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Primary and secondary prevention can highly benefit a personalized medicine approach through the accurate discrimination of individuals at high risk of developing a specific disease from those at moderate and low risk. To this end precise risk prediction models need to be built. This endeavor requires a precise characterization of the individual exposome, genome, and phenome. Massive molecular omics data representing the different layers of the biological processes of the host and the nonhost will enable to build more accurate risk prediction models. Epidemiologists aim to integrate omics data along with important information coming from other sources (questionnaires, candidate markers) that has been proved to be relevant in the discrimination risk assessment of complex diseases. However, the integrative models in large-scale epidemiologic research are still in their infancy and they face numerous challenges, some of them at the analytical stage. So far, there are a small number of studies that have integrated more than two omics data sets, and the inclusion of non-omics data in the same models is still missing in most of studies. In this contribution, we aim at approaching the omics and non-omics data integration from the epidemiology scope by considering the “massive” inclusion of variables in the risk assessment and predictive models. We also provide already available examples of integrative contributions in the field, propose analytical strategies that allow considering both omics and non-omics data in the models, and finally review the challenges imbedding this type of research., Fondo de Investigaciones Sanitarias (FIS), Instituto de Salud Carlos III, Spain, Red Temática de Investigación Cooperativa en Cáncer, ISCIII, Spain, European Cooperation in Science and Technology, World Cancer Research, Obra Social Fundación la Caixa, Depto. de Estadística y Ciencia de los Datos, Fac. de Estudios Estadísticos, TRUE, pub

Omics data integration is already a reality. However, few omics-based algorithms show enough predictive ability to be implemented into clinics or public health domains. Clinical/epidemiological data tend to explain most of the variation of health-related traits, and its joint modeling with omics data is crucial to increase the algorithm’s predictive ability. Only a small number of published studies performed a “real” integration of omics and non-omics (OnO) data, mainly to predict cancer outcomes. Challenges in OnO data integration regard the nature and heterogeneity of non-omics data, the possibility of integrating large-scale non-omics data with high-throughput omics data, the relationship between OnO data (i.e., ascertainment bias), the presence of interactions, the fairness of the models, and the presence of subphenotypes. These challenges demand the development and application of new analysis strategies to integrate OnO data. In this contribution we discuss different attempts of OnO data integration in clinical and epidemiological studies. Most of the reviewed papers considered only one type of omics data set, mainly RNA expression data. All selected papers incorporated non-omics data in a low-dimensionality fashion. The integrative strategies used in the identified papers adopted three modeling methods: Independent, conditional, and joint modeling. This review presents, discusses, and proposes integrative analytical strategies towards OnO data integration, Fondo de Investigaciones Sanitarias (FIS), España, Instituto de Salud Carlos III, España, European Cooperation in Science and Technology, World Cancer Research, Ministerio de Economía y Competitividad, España, Depto. de Estadística y Ciencia de los Datos, Fac. de Estudios Estadísticos, TRUE, pub

Omics data integration is becoming necessary to investigate the genomic mechanisms involved in complex diseases. During the integration process, many challenges arise such as data heterogeneity, the smaller number of individuals in comparison to the number of parameters, multicollinearity, and interpretation and validation of results due to their complexity and lack of knowledge about biological processes. To overcome some of these issues, innovative statistical approaches are being developed. In this work, we propose a permutation-based method to concomitantly assess significance and correct by multiple testing with the MaxT algorithm. This was applied with penalized regression methods (LASSO and ENET) when exploring relationships between common genetic variants, DNA methylation and gene expression measured in bladder tumor samples. The overall analysis flow consisted of three steps: (1) SNPs/CpGs were selected per each gene probe within 1Mb window upstream and downstream the gene; (2) LASSO and ENET were applied to assess the association between each expression probe and the selected SNPs/CpGs in three multivariable models (SNP, CPG, and Global models, the latter integrating SNPs and CPGs); and (3) the significance of each model was assessed using the permutation-based MaxT method. We identified 48 genes whose expression levels were significantly associated with both SNPs and CPGs. Importantly, 36 (75%) of them were replicated in an independent data set (TCGA) and the performance of the proposed method was checked with a simulation study. We further support our results with a biological interpretation based on an enrichment analysis. The approach we propose allows reducing computational time and is flexible and easy to implement when analyzing several types of omics data. Our results highlight the importance of integrating omics data by applying appropriate statistical strategies to discover new insights into the complex genetic mechanisms involved in disease cond, Fondo de Investigaciones Sanitarias (FIS), Red Temática de Investigación Cooperativa en Cáncer, Obra Social Fundación "la Caixa", Instituto de Salud Carlos III, EU-FP7-HEALTH, European Cooperation in Science and Technology, Depto. de Estadística y Ciencia de los Datos, Fac. de Estudios Estadísticos, TRUE, pub

Moonlighting proteins perform two or more cellular functions, which are selected based on various contexts including the cell type they are expressed, their oligomerization status, and the binding of different ligands at different sites. To understand overall landscape of their functional diversity, it is important to establish methods that can identify moonlighting proteins in a systematic fashion. Here, we have developed a computational framework to find moonlighting proteins on a genome scale and identified multiple proteomic characteristics of these proteins.

