Principal elementary mode analysis (PEMA)

Principal component analysis (PCA) has been widely applied in fluxomics to compress data into a few latent structures in order to simplify the identification of metabolic patterns. These latent structures lack a direct biological interpretation due to the intrinsic constraints associated with a PCA model. Here we introduce a new method that significantly improves the interpretability of the principal components with a direct link to metabolic pathways. This method, called principal elementary mode analysis (PEMA), establishes a bridge between a PCA-like model, aimed at explaining the maximum variance in flux data, and the set of elementary modes (EMs) of a metabolic network. It provides an easy way to identify metabolic patterns in large fluxomics datasets in terms of the simplest pathways of the organism metabolism. The results using a real metabolic model of Escherichia coli show the ability of PEMA to identify the EMs that generated the different simulated flux distributions. Actual flux data of E. coli and Pichia pastoris cultures confirm the results observed in the simulated study, providing a biologically meaningful model to explain flux data of both organisms in terms of the EM activation. The PEMA toolbox is freely available for non-commercial purposes on http://mseg.webs.upv.es.Research in this study was partially supported by the Spanish Ministry of Economy and Competitiveness and FEDER funds from the European Union through grants DPI2011-28112-C04-02 and DPI2014-55276-C5-1R. We would also acknowledge Fundacao para a Ciencia e Tecnologia for PhD fellowships with references SFRH/BD/67033/2009, SFRH/BD/70768/2010 and PTDC/BBB-BSS/2800/2012.Folch Fortuny, A.; Marques, R.; Isidro, IA.; Oliveira, R.; Ferrer, A. (2016). Principal elementary mode analysis (PEMA). Molecular BioSystems. 12(3):737-746. doi:10.1039/c5mb00828jS73774612

Fusion of genomic, proteomic and phenotypic data: the case of potyviruses

Data fusion has been widely applied to analyse different sources of information, combining all of them in a single multivariate model. This methodology is mandatory when different omic data sets must be integrated to fully understand an organism using a systems biology approach. Here, a data fusion procedure is presented to combine genomic, proteomic and phenotypic data sets gathered for Tobacco etch virus (TEV). The genomic data correspond to random mutations inserted in most viral genes. The proteomic data represent both the effect of these mutations on the encoded proteins and the perturbation induced by the mutated proteins to their neighbours in the protein protein interaction net- work (PPIN). Finally, the phenotypic trait evaluated for each mutant virus is replicative fitness. To analyse these three sources of information a Partial Least Squares (PLS) regression model is fitted in order to extract the latent variables from data that explain (and relate) the significant variables to the fitness of TEV. The final output of this methodology is a set of functional modules of the PPIN relating topology and mutations with fitness. Throughout the re-analysis of these diverse TEV data, we generated valuable information on the mechanism of action of certain mutations and how they translate into organismal fitness. Results show that the effect of some mutations goes beyond the protein they directly affect and spreads on the PPIN to neighbour proteins, thus defining functional modules.This work was supported by the Spanish Ministerio de Economia y Competitividad grants BFU2012-30805 (to SFE), and DPI2011-28112-C04-02, DPI2011-28112-C04-01, DPI2014-55276-C5-1-R (to AF and JP) and by Generalitat Valenciana grant PROMETEOII/2014/021 (to SFE). The first two authors are recipients of fellowships from the Spanish Ministerio de Economia y Competitividad: BES-2012-053772 (to GB) and BES-2012-057812 (to AF-F).Folch-Fortuny, A.; Bosque-Chacon, G.; Picó, J.; Ferrer, A.; Elena, S. (2016). Fusion of genomic, proteomic and phenotypic data: the case of potyviruses. Molecular BioSystems. 12(1):253-261. https://doi.org/10.1039/c5mb00507hS25326112

