP-dependent efflux transporter linked to the multidrug resistance phenomenon in many diseases such as epilepsy and cancer and a potential source of drug interactions. For these reasons, the early identification of substrates and nonsubstrates of this transporter during the drug discovery stage is of great interest. We have developed a computational nonlinear model ensemble based on conformational independent molecular descriptors using a combined strategy of genetic algorithms, J48 decision tree classifiers, and data fusion. The best model ensemble consists in averaging the ranking of the 12 decision trees that showed the best performance on the training set, which also demonstrated a good performance for the test set. It was experimentally validated using the ex vivo everted rat intestinal sac model. Five anticonvulsant drugs classified as nonsubstrates for BRCP by the model ensemble were experimentally evaluated, and none of them proved to be a BCRP substrate under the experimental conditions used, thus confirming the predictive ability of the model ensemble. The model ensemble reported here is a potentially valuable tool to be used as an in silico ADME filter in computer-aided drug discovery campaigns intended to overcome BCRP-mediated multidrug resistance issues and to prevent drug−drug interactions.Facultad de Ciencias ExactasLaboratorio de Investigación y Desarrollo de Bioactivo

Application of rank correlation, clustering and classification in information security

This article is devoted to experimental investigation of a novel application of a clustering technique introduced by the authors recently in order to use robust and stable consensus functions in information security, where it is often necessary to process large data sets and monitor outcomes in real time, as it is required, for example, for intrusion detection. Here we concentrate on a particular case of application to profiling of phishing websites. First, we apply several independent clustering algorithms to a randomized sample of data to obtain independent initial clusterings. Silhouette index is used to determine the number of clusters. Second, rank correlation is used to select a subset of features for dimensionality reduction. We investigate the effectiveness of the Pearson Linear Correlation Coefficient, the Spearman Rank Correlation Coefficient and the Goodman--Kruskal Correlation Coefficient in this application. Third, we use a consensus function to combine independent initial clusterings into one consensus clustering. Fourth, we train fast supervised classification algorithms on the resulting consensus clustering in order to enable them to process the whole large data set as well as new data. The precision and recall of classifiers at the final stage of this scheme are critical for the effectiveness of the whole procedure. We investigated various combinations of several correlation coefficients, consensus functions, and a variety of supervised classification algorithms.<br /

Inferring microbial co-occurrence networks from amplicon data: a systematic evaluation

Microbes commonly organize into communities consisting of hundreds of species involved in complex interactions with each other. 16S ribosomal RNA (16S rRNA) amplicon profiling provides snapshots that reveal the phylogenies and abundance profiles of these microbial communities. These snapshots, when collected from multiple samples, can reveal the co-occurrence of microbes, providing a glimpse into the network of associations in these communities. However, the inference of networks from 16S data involves numerous steps, each requiring specific tools and parameter choices. Moreover, the extent to which these steps affect the final network is still unclear. In this study, we perform a meticulous analysis of each step of a pipeline that can convert 16S sequencing data into a network of microbial associations. Through this process, we map how different choices of algorithms and parameters affect the co-occurrence network and identify the steps that contribute substantially to the variance. We further determine the tools and parameters that generate robust co-occurrence networks and develop consensus network algorithms based on benchmarks with mock and synthetic data sets. The Microbial Co-occurrence Network Explorer, or MiCoNE (available at https://github.com/segrelab/MiCoNE) follows these default tools and parameters and can help explore the outcome of these combinations of choices on the inferred networks. We envisage that this pipeline could be used for integrating multiple data sets and generating comparative analyses and consensus networks that can guide our understanding of microbial community assembly in different biomes. IMPORTANCE Mapping the interrelationships between different species in a microbial community is important for understanding and controlling their structure and function. The surge in the high-throughput sequencing of microbial communities has led to the creation of thousands of data sets containing information about microbial abundances. These abundances can be transformed into co-occurrence networks, providing a glimpse into the associations within microbiomes. However, processing these data sets to obtain co-occurrence information relies on several complex steps, each of which involves numerous choices of tools and corresponding parameters. These multiple options pose questions about the robustness and uniqueness of the inferred networks. In this study, we address this workflow and provide a systematic analysis of how these choices of tools affect the final network and guidelines on appropriate tool selection for a particular data set. We also develop a consensus network algorithm that helps generate more robust co-occurrence networks based on benchmark synthetic data sets.R21 CA279630 - NCI NIH HHS; R21 CA260382 - NCI NIH HHS; UH2 AG064704 - NIA NIH HHS; R01 DE024468 - NIDCR NIH HHS; R01 GM121950 - NIGMS NIH HHShttps://journals.asm.org/doi/reader/10.1128/msystems.00961-22Published versio