Following the advent of the high-throughput techniques for producing massive omics data, new possibilities and challenges have also emerged in different fields of biology and medicine. Dealing with such data on different scales with different scopes such as genomics, transcriptomics, proteomics and metabolomics, demands appropriate data collection, preprocessing, statistical analysis, interpretation and visualization. The overall goal of this thesis was to conceive omics-related questions in the context of four research titles and to apply a rational choice of the mentioned methods to conduct the study plans to answer them. Paper I asks whether we could propose potentially implicated genes in psoriasis; and tries to answer it using microarray transcriptomics data of psoriasis. Initially, quality control was performed on the microarray dataset and then the Differentially Expressed Genes (DEGs) were chosen for mapping to a protein-protein interaction (PPI) database to create a subnetwork of the respective PPI. Using network analysis, genes with higher scores were proposed as potentially relevant to psoriasis and finally, we evaluated the results concerning a gene-disease association database. Paper II asks whether the knockout of two genes followed by a transformation in E. coli could lead to an increase in bacterial growth in two different media; and deals with it through in vitro experiments followed by an in silico analysis of E. coli RNA-seq data. Here, we calculated the pairwise correlations between each target (knockout) gene and the rest of the genes in the RNA-seq dataset. Then, the significantly anti-correlated genes were shown to mainly belong to protein biosynthesis pathways compared to all other background pathways, which might indicate an increase in protein biosynthesis-related genes' transcription levels when there is an absolute decrease (knockout) in each of the target genes. Paper III asks if an anti-bone-resorption drug called Denosumab significa

Background: Despite the increasing prevalence of Parkinson’s Disease (PD) and research efforts to understand its underlying molecular pathogenesis, early diagnosis of PD remains a challenge. Machine learning analysis of blood-based omics data is a promising non-invasive approach to finding molecular fingerprints associated with PD that may enable an early and accurate diagnosis. Description: We applied several machine learning classification methods to public omics data from PD case/control studies. We used aggregation statistics and Pathifier’s pathway deregulation scores to generate higher order functional representations of the data such as pathway-level features. The models’ performance and most relevant predictive features were compared with individual feature level predictors. The resulting diagnostic models from individual features and Pathifier’s pathway deregulation scores achieve significant Area Under the Curve (AUC, a receiver operating characteristic curve) scores for both cross-validation and external testing. Furthermore, we identify plausible biological pathways associated with PD diagnosis. Conclusions: We have successfully built machine learning models at pathway-level and single-feature level to study blood-based omics data for PD diagnosis. Plausible biological pathway associations were identified. Furthermore, we show that pathway deregulation scores can serve as robust and biologically interpretable predictors for PD.

Following the advent of the high-throughput techniques for producing massive omics data, new possibilities and challenges have also emerged in different fields of biology and medicine. Dealing with such data on different scales with different scopes such as genomics, transcriptomics, proteomics and metabolomics, demands appropriate data collection, preprocessing, statistical analysis, interpretation and visualization. The overall goal of this thesis was to conceive omics-related questions in the context of four research titles and to apply a rational choice of the mentioned methods to conduct the study plans to answer them. Paper I asks whether we could propose potentially implicated genes in psoriasis; and tries to answer it using microarray transcriptomics data of psoriasis. Initially, quality control was performed on the microarray dataset and then the Differentially Expressed Genes (DEGs) were chosen for mapping to a protein-protein interaction (PPI) database to create a subnetwork of the respective PPI. Using network analysis, genes with higher scores were proposed as potentially relevant to psoriasis and finally, we evaluated the results concerning a gene-disease association database. Paper II asks whether the knockout of two genes followed by a transformation in E. coli could lead to an increase in bacterial growth in two different media; and deals with it through in vitro experiments followed by an in silico analysis of E. coli RNA-seq data. Here, we calculated the pairwise correlations between each target (knockout) gene and the rest of the genes in the RNA-seq dataset. Then, the significantly anti-correlated genes were shown to mainly belong to protein biosynthesis pathways compared to all other background pathways, which might indicate an increase in protein biosynthesis-related genes' transcription levels when there is an absolute decrease (knockout) in each of the target genes. Paper III asks if an anti-bone-resorption drug called Denosumab significa

Background: Despite the increasing prevalence of Parkinson’s Disease (PD) and research efforts to understand its underlying molecular pathogenesis, early diagnosis of PD remains a challenge. Machine learning analysis of blood-based omics data is a promising non-invasive approach to finding molecular fingerprints associated with PD that may enable an early and accurate diagnosis. Description: We applied several machine learning classification methods to public omics data from PD case/control studies. We used aggregation statistics and Pathifier’s pathway deregulation scores to generate higher order functional representations of the data such as pathway-level features. The models’ performance and most relevant predictive features were compared with individual feature level predictors. The resulting diagnostic models from individual features and Pathifier’s pathway deregulation scores achieve significant Area Under the Curve (AUC, a receiver operating characteristic curve) scores for both cross-validation and external testing. Furthermore, we identify plausible biological pathways associated with PD diagnosis. Conclusions: We have successfully built machine learning models at pathway-level and single-feature level to study blood-based omics data for PD diagnosis. Plausible biological pathway associations were identified. Furthermore, we show that pathway deregulation scores can serve as robust and biologically interpretable predictors for PD.