Dynamic elementary mode modelling of non-steady state flux data

[EN] A novel framework is proposed to analyse metabolic fluxes in non-steady state conditions, based on the new concept of dynamic elementary mode (dynEM): an elementary mode activated partially depending on the time point of the experiment.This research work was partially supported by the Spanish Ministry of Economy and Competitiveness under the project DPI2014-55276-C5-1R.Folch-Fortuny, A.; Teusink, B.; Hoefsloot, HC.; Smilde, AK.; Ferrer, A. (2018). Dynamic elementary mode modelling of non-steady state flux data. BMC Systems Biology. 12:1-15. https://doi.org/10.1186/s12918-018-0589-3S11512Bro R, Smilde AK. Principal component analysis. Anal Methods. 2014; 6(9):2812–31.González-Martínez JM, Folch-Fortuny A, Llaneras F, Tortajada M, Picó J, Ferrer A. Metabolic flux understanding of Pichia pastoris grown on heterogenous culture media. Chemometr Intell Lab Syst. 2014; 134:89–99.Barrett CL, Herrgard MJ, Palsson B. Decomposing complex reaction networks using random sampling, principal component analysis and basis rotation. BMC Syst Biol. 2009; 3(30):1–8.Jaumot J, Gargallo R, De Juan A, Tauler R. A graphical user-friendly interface for MCR-ALS: A new tool for multivariate curve resolution in MATLAB. Chemometr Intell Lab Syst. 2005; 76(1):101–10.Folch-Fortuny A, Tortajada M, Prats-Montalbán JM, Llaneras F, Picó J, Ferrer A. MCR-ALS on metabolic networks: Obtaining more meaningful pathways. Chemometr Intell Lab Syst. 2015; 142:293–303.Folch-Fortuny A, Marques R, Isidro IA, Oliveira R, Ferrer A. Principal elementary mode analysis (PEMA). Mol BioSyst. 2016; 12(3):737–46.Hood L. Systems biology: Integrating technology, biology, and computation. Mech Ageing Dev. 2003; 124(1):9–16.Teusink B, Passarge J, Reijenga CA, Esgalhado E, van der Weijden CC, Schepper M, Walsh MC, Bakker BM, van Dam K, Westerhoff HV, Snoep JL. 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PCA model building with missing data: New proposals and a comparative study

[EN] This paper introduces new methods for building principal component analysis (PCA) models with missing data: projection to the model plane (PMP), known data regression (KDR), KDR with principal component regression (PCR), KDR with partial least squares regression (PLS) and trimmed scores regression (TSR). These methods are adapted from their PCA model exploitation version to deal with the more general problem of PCA model building when the training set has missing values. A comparative study is carried out comparing these new methods with the standard ones, such as the modified nonlinear iterative partial least squares (NIPALS), the it- erative algorithm (IA), the data augmentation method (DA) and the nonlinear programming approach (NLP). The performance is assessed using the mean squared prediction error of the reconstructed matrix and the cosines between the actual principal components and the ones extracted by each method. Four data sets, two simulated and two real ones, with several percentages of missing data, are used to perform the comparison. Guardar / Salir Siguiente >Research in this study was partially supported by the Spanish Ministry of Science and Innovation and FEDER funds from the European Union through grant DPI2011-28112-C04-02, and the Spanish Ministry of Economy and Competitiveness through grant ECO2013-43353-R. The authors gratefully acknowledge Salvador Garcia-Munoz for providing the Phi toolbox (version 1.7) to perform the nonlinear programming approach (NLP) method.Folch-Fortuny, A.; Arteaga Moreno, FJ.; Ferrer Riquelme, AJ. (2015). PCA model building with missing data: New proposals and a comparative study. Chemometrics and Intelligent Laboratory Systems. 146:77-88. https://doi.org/10.1016/j.chemolab.2015.05.006S778814

Metabolic flux understanding of Pichia pastoris grown on heterogenous culture media

[EN] Within the emergent field of Systems Biology, mathematical models obtained from physical chemical laws (the so-called first principles-based models) of microbial systems are employed to discern the principles that govern cellular behaviour and achieve a predictive understanding of cellular functions. The reliance on this biochemical knowledge has the drawback that some of the assumptions (specific kinetics of the reaction system, unknown dynamics and values of the model parameters) may not be valid for all the metabolic possible states of the network. In this uncertainty context, the combined use of fundamental knowledge and data measured in the fermentation that describe the behaviour of the microorganism in the manufacturing process is paramount to overcome this problem. In this paper, a grey modelling approach is presented combining data-driven and first principles information at different scales, developed for Pichia pastoris cultures grown on different carbon sources. This approach will allow us to relate patterns of recombinant protein production to intracellular metabolic states and correlate intra and extracellular reactions in order to understand how the internal state of the cells determines the observed behaviour in P. pastoris cultivations.Research in this study was partially supported by the Spanish Ministry of Science and Innovation and FEDER funds from the European Union through grants DPI2011-28112-C04-01 and DPI2011-28112-C04-02. The authors are also grateful to Biopolis SL for supporting this research. We also gratefully acknowledge Associate Professor Jose Camacho for providing the Exploratory Data Analysis Toolbox.González Martínez, JM.; Folch-Fortuny, A.; Llaneras Estrada, F.; Tortajada Serra, M.; Picó Marco, JA.; Ferrer, A. (2014). Metabolic flux understanding of Pichia pastoris grown on heterogenous culture media. Chemometrics and Intelligent Laboratory Systems. 134:89-99. https://doi.org/10.1016/j.chemolab.2014.02.003S899913

