bluuebunny/crossref_metadata_2025_split huggingface dataset:
Finding optimal interaction interface alignments between biological complexes
Authors: Cui Xuefeng , Naveed Hammad , Gao Xin 
Published: June 2015

AbstractMotivation: Biological molecules perform their functions through interactions with other molecules. Structure alignment of interaction interfaces between biological complexes is an indispensable step in detecting their structural similarities, which are keys to understanding their evolutionary histories and functions. Although various structure alignment methods have been developed to successfully access the similarities of protein structures or certain types of interaction interfaces, existing alignment tools cannot directly align arbitrary types of interfaces formed by protein, DNA or RNA molecules. Specifically, they require a ‘blackbox preprocessing’ to standardize interface types and chain identifiers. Yet their performance is limited and sometimes unsatisfactory.Results: Here we introduce a novel method, PROSTA-inter, that automatically determines and aligns interaction interfaces between two arbitrary types of complex structures. Our method uses sequentially remote fragments to search for the optimal superimposition. The optimal residue matching problem is then formulated as a maximum weighted bipartite matching problem to detect the optimal sequence order-independent alignment. Benchmark evaluation on all non-redundant protein–DNA complexes in PDB shows significant performance improvement of our method over TM-align and iAlign (with the ‘blackbox preprocessing’). Two case studies where our method discovers, for the first time, structural similarities between two pairs of functionally related protein–DNA complexes are presented. We further demonstrate the power of our method on detecting structural similarities between a protein–protein complex and a protein–RNA complex, which is biologically known as a protein–RNA mimicry case.Availability and implementation: The PROSTA-inter web-server is publicly available at http://www.cbrc.kaust.edu.sa/prosta/.Contact: xin.gao@kaust.edu.sa
Integrating different data types by regularized unsupervised multiple kernel learning with application to cancer subtype discovery
Authors: Speicher Nora K. , Pfeifer Nico 
Published: June 2015

Abstract
Motivation: Despite ongoing cancer research, available therapies are still limited in quantity and effectiveness, and making treatment decisions for individual patients remains a hard problem. Established subtypes, which help guide these decisions, are mainly based on individual data types. However, the analysis of multidimensional patient data involving the measurements of various molecular features could reveal intrinsic characteristics of the tumor. Large-scale projects accumulate this kind of data for various cancer types, but we still lack the computational methods to reliably integrate this information in a meaningful manner. Therefore, we apply and extend current multiple kernel learning for dimensionality reduction approaches. On the one hand, we add a regularization term to avoid overfitting during the optimization procedure, and on the other hand, we show that one can even use several kernels per data type and thereby alleviate the user from having to choose the best kernel functions and kernel parameters for each data type beforehand.
Results: We have identified biologically meaningful subgroups for five different cancer types. Survival analysis has revealed significant differences between the survival times of the identified subtypes, with P values comparable or even better than state-of-the-art methods. Moreover, our resulting subtypes reflect combined patterns from the different data sources, and we demonstrate that input kernel matrices with only little information have less impact on the integrated kernel matrix. Our subtypes show different responses to specific therapies, which could eventually assist in treatment decision making.
Availability and implementation: An executable is available upon request.
Contact: nora@mpi-inf.mpg.de or npfeifer@mpi-inf.mpg.de
Phenome-driven disease genetics prediction toward drug discovery
Authors: Chen Yang , Li Li , Zhang Guo-Qiang , Xu Rong 
Published: June 2015