Background: Despite the increasing prevalence of Parkinson’s Disease (PD) and research efforts to understand its underlying molecular pathogenesis, early diagnosis of PD remains a challenge. Machine learning analysis of blood-based omics data is a promising non-invasive approach to finding molecular fingerprints associated with PD that may enable an early and accurate diagnosis. Description: We applied several machine learning classification methods to public omics data from PD case/control studies. We used aggregation statistics and Pathifier’s pathway deregulation scores to generate higher order functional representations of the data such as pathway-level features. The models’ performance and most relevant predictive features were compared with individual feature level predictors. The resulting diagnostic models from individual features and Pathifier’s pathway deregulation scores achieve significant Area Under the Curve (AUC, a receiver operating characteristic curve) scores for both cross-validation and external testing. Furthermore, we identify plausible biological pathways associated with PD diagnosis. Conclusions: We have successfully built machine learning models at pathway-level and single-feature level to study blood-based omics data for PD diagnosis. Plausible biological pathway associations were identified. Furthermore, we show that pathway deregulation scores can serve as robust and biologically interpretable predictors for PD.

Background: Despite the increasing prevalence of Parkinson’s Disease (PD) and research efforts to understand its underlying molecular pathogenesis, early diagnosis of PD remains a challenge. Machine learning analysis of blood-based omics data is a promising non-invasive approach to finding molecular fingerprints associated with PD that may enable an early and accurate diagnosis. Description: We applied several machine learning classification methods to public omics data from PD case/control studies. We used aggregation statistics and Pathifier’s pathway deregulation scores to generate higher order functional representations of the data such as pathway-level features. The models’ performance and most relevant predictive features were compared with individual feature level predictors. The resulting diagnostic models from individual features and Pathifier’s pathway deregulation scores achieve significant Area Under the Curve (AUC, a receiver operating characteristic curve) scores for both cross-validation and external testing. Furthermore, we identify plausible biological pathways associated with PD diagnosis. Conclusions: We have successfully built machine learning models at pathway-level and single-feature level to study blood-based omics data for PD diagnosis. Plausible biological pathway associations were identified. Furthermore, we show that pathway deregulation scores can serve as robust and biologically interpretable predictors for PD.

Background: Despite the increasing prevalence of Parkinson’s Disease (PD) and research efforts to understand its underlying molecular pathogenesis, early diagnosis of PD remains a challenge. Machine learning analysis of blood-based omics data is a promising non-invasive approach to finding molecular fingerprints associated with PD that may enable an early and accurate diagnosis. Description: We applied several machine learning classification methods to public omics data from PD case/control studies. We used aggregation statistics and Pathifier’s pathway deregulation scores to generate higher order functional representations of the data such as pathway-level features. The models’ performance and most relevant predictive features were compared with individual feature level predictors. The resulting diagnostic models from individual features and Pathifier’s pathway deregulation scores achieve significant Area Under the Curve (AUC, a receiver operating characteristic curve) scores for both cross-validation and external testing. Furthermore, we identify plausible biological pathways associated with PD diagnosis. Conclusions: We have successfully built machine learning models at pathway-level and single-feature level to study blood-based omics data for PD diagnosis. Plausible biological pathway associations were identified. Furthermore, we show that pathway deregulation scores can serve as robust and biologically interpretable predictors for PD.

Background: Despite the increasing prevalence of Parkinson’s Disease (PD) and research efforts to understand its underlying molecular pathogenesis, early diagnosis of PD remains a challenge. Machine learning analysis of blood-based omics data is a promising non-invasive approach to finding molecular fingerprints associated with PD that may enable an early and accurate diagnosis. Description: We applied several machine learning classification methods to public omics data from PD case/control studies. We used aggregation statistics and Pathifier’s pathway deregulation scores to generate higher order functional representations of the data such as pathway-level features. The models’ performance and most relevant predictive features were compared with individual feature level predictors. The resulting diagnostic models from individual features and Pathifier’s pathway deregulation scores achieve significant Area Under the Curve (AUC, a receiver operating characteristic curve) scores for both cross-validation and external testing. Furthermore, we identify plausible biological pathways associated with PD diagnosis. Conclusions: We have successfully built machine learning models at pathway-level and single-feature level to study blood-based omics data for PD diagnosis. Plausible biological pathway associations were identified. Furthermore, we show that pathway deregulation scores can serve as robust and biologically interpretable predictors for PD.

Background: Despite the increasing prevalence of Parkinson’s Disease (PD) and research efforts to understand its underlying molecular pathogenesis, early diagnosis of PD remains a challenge. Machine learning analysis of blood-based omics data is a promising non-invasive approach to finding molecular fingerprints associated with PD that may enable an early and accurate diagnosis. Description: We applied several machine learning classification methods to public omics data from PD case/control studies. We used aggregation statistics and Pathifier’s pathway deregulation scores to generate higher order functional representations of the data such as pathway-level features. The models’ performance and most relevant predictive features were compared with individual feature level predictors. The resulting diagnostic models from individual features and Pathifier’s pathway deregulation scores achieve significant Area Under the Curve (AUC, a receiver operating characteristic curve) scores for both cross-validation and external testing. Furthermore, we identify plausible biological pathways associated with PD diagnosis. Conclusions: We have successfully built machine learning models at pathway-level and single-feature level to study blood-based omics data for PD diagnosis. Plausible biological pathway associations were identified. Furthermore, we show that pathway deregulation scores can serve as robust and biologically interpretable predictors for PD.