MCR-ALS on metabolic networks: Obtaining more meaningful pathways

[EN] With the aim of understanding the flux distributions across a metabolic network, i.e. within living cells, Principal Component Analysis (PCA) has been proposed to obtain a set of orthogonal components (pathways) capturing most of the variance in the flux data. The problems with this method are (i) that no additional information can be included in the model, and (ii) that orthogonality imposes a hard constraint, not always reasonably. To overcome these drawbacks, here we propose to use a more flexible approach such as Multivariate Curve Resolution-Alternating Least Squares (MCR-ALS) to obtain this set of biological pathways through the network. By using this method, different constraints can be included in the model, and the same source of variability can be present in different pathways, which is reasonable from a biological standpoint. This work follows a methodology developed for Pichia pastoris cultures grown on different carbon sources, lately presented in González-Martínez et al. (2014). In this paper a different grey modelling approach, which aims to incorporate a priori knowledge through constraints on the modelling algorithms, is applied to the same case of study. The results of both models are compared to show their strengths and weaknesses.Research in this study was partially supported by the Spanish Ministry of Science and Innovation and FEDER funds from the European Union through grants DPI2011-28112-C04-01 and DPI2011-28112-C04-02. The authors are also grateful to Biopolis SL for supporting this research.Folch-Fortuny, A.; Tortajada Serra, M.; Prats-Montalbán, JM.; Llaneras Estrada, F.; Picó Marco, JA.; Ferrer Riquelme, AJ. (2015). MCR-ALS on metabolic networks: Obtaining more meaningful pathways. Chemometrics and Intelligent Laboratory Systems. 142:293-303. https://doi.org/10.1016/j.chemolab.2014.10.004S29330314

Topology analysis and visualization of Potyvirus protein-protein interaction network

Background: One of the central interests of Virology is the identification of host factors that contribute to virus infection. Despite tremendous efforts, the list of factors identified remains limited. With omics techniques, the focus has changed from identifying and thoroughly characterizing individual host factors to the simultaneous analysis of thousands of interactions, framing them on the context of protein-protein interaction networks and of transcriptional regulatory networks. This new perspective is allowing the identification of direct and indirect viral targets. Such information is available for several members of the Potyviridae family, one of the largest and more important families of plant viruses. Results: After collecting information on virus protein-protein interactions from different potyviruses, we have processed it and used it for inferring a protein-protein interaction network. All proteins are connected into a single network component. Some proteins show a high degree and are highly connected while others are much less connected, with the network showing a significant degree of dissortativeness. We have attempted to integrate this virus protein-protein interaction network into the largest protein-protein interaction network of Arabidopsis thaliana, a susceptible laboratory host. To make the interpretation of data and results easier, we have developed a new approach for visualizing and analyzing the dynamic spread on the host network of the local perturbations induced by viral proteins. We found that local perturbations can reach the entire host protein-protein interaction network, although the efficiency of this spread depends on the particular viral proteins. By comparing the spread dynamics among viral proteins, we found that some proteins spread their effects fast and efficiently by attacking hubs in the host network while other proteins exert more local effects. Conclusions: Our findings confirm that potyvirus protein-protein interaction networks are highly connected, with some proteins playing the role of hubs. Several topological parameters depend linearly on the protein degree. Some viral proteins focus their effect in only host hubs while others diversify its effect among several proteins at the first step. Future new data will help to refine our model and to improve our predictions.This work was supported by the Spanish Ministerio de Economia y Competitividad grants BFU2012-30805 (to SFE), DPI2011-28112-C04-02 (to AF) and DPI2011-28112-C04-01 (to JP). The first two authors are recipients of fellowships from the Spanish Ministerio de Economia y Competitividad: BES-2012-053772 (to GB) and BES-2012-057812 (to AF-F).Bosque, G.; Folch Fortuny, A.; Picó Marco, JA.; Ferrer, A.; Elena Fito, SF. (2014). Topology analysis and visualization of Potyvirus protein-protein interaction network. 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The effects of long-term saturated fat enriched diets on the brain lipidome