Abstract
Motivation: Discerning genetic contributions to diseases not only enhances our understanding of disease mechanisms, but also leads to translational opportunities for drug discovery. Recent computational approaches incorporate disease phenotypic similarities to improve the prediction power of disease gene discovery. However, most current studies used only one data source of human disease phenotype. We present an innovative and generic strategy for combining multiple different data sources of human disease phenotype and predicting disease-associated genes from integrated phenotypic and genomic data.
Results: To demonstrate our approach, we explored a new phenotype database from biomedical ontologies and constructed Disease Manifestation Network (DMN). We combined DMN with mimMiner, which was a widely used phenotype database in disease gene prediction studies. Our approach achieved significantly improved performance over a baseline method, which used only one phenotype data source. In the leave-one-out cross-validation and de novo gene prediction analysis, our approach achieved the area under the curves of 90.7% and 90.3%, which are significantly higher than 84.2% (P &lt; e−4) and 81.3% (P &lt; e−12) for the baseline approach. We further demonstrated that our predicted genes have the translational potential in drug discovery. We used Crohn’s disease as an example and ranked the candidate drugs based on the rank of drug targets. Our gene prediction approach prioritized druggable genes that are likely to be associated with Crohn’s disease pathogenesis, and our rank of candidate drugs successfully prioritized the Food and Drug Administration-approved drugs for Crohn’s disease. We also found literature evidence to support a number of drugs among the top 200 candidates. In summary, we demonstrated that a novel strategy combining unique disease phenotype data with system approaches can lead to rapid drug discovery.
Availability and implementation: nlp.case.edu/public/data/DMN
Contact: rxx@case.edu
MEMCover: integrated analysis of mutual exclusivity and functional network reveals dysregulated pathways across multiple cancer types
Authors: Kim Yoo-Ah , Cho Dong-Yeon , Dao Phuong , Przytycka Teresa M. 
Published: June 2015

Abstract
Motivation: The data gathered by the Pan-Cancer initiative has created an unprecedented opportunity for illuminating common features across different cancer types. However, separating tissue-specific features from across cancer signatures has proven to be challenging. One of the often-observed properties of the mutational landscape of cancer is the mutual exclusivity of cancer driving mutations. Even though studies based on individual cancer types suggested that mutually exclusive pairs often share the same functional pathway, the relationship between across cancer mutual exclusivity and functional connectivity has not been previously investigated.
Results: We introduce a classification of mutual exclusivity into three basic classes: within tissue type exclusivity, across tissue type exclusivity and between tissue type exclusivity. We then combined across-cancer mutual exclusivity with interactions data to uncover pan-cancer dysregulated pathways. Our new method, Mutual Exclusivity Module Cover (MEMCover) not only identified previously known Pan-Cancer dysregulated subnetworks but also novel subnetworks whose across cancer role has not been appreciated well before. In addition, we demonstrate the existence of mutual exclusivity hubs, putatively corresponding to cancer drivers with strong growth advantages. Finally, we show that while mutually exclusive pairs within or across cancer types are predominantly functionally interacting, the pairs in between cancer mutual exclusivity class are more often disconnected in functional networks.
Contact: przytyck@ncbi.nlm.nih.gov
Supplementary information: Supplementary data are available at Bioinformatics online.
Deconvolving molecular signatures of interactions between microbial colonies
Authors: Harn Y.-C. , Powers M. J. , Shank E. A. , Jojic V. 
Published: June 2015

Abstract
Motivation: The interactions between microbial colonies through chemical signaling are not well understood. A microbial colony can use different molecules to inhibit or accelerate the growth of other colonies. A better understanding of the molecules involved in these interactions could lead to advancements in health and medicine. Imaging mass spectrometry (IMS) applied to co-cultured microbial communities aims to capture the spatial characteristics of the colonies’ molecular fingerprints. These data are high-dimensional and require computational analysis methods to interpret.
Results: Here, we present a dictionary learning method that deconvolves spectra of different molecules from IMS data. We call this method MOLecular Dictionary Learning (MOLDL). Unlike standard dictionary learning methods which assume Gaussian-distributed data, our method uses the Poisson distribution to capture the count nature of the mass spectrometry data. Also, our method incorporates universally applicable information on common ion types of molecules in MALDI mass spectrometry. This greatly reduces model parameterization and increases deconvolution accuracy by eliminating spurious solutions. Moreover, our method leverages the spatial nature of IMS data by assuming that nearby locations share similar abundances, thus avoiding overfitting to noise. Tests on simulated datasets show that this method has good performance in recovering molecule dictionaries. We also tested our method on real data measured on a microbial community composed of two species. We confirmed through follow-up validation experiments that our method recovered true and complete signatures of molecules. These results indicate that our method can discover molecules in IMS data reliably, and hence can help advance the study of interaction of microbial colonies.
Availability and implementation: The code used in this paper is available at: https://github.com/frizfealer/IMS_project.
Contact: vjojic@cs.unc.edu
Supplementary information: Supplementary data are available at Bioinformatics online.
Dynamic changes of RNA-sequencing expression for precision medicine: N-of-1-pathways Mahalanobis distance within pathways of single subjects predicts breast cancer survival
Authors: Schissler A. Grant , Gardeux Vincent , Li Qike , Achour Ikbel , Li Haiquan , Piegorsch Walter W. , Lussier Yves A. 
Published: June 2015