Data integration using hierarchical analysis based on the central dogma or common pathway enrichment analysis may not reveal non-obvious relationships among omic data. Here, we applied factor analysis (FA) and Bayesian network (BN) modeling to integrate different omic data and complex traits by latent variables (production, carcass, and meat quality traits). A total of 14 latent variables were identified: five for phenotype, three for miRNA, four for protein, and two for mRNA data. Pearson correlation coefficients showed negative correlations between latent variables miRNA 1 (mirna1) and miRNA 2 (mirna2) (-0.47), ribeye area (REA) and protein 4 (prot4) (-0.33), REA and protein 2 (prot2) (-0.3), carcass and prot4 (-0.31), carcass and prot2 (-0.28), and backfat thickness (BFT) and miRNA 3 (mirna3) (-0.25). Positive correlations were observed among the four protein factors (0.45-0.83): between meat quality and fat content (0.71), fat content and carcass (0.74), fat content and REA (0.76), and REA and carcass (0.99). BN presented arcs from the carcass, meat quality, prot2, and prot4 latent variables to REA; from meat quality, REA, mirna2, and gene expression mRNA1 to fat content; from protein 1 (prot1) and mirna2 to protein 5 (prot5); and from prot5 and carcass to prot2. The relations of protein latent variables suggest new hypotheses about the impact of these proteins on REA. The network also showed relationships among miRNAs and nebulin proteins. REA seems to be the central node in the network, influencing carcass, prot2, prot4, mRNA1, and meat quality, suggesting that REA is a good indicator of meat quality. The connection among miRNA latent variables, BFT, and fat content relates to the influence of miRNAs on lipid metabolism. The relationship between mirna1 and prot5 composed of isoforms of nebulin needs further investigation. The FA identified latent variables, decreasing the dimensionality and complexity of the data. The BN was capable of generating interrelation

With the significant development of high-throughput experimental technologies, different types of omics (e.g., genomics, epigenomics, transcriptomics, proteomics, and metabolomics) data are produced from clinical samples at an unprecedented speed. The correlations between different types of omics data attract enormous research interest. In contrast, the study on genome-wide omics-to-omics translation (i.e., generation and prediction of one type of omics data from another type of omics data) is almost blank. Generative adversarial networks and variants are among the most state-of-the-art deep learning technologies, which have shown great success in image-to-image translation, text-to-image translation, etc. Here we propose OmiTrans, a deep learning framework that adopted the idea of generative adversarial networks to achieve omics-to-omics translation with promising results. OmiTrans can faithfully reconstruct genome-wide gene expression profiles from DNA methylation data with high accuracy and excellent model generalisation, as demonstrated in the experiments. © 2022 IEEE.

Biological networks are often used to represent complex biological systems, which can contain several types of entities. Analysis and visualization of such networks is supported by the Cytoscape software tool and its many apps. While earlier versions of stringApp focused on providing intraspecies protein-protein interactions from the STRING database, the new stringApp 2.0 greatly improves the support for heterogeneous networks. Here, we highlight new functionality that makes it possible to create networks that contain proteins and interactions from STRING as well as other biological entities and associations from other sources. We exemplify this by complementing a published SARS-CoV-2 interactome with interactions from STRING. We have also extended stringApp with new data and query functionality for protein-protein interactions between eukaryotic parasites and their hosts. We show how this can be used to retrieve and visualize a cross-species network for a malaria parasite, its host, and its vector. Finally, the latest stringApp version has an improved user interface, allows retrieval of both functional associations and physical interactions, and supports group-wise enrichment analysis of different parts of a network to aid biological interpretation. stringApp is freely available at https://apps.cytoscape.org/apps/stringapp.

Following the advent of the high-throughput techniques for producing massive omics data, new possibilities and challenges have also emerged in different fields of biology and medicine. Dealing with such data on different scales with different scopes such as genomics, transcriptomics, proteomics and metabolomics, demands appropriate data collection, preprocessing, statistical analysis, interpretation and visualization. The overall goal of this thesis was to conceive omics-related questions in the context of four research titles and to apply a rational choice of the mentioned methods to conduct the study plans to answer them. Paper I asks whether we could propose potentially implicated genes in psoriasis; and tries to answer it using microarray transcriptomics data of psoriasis. Initially, quality control was performed on the microarray dataset and then the Differentially Expressed Genes (DEGs) were chosen for mapping to a protein-protein interaction (PPI) database to create a subnetwork of the respective PPI. Using network analysis, genes with higher scores were proposed as potentially relevant to psoriasis and finally, we evaluated the results concerning a gene-disease association database. Paper II asks whether the knockout of two genes followed by a transformation in E. coli could lead to an increase in bacterial growth in two different media; and deals with it through in vitro experiments followed by an in silico analysis of E. coli RNA-seq data. Here, we calculated the pairwise correlations between each target (knockout) gene and the rest of the genes in the RNA-seq dataset. Then, the significantly anti-correlated genes were shown to mainly belong to protein biosynthesis pathways compared to all other background pathways, which might indicate an increase in protein biosynthesis-related genes' transcription levels when there is an absolute decrease (knockout) in each of the target genes. Paper III asks if an anti-bone-resorption drug called Denosumab significa

