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Inspired by the competition exclusion principle, this work aims at providing a computational framework to explore the theoretical feasibility of viral co-infection as a possible strategy to reduce the spread of a fatal strain in a population. We propose a stochastic-based model—called Co-Wish—to understand how competition between two viruses over a shared niche can affect the spread of each virus in infected tissue. To demonstrate the co-infection of two viruses, we first simulate the characteristics of two virus growth processes separately. Then, we examine their interactions until one can dominate the other. We use Co-Wish to explore how the model varies as the parameters of each virus growth process change when two viruses infect the host simultaneously. We will also investigate the effect of the delayed initiation of each infection. Moreover, Co-Wish not only examines the co-infection at the cell level but also includes the innate immune response during viral infection. The results highlight that the waiting times in the five stages of the viral infection of a cell in the model—namely attachment, penetration, eclipse, replication, and release—play an essential role in the competition between the two viruses. While it could prove challenging to fully understand the therapeutic potentials of viral co-infection, we discuss that our theoretical framework hints at an intriguing research direction in applying co-infection dynamics in controlling any viral outbreak’s speed.

PurposeSARS-CoV-2 infects cells via the human Angiotensin-converting enzyme 2 (ACE2) protein. The genetic variation of ACE2 function and expression across populations is still poorly understood. This study aims at better understanding the genetic basis of COVID-19 outcomes by studying association between genetic variation in ACE2 and disease severity in the Iranian population.MethodsWe analyzed two large Iranian cohorts and several publicly available human population variant databases to identify novel and previously known ACE2 exonic variants present in the Iranian population and considered those as candidate variants for association between genetic variation and disease severity. We genotyped these variants across three groups of COVID-19 patients with different clinical outcomes (mild disease, severe disease, and death) and evaluated this genetic variation with regard to clinical outcomes.ResultsWe identified 32 exonic variants present in Iranian cohorts or other public variant databases. Among those, 11 variants are novel and have thus not been described in other populations previously. Following genotyping of these 32 candidate variants, only the synonymous polymorphism (c.2247G>A) was detected across the three groups of COVID-19 patients.ConclusionGenetic variability of known and novel exonic variants was low among our COVID-19 patients. Our results do not provide support for the hypothesis that exonic variation in ACE2 has a sizeable impact on COVID-19 severity across the Iranian population.

High-dimensional multi-omics data are now standard in biology. They can greatly enhance our understanding of biological systems when effectively integrated. To achieve this multi-omics data integration, Joint Dimensionality Reduction (jDR) methods are among the most efficient approaches. However, several jDR methods are available, urging the need for a comprehensive benchmark with practical guidelines.; We performed a systematic evaluation of nine representative jDR methods using three complementary benchmarks. First, we evaluated their performances in retrieving ground-truth sample clustering from simulated multi-omics datasets. Second, we used TCGA cancer data to assess their strengths in predicting survival, clinical annotations and known pathways/biological processes. Finally, we assessed their classification of multi-omics single-cell data.; From these in-depth comparisons, we observed that intNMF performs best in clustering, while MCIA offers a consistent and effective behavior across many contexts. The full code of this benchmark is implemented in a Jupyter notebook - multi-omics mix (momix) - to foster reproducibility, and support data producers, users and future developers.; High-dimensional multi-omics data are now standard in biology. They can greatly enhance our understanding of biological systems when effectively integrated. To achieve this multi-omics data integration, Joint Dimensionality Reduction (jDR) methods are among the most efficient approaches. However, several jDR methods are available, urging the need for a comprehensive benchmark with practical guidelines. We performed a systematic evaluation of nine representative jDR methods using three complementary benchmarks. First, we evaluated their performances in retrieving ground-truth sample clustering from simulated multi-omics datasets. Second, we used TCGA cancer data to assess their strengths in predicting survival, clinical annotations and known pathways/biological processes. Finally, we assessed their classification of multi-omics single-cell data. From these in-depth comparisons, we observed that intNMF performs best in clustering, while MCIA offers a consistent and effective behavior across many contexts. The full code of this benchmark is implemented in a Jupyter notebook-multi-omics mix (momix)-to foster reproducibility, and support data producers, users and future developers.

Despite the abundance of large-scale molecular and drug-response data, the insights gained about the mechanisms underlying treatment efficacy in cancer has been in general limited. Machine learning algorithms applied to those datasets most often are used to provide predictions without interpretation, or reveal single drug-gene association and fail to derive robust insights. We propose to use Macau, a bayesian multitask multi-relational algorithm to generalize from individual drugs and genes and explore the interactions between the drug targets and signaling pathways' activation. A typical insight would be: "Activation of pathway Y will confer sensitivity to any drug targeting protein X". We applied our methodology to the Genomics of Drug Sensitivity in Cancer (GDSC) screening, using gene expression of 990 cancer cell lines, activity scores of 11 signaling pathways derived from the tool PROGENy as cell line input and 228 nominal targets for 265 drugs as drug input. These interactions can guide a tissue-specific combination treatment strategy, for example suggesting to modulate a certain pathway to maximize the drug response for a given tissue. We confirmed in literature drug combination strategies derived from our result for brain, skin and stomach tissues. Such an analysis of interactions across tissues might help target discovery, drug repurposing and patient stratification strategies.