The brain is highly enriched in lipids, where they influence neurotransmission, synaptic plasticity and inflammation. Non-pathological modulation of the brain lipidome has not been previously reported and few studies have investigated the interplay between plasma lipid homeostasis relative to cerebral lipids. This study explored whether changes in plasma lipids induced by chronic consumption of a well-tolerated diet enriched in saturated fatty acids (SFA) was associated with parallel changes in cerebral lipid homeostasis. Male C57Bl/6 mice were fed regular chow or the SFA diet for six months. Plasma, hippocampus (HPF) and cerebral cortex (CTX) lipids were analysed by LC-ESI-MS/MS. A total of 348 lipid species were determined, comprising 25 lipid classes. The general abundance of HPF and CTX lipids was comparable in SFA fed mice versus controls, despite substantial differences in plasma lipid-class abundance. However, significant differences in 50 specific lipid species were identified as a consequence of SFA treatment, restricted to phosphatidylcholine (PC), phosphatidylethanolamine (PE), alkyl-PC, alkenyl-PC, alkyl-PE, alkenyl-PE, cholesterol ester (CE), diacylglycerol (DG), phosphatidylinositol (PI) and phosphatidylserine (PS) classes. Partial least squares regression of the HPF/CTX lipidome versus plasma lipidome revealed the plasma lipidome could account for a substantial proportion of variation. The findings demonstrate that cerebral abundance of specific lipid species is strongly associated with plasma lipid homeostasis

Flux-dependent graphs for metabolic networks

Cells adapt their metabolic fluxes in response to changes in the environment. We present a framework for the systematic construction of flux-based graphs derived from organism-wide metabolic networks. Our graphs encode the directionality of metabolic fluxes via edges that represent the flow of metabolites from source to target reactions. The methodology can be applied in the absence of a specific biological context by modelling fluxes probabilistically, or can be tailored to different environmental conditions by incorporating flux distributions computed through constraint-based approaches such as Flux Balance Analysis. We illustrate our approach on the central carbon metabolism of Escherichia coli and on a metabolic model of human hepatocytes. The flux-dependent graphs under various environmental conditions and genetic perturbations exhibit systemic changes in their topological and community structure, which capture the re-routing of metabolic fluxes and the varying importance of specific reactions and pathways. By integrating constraint-based models and tools from network science, our framework allows the study of context-specific metabolic responses at a system level beyond standard pathway descriptions

How to Simulate Outliers with the Desired Properties

[EN] Deviating multivariate observations are used typically to test the performance of outlier detection methods. Yet, the generation of outlying cases itself usually appears as a secondary methodological step in methods comparison. In the literature, outliers are defined using certain distribution parameters which differ from those of the clean or reference data. However, these parameters change among authors, leading to a lack of a standard and measurable definition of the characteristics simulated outliers. This makes the comparison between methods hard and its results dependent on the procedure followed to simulate the data. In order to set a standard procedure, a framework to simulate outliers is defined here. Since it is based on certain specifications for both the Squared Prediction Error (SPE) and Hotelling's T2 statistics from a Principal Component Analysis (PCA) model, tuning them becomes a simple and efficient task. This procedure has been implemented in a set of Matlab functions.Financial support was granted by the Research and Development Support Programme PAID-01-17 of the UPV and also by the Spanish Ministry of Economy and Competitiveness under the project DPI2017-82896-C2-1-R.González-Cebrián, A.; Arteaga, F.; Folch-Fortuny, A.; Ferrer, A. (2021). How to Simulate Outliers with the Desired Properties. Chemometrics and Intelligent Laboratory Systems. 212:1-16. https://doi.org/10.1016/j.chemolab.2021.104301S11621