Following the advent of the high-throughput techniques for producing massive omics data, new possibilities and challenges have also emerged in different fields of biology and medicine. Dealing with such data on different scales with different scopes such as genomics, transcriptomics, proteomics and metabolomics, demands appropriate data collection, preprocessing, statistical analysis, interpretation and visualization. The overall goal of this thesis was to conceive omics-related questions in the context of four research titles and to apply a rational choice of the mentioned methods to conduct the study plans to answer them. Paper I asks whether we could propose potentially implicated genes in psoriasis; and tries to answer it using microarray transcriptomics data of psoriasis. Initially, quality control was performed on the microarray dataset and then the Differentially Expressed Genes (DEGs) were chosen for mapping to a protein-protein interaction (PPI) database to create a subnetwork of the respective PPI. Using network analysis, genes with higher scores were proposed as potentially relevant to psoriasis and finally, we evaluated the results concerning a gene-disease association database. Paper II asks whether the knockout of two genes followed by a transformation in E. coli could lead to an increase in bacterial growth in two different media; and deals with it through in vitro experiments followed by an in silico analysis of E. coli RNA-seq data. Here, we calculated the pairwise correlations between each target (knockout) gene and the rest of the genes in the RNA-seq dataset. Then, the significantly anti-correlated genes were shown to mainly belong to protein biosynthesis pathways compared to all other background pathways, which might indicate an increase in protein biosynthesis-related genes' transcription levels when there is an absolute decrease (knockout) in each of the target genes. Paper III asks if an anti-bone-resorption drug called Denosumab significa

Following the advent of the high-throughput techniques for producing massive omics data, new possibilities and challenges have also emerged in different fields of biology and medicine. Dealing with such data on different scales with different scopes such as genomics, transcriptomics, proteomics and metabolomics, demands appropriate data collection, preprocessing, statistical analysis, interpretation and visualization. The overall goal of this thesis was to conceive omics-related questions in the context of four research titles and to apply a rational choice of the mentioned methods to conduct the study plans to answer them. Paper I asks whether we could propose potentially implicated genes in psoriasis; and tries to answer it using microarray transcriptomics data of psoriasis. Initially, quality control was performed on the microarray dataset and then the Differentially Expressed Genes (DEGs) were chosen for mapping to a protein-protein interaction (PPI) database to create a subnetwork of the respective PPI. Using network analysis, genes with higher scores were proposed as potentially relevant to psoriasis and finally, we evaluated the results concerning a gene-disease association database. Paper II asks whether the knockout of two genes followed by a transformation in E. coli could lead to an increase in bacterial growth in two different media; and deals with it through in vitro experiments followed by an in silico analysis of E. coli RNA-seq data. Here, we calculated the pairwise correlations between each target (knockout) gene and the rest of the genes in the RNA-seq dataset. Then, the significantly anti-correlated genes were shown to mainly belong to protein biosynthesis pathways compared to all other background pathways, which might indicate an increase in protein biosynthesis-related genes' transcription levels when there is an absolute decrease (knockout) in each of the target genes. Paper III asks if an anti-bone-resorption drug called Denosumab significa

COVID-19 is associated with mitochondrial dysfunction and metabolic abnormalities, including the deficiencies in nicotinamide adenine dinucleotide (NAD+) and glutathione metabolism. Here it is investigated if administration of a mixture of combined metabolic activators (CMAs) consisting of glutathione and NAD+ precursors can restore metabolic function and thus aid the recovery of COVID-19 patients. CMAs include l-serine, N-acetyl-l-cysteine, nicotinamide riboside, and l-carnitine tartrate, salt form of l-carnitine. Placebo-controlled, open-label phase 2 study and double-blinded phase 3 clinical trials are conducted to investigate the time of symptom-free recovery on ambulatory patients using CMAs. The results of both studies show that the time to complete recovery is significantly shorter in the CMA group (6.6 vs 9.3 d) in phase 2 and (5.7 vs 9.2 d) in phase 3 trials compared to placebo group. A comprehensive analysis of the plasma metabolome and proteome reveals major metabolic changes. Plasma levels of proteins and metabolites associated with inflammation and antioxidant metabolism are significantly improved in patients treated with CMAs as compared to placebo. The results show that treating patients infected with COVID-19 with CMAs lead to a more rapid symptom-free recovery, suggesting a role for such a therapeutic regime in the treatment of infections leading to respiratory problems., QC 20220323

Most medical treatments have been developed aiming at the best-on-average efficacy for large populations, resulting in treatments successful for some patients but not for others. It necessitates the need for precision medicine that tailors medical treatment to individual patients. Omics data holds comprehensive genetic information on individual variability at the molecular level and hence the potential to be translated into personalized therapy. However, the attempts to transform omics data-driven insights into clinically actionable models for individual patients have been limited. Meanwhile, advances in deep learning, one of the most promising branches of artificial intelligence, have produced unprecedented performance in various fields. Although several deep learning-based methods have been proposed to predict individual phenotypes, they have not established the state of the practice, due to instability of selected or learned features derived from extremely high dimensional data with low sample sizes, which often results in overfitted models with high variance. To overcome the limitation of omics data, recent advances in deep learning models, including representation learning models, generative models, and interpretable models, can be considered. The goal of the proposed work is to develop deep learning models that can overcome the limitation of omics data to enhance the prediction of personalized medical decisions. To achieve this, three key challenges should be addressed: 1) effectively reducing dimensions of omics data, 2) systematically augmenting omics data, and 3) improving the interpretability of omics data.