Motivation Most gene prioritization methods model each disease or phenotype individually, but this fails to capture patterns common to several diseases or phenotypes. To overcome this limitation, we formulate the gene prioritization task as the factorization of a sparsely filled gene-phenotype matrix, where the objective is to predict the unknown matrix entries. To deliver more accurate gene-phenotype matrix completion, we extend classical Bayesian matrix factorization to work with multiple side information sources. The availability of side information allows us to make non-trivial predictions for genes for which no previous disease association is known. Results Our gene prioritization method can innovatively not only integrate data sources describing genes, but also data sources describing Human Phenotype Ontology terms. Experimental results on our benchmarks show that our proposed model can effectively improve accuracy over the well-established gene prioritization method, Endeavour. In particular, our proposed method offers promising results on diseases of the nervous system; diseases of the eye and adnexa; endocrine, nutritional and metabolic diseases; and congenital malformations, deformations and chromosomal abnormalities, when compared to Endeavour. Availability and implementation The Bayesian data fusion method is implemented as a Python/C++ package: https://github.com/jaak-s/macau. It is also available as a Julia package: https://github.com/jaak-s/BayesianDataFusion.jl. All data and benchmarks generated or analyzed during this study can be downloaded at https://owncloud.esat.kuleuven.be/index.php/s/UGb89WfkZwMYoTn. Supplementary information Supplementary data are available at Bioinformatics online.

Despite the abundance of large-scale molecular and drug-response data, the insights gained about the mechanisms underlying treatment efficacy in cancer has been in general limited. Machine learning algorithms applied to those datasets most often are used to provide predictions without interpretation, or reveal single drug-gene association and fail to derive robust insights. We propose to use Macau, a bayesian multitask multi-relational algorithm to generalize from individual drugs and genes and explore the interactions between the drug targets and signaling pathways' activation. A typical insight would be: "Activation of pathway Y will confer sensitivity to any drug targeting protein X". We applied our methodology to the Genomics of Drug Sensitivity in Cancer (GDSC) screening, using gene expression of 990 cancer cell lines, activity scores of 11 signaling pathways derived from the tool PROGENy as cell line input and 228 nominal targets for 265 drugs as drug input. These interactions can guide a tissue-specific combination treatment strategy, for example suggesting to modulate a certain pathway to maximize the drug response for a given tissue. We confirmed in literature drug combination strategies derived from our result for brain, skin and stomach tissues. Such an analysis of interactions across tissues might help target discovery, drug repurposing and patient stratification strategies. ispartof: SCIENTIFIC REPORTS vol:8 issue:1 ispartof: location:England status: published

Bayesian matrix factorization is a method of choice for making predictions for large-scale incomplete matrices, due to availability of efficient Gibbs sampling schemes and its robustness to overfitting. In this paper, we consider factorization of large scale matrices with high-dimensional side information. However, sampling the link matrix for the side information with standard approaches costs O(F3) time, where F is the dimensionality of the features. To overcome this limitation we, firstly, propose a prior for the link matrix whose strength is proportional to the scale of latent variables. Secondly, using this prior we derive an efficient sampler, with linear complexity in the number of non-zeros, O(N nz ), by leveraging Krylov subspace methods, such as block conjugate gradient, allowing us to handle million-dimensional side information. We demonstrate the effectiveness of our proposed method in drug-protein interaction prediction task.

In this study, the predictors are developed for protein submitochondria locations based on various features of sequences. Information about the submitochondria location for a mitochondria protein can provide much better understanding about its function. We use ten representative models of protein samples such as pseudo amino acid composition, dipeptide composition, functional domain composition, the combining discrete model based on prediction of solvent accessibility and secondary structure elements, the discrete model of pairwise sequence similarity, etc. We construct a predictor based on support vector machines (SVMs) for each representative model. The overall prediction accuracy by the leave-one-out cross validation test obtained by the predictor which is based on the discrete model of pairwise sequence similarity is 1% better than the best computational system that exists for this problem. Moreover, we develop a method based on ordered weighted averaging (OWA) which is one of the fusion data operators. Therefore, OWA is applied on the 11 best SVM-based classifiers that are constructed based on various features of sequence. This method is called Mito-Loc. The overall leave-one-out cross validation accuracy obtained by Mito-Loc is about 95%. This indicates that our proposed approach (Mito-Loc) is superior to the result of the best existing approach which has already been reported.