Abstract
Motivation: The conventional approach to personalized medicine relies on molecular data analytics across multiple patients. The path to precision medicine lies with molecular data analytics that can discover interpretable single-subject signals (N-of-1). We developed a global framework, N-of-1-pathways, for a mechanistic-anchored approach to single-subject gene expression data analysis. We previously employed a metric that could prioritize the statistical significance of a deregulated pathway in single subjects, however, it lacked in quantitative interpretability (e.g. the equivalent to a gene expression fold-change).
Results: In this study, we extend our previous approach with the application of statistical Mahalanobis distance (MD) to quantify personal pathway-level deregulation. We demonstrate that this approach, N-of-1-pathways Paired Samples MD (N-OF-1-PATHWAYS-MD), detects deregulated pathways (empirical simulations), while not inflating false-positive rate using a study with biological replicates. Finally, we establish that N-OF-1-PATHWAYS-MD scores are, biologically significant, clinically relevant and are predictive of breast cancer survival (P &lt; 0.05, n = 80 invasive carcinoma; TCGA RNA-sequences).
Conclusion: N-of-1-pathways MD provides a practical approach towards precision medicine. The method generates the magnitude and the biological significance of personal deregulated pathways results derived solely from the patient’s transcriptome. These pathways offer the opportunities for deriving clinically actionable decisions that have the potential to complement the clinical interpretability of personal polymorphisms obtained from DNA acquired or inherited polymorphisms and mutations. In addition, it offers an opportunity for applicability to diseases in which DNA changes may not be relevant, and thus expand the ‘interpretable ‘omics’ of single subjects (e.g. personalome).
Availability and implementation: http://www.lussierlab.net/publications/N-of-1-pathways.
Contact: yves@email.arizona.edu or piegorsch@math.arizona.edu
Supplementary information: Supplementary data are available at Bioinformatics online.
FERAL: network-based classifier with application to breast cancer outcome prediction
Authors: Allahyar Amin , de Ridder Jeroen 
Published: June 2015

Abstract
Motivation: Breast cancer outcome prediction based on gene expression profiles is an important strategy for personalize patient care. To improve performance and consistency of discovered markers of the initial molecular classifiers, network-based outcome prediction methods (NOPs) have been proposed. In spite of the initial claims, recent studies revealed that neither performance nor consistency can be improved using these methods. NOPs typically rely on the construction of meta-genes by averaging the expression of several genes connected in a network that encodes protein interactions or pathway information. In this article, we expose several fundamental issues in NOPs that impede on the prediction power, consistency of discovered markers and obscures biological interpretation.
Results: To overcome these issues, we propose FERAL, a network-based classifier that hinges upon the Sparse Group Lasso which performs simultaneous selection of marker genes and training of the prediction model. An important feature of FERAL, and a significant departure from existing NOPs, is that it uses multiple operators to summarize genes into meta-genes. This gives the classifier the opportunity to select the most relevant meta-gene for each gene set. Extensive evaluation revealed that the discovered markers are markedly more stable across independent datasets. Moreover, interpretation of the marker genes detected by FERAL reveals valuable mechanistic insight into the etiology of breast cancer.
Availability and implementation: All code is available for download at: http://homepage.tudelft.nl/53a60/resources/FERAL/FERAL.zip.
Contact: j.deridder@tudelft.nl
Supplementary information: Supplementary data are available at Bioinformatics online.
Improving compound–protein interaction prediction by building up highly credible negative samples
Authors: Liu Hui , Sun Jianjiang , Guan Jihong , Zheng Jie , Zhou Shuigeng 
Published: June 2015