The lack of explainability is one of the most prominent disadvantages of deep learning applications in omics. This 'black box' problem can undermine the credibility and limit the practical implementation of biomedical deep learning models. Here we present XOmiVAE, a variational autoencoder (VAE)-based interpretable deep learning model for cancer classification using high-dimensional omics data. XOmiVAE is capable of revealing the contribution of each gene and latent dimension for each classification prediction and the correlation between each gene and each latent dimension. It is also demonstrated that XOmiVAE can explain not only the supervised classification but also the unsupervised clustering results from the deep learning network. To the best of our knowledge, XOmiVAE is one of the first activation level-based interpretable deep learning models explaining novel clusters generated by VAE. The explainable results generated by XOmiVAE were validated by both the performance of downstream tasks and the biomedical knowledge. In our experiments, XOmiVAE explanations of deep learning-based cancer classification and clustering aligned with current domain knowledge including biological annotation and academic literature, which shows great potential for novel biomedical knowledge discovery from deep learning models. © The Author(s) 2021. Published by Oxford University Press.

Cytoscape is an open-source software used to analyze and visualize biological networks. In addition to being able to import networks from a variety of sources, Cytoscape allows users to import tabular node data and visualize it onto networks. Unfortunately, such data tables can only contain one row of data per node, whereas omics data often have multiple rows for the same gene or protein, representing different post-translational modification sites, peptides, splice isoforms, or conditions. Here, we present a new app, Omics Visualizer, that allows users to import data tables with several rows referring to the same node, connect them to one or more networks, and visualize the connected data onto networks. Omics Visualizer uses the Cytoscape enhancedGraphics app to show the data either in the nodes (pie visualization) or around the nodes (donut visualization), where the colors of the slices represent the imported values. If the user does not provide a network, the app can retrieve one from the STRING database using the Cytoscape stringApp. The Omics Visualizer app is freely available at https://apps.cytoscape.org/apps/omicsvisualizer.

Cytoscape is an open-source software used to analyze and visualize biological networks. In addition to being able to import networks from a variety of sources, Cytoscape allows users to import tabular node data and visualize it onto networks. Unfortunately, such data tables can only contain one row of data per node, whereas omics data often have multiple rows for the same gene or protein, representing different post-translational modification sites, peptides, splice isoforms, or conditions. Here, we present a new app, Omics Visualizer, that allows users to import data tables with several rows referring to the same node, connect them to one or more networks, and visualize the connected data onto networks. Omics Visualizer uses the Cytoscape enhancedGraphics app to show the data either in the nodes (pie visualization) or around the nodes (donut visualization), where the colors of the slices represent the imported values. If the user does not provide a network, the app can retrieve one from the STRING database using the Cytoscape stringApp. The Omics Visualizer app is freely available at https://apps.cytoscape.org/apps/omicsvisualizer.

Cytoscape is an open-source software used to analyze and visualize biological networks. In addition to being able to import networks from a variety of sources, Cytoscape allows users to import tabular node data and visualize it onto networks. Unfortunately, such data tables can only contain one row of data per node, whereas omics data often have multiple rows for the same gene or protein, representing different post-translational modification sites, peptides, splice isoforms, or conditions. Here, we present a new app, Omics Visualizer, that allows users to import data tables with several rows referring to the same node, connect them to one or more networks, and visualize the connected data onto networks. Omics Visualizer uses the Cytoscape enhancedGraphics app to show the data either in the nodes (pie visualization) or around the nodes (donut visualization), where the colors of the slices represent the imported values. If the user does not provide a network, the app can retrieve one from the STRING database using the Cytoscape stringApp. The Omics Visualizer app is freely available at https://apps.cytoscape.org/apps/omicsvisualizer.

Synthetic biology is a rapidly developing field that pursues the application of engineering principles and development approaches to biological engineering. Synthetic biology is poised to change the way biology is practiced, and has important practical applications: for example, building genetically engineered organisms to produce biofuels, medicines, and other chemicals. Traditionally, synthetic biology has focused on manipulating a few genes (e.g., in a single pathway or genetic circuit), but its combination with systems biology holds the promise of creating new cellular architectures and constructing complex biological systems from the ground up. Enabling this merge of synthetic and systems biology will require greater predictive capability for modeling the behavior of cellular systems, and more comprehensive data sets for building and calibrating these models. The so-called "-omics" data sets can now be generated via high throughput techniques in the form of genomic, proteomic, transcriptomic, and metabolomic information on the engineered biological system. Of particular interest with respect to the engineering of microbes capable of producing biofuels and other chemicals economically and at scale are metabolomic datasets, and their insights into intracellular metabolic fluxes. Metabolic fluxes provide a rapid and easy to understand picture of how carbon and energy flow throughout the cell. Here, we present a detailed guide to performing metabolic flux analysis and modeling using the open source JBEI Quantitative Metabolic Modeling (jQMM) library. This library allows the user to transform metabolomics data in the form of isotope labeling data from a 13C labeling experiment into a determination of cellular fluxes that can be used to develop genetic engineering strategies for metabolic engineering.The jQMM library presents a complete toolbox for performing a range of different tasks of interest in metabolic engineering. Various different types of flux analysis and