A document containing a subset of CAFA2 analyses that are equivalent to those provided about the CAFA1 experiment in the CAFA1 supplement. (PDF 11100 kb)

BACKGROUND: A major bottleneck in our understanding of the molecular underpinnings of life is the assignment of function to proteins. While molecular experiments provide the most reliable annotation of proteins, their relatively low throughput and restricted purview have led to an increasing role for computational function prediction. However, assessing methods for protein function prediction and tracking progress in the field remain challenging. RESULTS: We conducted the second critical assessment of functional annotation (CAFA), a timed challenge to assess computational methods that automatically assign protein function. We evaluated 126 methods from 56 research groups for their ability to predict biological functions using Gene Ontology and gene-disease associations using Human Phenotype Ontology on a set of 3681 proteins from 18 species. CAFA2 featured expanded analysis compared with CAFA1, with regards to data set size, variety, and assessment metrics. To review progress in the field, the analysis compared the best methods from CAFA1 to those of CAFA2. CONCLUSIONS: The top-performing methods in CAFA2 outperformed those from CAFA1. This increased accuracy can be attributed to a combination of the growing number of experimental annotations and improved methods for function prediction. The assessment also revealed that the definition of top-performing algorithms is ontology specific, that different performance metrics can be used to probe the nature of accurate predictions, and the relative diversity of predictions in the biological process and human phenotype ontologies. While there was methodological improvement between CAFA1 and CAFA2, the interpretation of results and usefulness of individual methods remain context-dependent., We acknowledge the contributions of Maximilian Hecht, Alexander Grün, Julia Krumhoff, My Nguyen Ly, Jonathan Boidol, Rene Schoeffel, Yann Spöri, Jessika Binder, Christoph Hamm and Karolina Worf. This work was partially supported by the following grants: National Science Foundation grants DBI-1458477 (PR), DBI-1458443 (SDM), DBI-1458390 (CSG), DBI-1458359 (IF), IIS-1319551 (DK), DBI-1262189 (DK), and DBI-1149224 (JC); National Institutes of Health grants R01GM093123 (JC), R01GM097528 (DK), R01GM076990 (PP), R01GM071749 (SEB), R01LM009722 (SDM), and UL1TR000423 (SDM); the National Natural Science Foundation of China grants 3147124 (WT) and 91231116 (WT); the National Basic Research Program of China grant 2012CB316505 (WT); NSERC grant RGPIN 371348-11 (PP); FP7 infrastructure project TransPLANT Award 283496 (ADJvD); Microsoft Research/FAPESP grant 2009/53161-6 and FAPESP fellowship 2010/50491-1 (DCAeS); Biotechnology and Biological Sciences Research Council grants BB/L020505/1 (DTJ), BB/F020481/1 (MJES), BB/K004131/1 (AP), BB/F00964X/1 (AP), and BB/L018241/1 (CD); the Spanish Ministry of Economics and Competitiveness grant BIO2012-40205 (MT); KU Leuven CoE PFV/10/016 SymBioSys (YM); the Newton International Fellowship Scheme of the Royal Society grant NF080750 (TN). CSG was supported in part by the Gordon and Betty Moore Foundation’s Data-Driven Discovery Initiative grant GBMF4552. Computational resources were provided by CSC – IT Center for Science Ltd., Espoo, Finland (TS). This work was supported by the Academy of Finland (TS). RCL and ANM were supported by British Heart Foundation grant RG/13/5/30112. PD, RCL, and REF were supported by Parkinson’s UK grant G-1307, the Alexander von Humboldt Foundation through the German Federal Ministry for Education and Research, Ernst Ludwig Ehrlich Studienwerk, and the Ministry of Education, Science and Technological Development of the Republic of Serbia grant 173001. This work was a Technology Development effort for ENIGMA – Ecosystems and Networks Integrated with Genes and Molecular Assemblies (http://enigma.lbl.gov), a Scientific Focus Area Program at Lawrence Berkeley National Laboratory, which is based upon work supported by the U.S. Department of Energy, Office of Science, Office of Biological & Environmental Research grant DE-AC02-05CH11231. ENIGMA only covers the application of this work to microbial proteins. NSF DBI-0965616 and Australian Research Council grant DP150101550 (KMV). NSF DBI-0965768 (ABH). NIH T15 LM00945102 (training grant for CSF). FP7 FET grant MAESTRA ICT-2013-612944 and FP7 REGPOT grant InnoMol (FS). NIH R01 GM60595 (PCB). University of Padova grants CPDA138081/13 (ST) and GRIC13AAI9 (EL). Swiss National Science Foundation grant 150654 and UK BBSRC grant BB/M015009/1 (COD). PRB2 IPT13/0001 - ISCIII-SGEFI / FEDER (JMF)., This is the final version of the article. It first appeared from BioMed Central at http://dx.doi.org/10.1186/s13059-016-1037-6.

In biology there is often the need to discover the most promising genes, among a large list of candidate genes, to further investigate. While a single data source might not be effective enough, integrating several complementary genomic data sources leads to more accurate prediction.