Abstract
Motivation: Computational prediction of compound–protein interactions (CPIs) is of great importance for drug design and development, as genome-scale experimental validation of CPIs is not only time-consuming but also prohibitively expensive. With the availability of an increasing number of validated interactions, the performance of computational prediction approaches is severely impended by the lack of reliable negative CPI samples. A systematic method of screening reliable negative sample becomes critical to improving the performance of in silico prediction methods.
Results: This article aims at building up a set of highly credible negative samples of CPIs via an in silico screening method. As most existing computational models assume that similar compounds are likely to interact with similar target proteins and achieve remarkable performance, it is rational to identify potential negative samples based on the converse negative proposition that the proteins dissimilar to every known/predicted target of a compound are not much likely to be targeted by the compound and vice versa. We integrated various resources, including chemical structures, chemical expression profiles and side effects of compounds, amino acid sequences, protein–protein interaction network and functional annotations of proteins, into a systematic screening framework. We first tested the screened negative samples on six classical classifiers, and all these classifiers achieved remarkably higher performance on our negative samples than on randomly generated negative samples for both human and Caenorhabditis elegans. We then verified the negative samples on three existing prediction models, including bipartite local model, Gaussian kernel profile and Bayesian matrix factorization, and found that the performances of these models are also significantly improved on the screened negative samples. Moreover, we validated the screened negative samples on a drug bioactivity dataset. Finally, we derived two sets of new interactions by training an support vector machine classifier on the positive interactions annotated in DrugBank and our screened negative interactions. The screened negative samples and the predicted interactions provide the research community with a useful resource for identifying new drug targets and a helpful supplement to the current curated compound–protein databases.
Availability: Supplementary files are available at: http://admis.fudan.edu.cn/negative-cpi/.
Contact: sgzhou@fudan.edu.cn
Supplementary Information: Supplementary data are available at Bioinformatics online.
Reconstructing gene regulatory dynamics from high-dimensional single-cell snapshot data
Authors: Ocone Andrea , Haghverdi Laleh , Mueller Nikola S. , Theis Fabian J. 
Published: June 2015

Abstract
Motivation: High-dimensional single-cell snapshot data are becoming widespread in the systems biology community, as a mean to understand biological processes at the cellular level. However, as temporal information is lost with such data, mathematical models have been limited to capture only static features of the underlying cellular mechanisms.
Results: Here, we present a modular framework which allows to recover the temporal behaviour from single-cell snapshot data and reverse engineer the dynamics of gene expression. The framework combines a dimensionality reduction method with a cell time-ordering algorithm to generate pseudo time-series observations. These are in turn used to learn transcriptional ODE models and do model selection on structural network features. We apply it on synthetic data and then on real hematopoietic stem cells data, to reconstruct gene expression dynamics during differentiation pathways and infer the structure of a key gene regulatory network.
Availability and implementation: C++ and Matlab code available at https://www.helmholtz-muenchen.de/fileadmin/ICB/software/inferenceSnapshot.zip.
Contact: fabian.theis@helmholtz-muenchen.de
Supplementary information: Supplementary data are available at Bioinformatics online.
Gene network inference by fusing data from diverse distributions
Authors: Žitnik Marinka , Zupan Blaž 
Published: June 2015