Synthetic biology is a rapidly developing field that pursues the application of engineering principles and development approaches to biological engineering. Synthetic biology is poised to change the way biology is practiced, and has important practical applications: for example, building genetically engineered organisms to produce biofuels, medicines, and other chemicals. Traditionally, synthetic biology has focused on manipulating a few genes (e.g., in a single pathway or genetic circuit), but its combination with systems biology holds the promise of creating new cellular architectures and constructing complex biological systems from the ground up. Enabling this merge of synthetic and systems biology will require greater predictive capability for modeling the behavior of cellular systems, and more comprehensive data sets for building and calibrating these models. The so-called "-omics" data sets can now be generated via high throughput techniques in the form of genomic, proteomic, transcriptomic, and metabolomic information on the engineered biological system. Of particular interest with respect to the engineering of microbes capable of producing biofuels and other chemicals economically and at scale are metabolomic datasets, and their insights into intracellular metabolic fluxes. Metabolic fluxes provide a rapid and easy to understand picture of how carbon and energy flow throughout the cell. Here, we present a detailed guide to performing metabolic flux analysis and modeling using the open source JBEI Quantitative Metabolic Modeling (jQMM) library. This library allows the user to transform metabolomics data in the form of isotope labeling data from a 13C labeling experiment into a determination of cellular fluxes that can be used to develop genetic engineering strategies for metabolic engineering.The jQMM library presents a complete toolbox for performing a range of different tasks of interest in metabolic engineering. Various different types of flux analysis and

Accelerating the Design-Build-Test-Learn (DBTL) cycle in synthetic biology is critical to achieving rapid and facile bioengineering of organisms for the production of, e.g., biofuels and other chemicals. The Learn phase involves using data obtained from the Test phase to inform the next Design phase. As part of the Learn phase, mathematical models of metabolic fluxes give a mechanistic level of comprehension to cellular metabolism, isolating the principle drivers of metabolic behavior from the peripheral ones, and directing future experimental designs and engineering methodologies. Furthermore, the measurement of intracellular metabolic fluxes is specifically noteworthy as providing a rapid and easy-to-understand picture of how carbon and energy flow throughout the cell. Here, we present a detailed guide to performing metabolic flux analysis in the Learn phase of the DBTL cycle, where we show how one can take the isotope labeling data from a 13C labeling experiment and immediately turn it into a determination of cellular fluxes that points in the direction of genetic engineering strategies that will advance the metabolic engineering process.For our modeling purposes we use the Joint BioEnergy Institute (JBEI) Quantitative Metabolic Modeling (jQMM) library, which provides an open-source, python-based framework for modeling internal metabolic fluxes and making actionable predictions on how to modify cellular metabolism for specific bioengineering goals. It presents a complete toolbox for performing different types of flux analysis such as Flux Balance Analysis, 13C Metabolic Flux Analysis, and it introduces the capability to use 13C labeling experimental data to constrain comprehensive genome-scale models through a technique called two-scale 13C Metabolic Flux Analysis (2S-13C MFA) [1]. In addition to several other capabilities, the jQMM is also able to predict the effects of knockouts using the MoMA and ROOM methodologies. The use of the jQMM library is illustrated t

Accelerating the Design-Build-Test-Learn (DBTL) cycle in synthetic biology is critical to achieving rapid and facile bioengineering of organisms for the production of, e.g., biofuels and other chemicals. The Learn phase involves using data obtained from the Test phase to inform the next Design phase. As part of the Learn phase, mathematical models of metabolic fluxes give a mechanistic level of comprehension to cellular metabolism, isolating the principle drivers of metabolic behavior from the peripheral ones, and directing future experimental designs and engineering methodologies. Furthermore, the measurement of intracellular metabolic fluxes is specifically noteworthy as providing a rapid and easy-to-understand picture of how carbon and energy flow throughout the cell. Here, we present a detailed guide to performing metabolic flux analysis in the Learn phase of the DBTL cycle, where we show how one can take the isotope labeling data from a 13C labeling experiment and immediately turn it into a determination of cellular fluxes that points in the direction of genetic engineering strategies that will advance the metabolic engineering process.For our modeling purposes we use the Joint BioEnergy Institute (JBEI) Quantitative Metabolic Modeling (jQMM) library, which provides an open-source, python-based framework for modeling internal metabolic fluxes and making actionable predictions on how to modify cellular metabolism for specific bioengineering goals. It presents a complete toolbox for performing different types of flux analysis such as Flux Balance Analysis, 13C Metabolic Flux Analysis, and it introduces the capability to use 13C labeling experimental data to constrain comprehensive genome-scale models through a technique called two-scale 13C Metabolic Flux Analysis (2S-13C MFA) [1]. In addition to several other capabilities, the jQMM is also able to predict the effects of knockouts using the MoMA and ROOM methodologies. The use of the jQMM library is illustrated t