Abstract
Motivation: Markov networks are undirected graphical models that are widely used to infer relations between genes from experimental data. Their state-of-the-art inference procedures assume the data arise from a Gaussian distribution. High-throughput omics data, such as that from next generation sequencing, often violates this assumption. Furthermore, when collected data arise from multiple related but otherwise nonidentical distributions, their underlying networks are likely to have common features. New principled statistical approaches are needed that can deal with different data distributions and jointly consider collections of datasets.
Results: We present FuseNet, a Markov network formulation that infers networks from a collection of nonidentically distributed datasets. Our approach is computationally efficient and general: given any number of distributions from an exponential family, FuseNet represents model parameters through shared latent factors that define neighborhoods of network nodes. In a simulation study, we demonstrate good predictive performance of FuseNet in comparison to several popular graphical models. We show its effectiveness in an application to breast cancer RNA-sequencing and somatic mutation data, a novel application of graphical models. Fusion of datasets offers substantial gains relative to inference of separate networks for each dataset. Our results demonstrate that network inference methods for non-Gaussian data can help in accurate modeling of the data generated by emergent high-throughput technologies.
Availability and implementation: Source code is at https://github.com/marinkaz/fusenet.
Contact: blaz.zupan@fri.uni-lj.si
Supplementary information: Supplementary information is available at Bioinformatics online.
Knowledge-driven geospatial location resolution for phylogeographic models of virus migration
Authors: Weissenbacher Davy , Tahsin Tasnia , Beard Rachel , Figaro Mari , Rivera Robert , Scotch Matthew , Gonzalez Graciela 
Published: June 2015

AbstractSummary: Diseases caused by zoonotic viruses (viruses transmittable between humans and animals) are a major threat to public health throughout the world. By studying virus migration and mutation patterns, the field of phylogeography provides a valuable tool for improving their surveillance. A key component in phylogeographic analysis of zoonotic viruses involves identifying the specific locations of relevant viral sequences. This is usually accomplished by querying public databases such as GenBank and examining the geospatial metadata in the record. When sufficient detail is not available, a logical next step is for the researcher to conduct a manual survey of the corresponding published articles.Motivation: In this article, we present a system for detection and disambiguation of locations (toponym resolution) in full-text articles to automate the retrieval of sufficient metadata. Our system has been tested on a manually annotated corpus of journal articles related to phylogeography using integrated heuristics for location disambiguation including a distance heuristic, a population heuristic and a novel heuristic utilizing knowledge obtained from GenBank metadata (i.e. a ‘metadata heuristic’).Results: For detecting and disambiguating locations, our system performed best using the metadata heuristic (0.54 Precision, 0.89 Recall and 0.68 F-score). Precision reaches 0.88 when examining only the disambiguation of location names. Our error analysis showed that a noticeable increase in the accuracy of toponym resolution is possible by improving the geospatial location detection. By improving these fundamental automated tasks, our system can be a useful resource to phylogeographers that rely on geospatial metadata of GenBank sequences.Contact: davy.weissenbacher@asu.edu
Reconstruction of clonal trees and tumor composition from multi-sample sequencing data
Authors: El-Kebir Mohammed , Oesper Layla , Acheson-Field Hannah , Raphael Benjamin J. 
Published: June 2015

Abstract
Motivation: DNA sequencing of multiple samples from the same tumor provides data to analyze the process of clonal evolution in the population of cells that give rise to a tumor.
Results: We formalize the problem of reconstructing the clonal evolution of a tumor using single-nucleotide mutations as the variant allele frequency (VAF) factorization problem. We derive a combinatorial characterization of the solutions to this problem and show that the problem is NP-complete. We derive an integer linear programming solution to the VAF factorization problem in the case of error-free data and extend this solution to real data with a probabilistic model for errors. The resulting AncesTree algorithm is better able to identify ancestral relationships between individual mutations than existing approaches, particularly in ultra-deep sequencing data when high read counts for mutations yield high confidence VAFs.
Availability and implementation: An implementation of AncesTree is available at: http://compbio.cs.brown.edu/software.
Contact: braphael@brown.edu
Supplementary information: Supplementary data are available at Bioinformatics online.