Understanding the complex interactions of protein posttranslational modifications (PTMs) represents a major challenge in metabolic engineering, synthetic biology, and the biomedical sciences. Here, we present a workflow that integrates multiplex automated genome editing (MAGE), genome-scale metabolic modeling, and atomistic molecular dynamics to study the effects of PTMs on metabolic enzymes and microbial fitness. This workflow incorporates complementary approaches across scientific disciplines; provides molecular insight into how PTMs influence cellular fitness during nutrient shifts; and demonstrates how mechanistic details of PTMs can be explored at different biological scales. As a proof of concept, we present a global analysis of PTMs on enzymes in the metabolic network of Escherichia coli Based on our workflow results, we conduct a more detailed, mechanistic analysis of the PTMs in three proteins: enolase, serine hydroxymethyltransferase, and transaldolase. Application of this workflow identified the roles of specific PTMs in observed experimental phenomena and demonstrated how individual PTMs regulate enzymes, pathways, and, ultimately, cell phenotypes.

Understanding the complex interactions of protein posttranslational modifications (PTMs) represents a major challenge in metabolic engineering, synthetic biology, and the biomedical sciences. Here, we present a workflow that integrates multiplex automated genome editing (MAGE), genome-scale metabolic modeling, and atomistic molecular dynamics to study the effects of PTMs on metabolic enzymes and microbial fitness. This workflow incorporates complementary approaches across scientific disciplines; provides molecular insight into how PTMs influence cellular fitness during nutrient shifts; and demonstrates how mechanistic details of PTMs can be explored at different biological scales. As a proof of concept, we present a global analysis of PTMs on enzymes in the metabolic network of Escherichia coli. Based on our workflow results, we conduct a more detailed, mechanistic analysis of the PTMs in three proteins: enolase, serine hydroxymethyltransferase, and transaldolase. Application of this workflow identified the roles of specific PTMs in observed experimental phenomena and demonstrated how individual PTMs regulate enzymes, pathways, and, ultimately, cell phenotypes.

Although recent advances in synthetic biology allow us to produce biological designs more efficiently than ever, our ability to predict the end result of these designs is still nascent. Predictive models require large amounts of high-quality data to be parametrized and tested, which are not generally available. Here, we present the Experiment Data Depot (EDD), an online tool designed as a repository of experimental data and metadata. EDD provides a convenient way to upload a variety of data types, visualize these data, and export them in a standardized fashion for use with predictive algorithms. In this paper, we describe EDD and showcase its utility for three different use cases: storage of characterized synthetic biology parts, leveraging proteomics data to improve biofuel yield, and the use of extracellular metabolite concentrations to predict intracellular metabolic fluxes.

BackgroundModeling of microbial metabolism is a topic of growing importance in biotechnology. Mathematical modeling helps provide a mechanistic understanding for the studied process, separating the main drivers from the circumstantial ones, bounding the outcomes of experiments and guiding engineering approaches. Among different modeling schemes, the quantification of intracellular metabolic fluxes (i.e. the rate of each reaction in cellular metabolism) is of particular interest for metabolic engineering because it describes how carbon and energy flow throughout the cell. In addition to flux analysis, new methods for the effective use of the ever more readily available and abundant -omics data (i.e. transcriptomics, proteomics and metabolomics) are urgently needed.ResultsThe jQMM library presented here provides an open-source, Python-based framework for modeling internal metabolic fluxes and leveraging other -omics data for the scientific study of cellular metabolism and bioengineering purposes. Firstly, it presents a complete toolbox for simultaneously performing two different types of flux analysis that are typically disjoint: Flux Balance Analysis and 13C Metabolic Flux Analysis. Moreover, it introduces the capability to use 13C labeling experimental data to constrain comprehensive genome-scale models through a technique called two-scale 13C Metabolic Flux Analysis (2S-13C MFA). In addition, the library includes a demonstration of a method that uses proteomics data to produce actionable insights to increase biofuel production. Finally, the use of the jQMM library is illustrated through the addition of several Jupyter notebook demonstration files that enhance reproducibility and provide the capability to be adapted to the user's specific needs.ConclusionsjQMM will facilitate the design and metabolic engineering of organisms for biofuels and other chemicals, as well as investigations of cellular metabolism and leveraging -omics data. As an open source software proje

The reductionist approach of dissecting biological systems into their constituents has been successful in the first stage of the molecular biology to elucidate the chemical basis of several biological processes. This knowledge helped biologists to understand the complexity of the biological systems evidencing that most biological functions do not arise from individual molecules; thus, realizing that the emergent properties of the biological systems cannot be explained or be predicted by investigating individual molecules without taking into consideration their relations. Thanks to the improvement of the current -omics technologies and the increasing understanding of the molecular relationships, even more studies are evaluating the biological systems through approaches based on graph theory. Genomic and proteomic data are often combined with protein-protein interaction (PPI) networks whose structure is routinely analyzed by algorithms and tools to characterize hubs/bottlenecks and topological, functional, and disease modules. On the other hand, co-expression networks represent a complementary procedure that give the opportunity to evaluate at system level including organisms that lack information on PPIs. Based on these premises, we introduce the reader to the PPI and to the co-expression networks, including aspects of reconstruction and analysis. In particular, the new idea to evaluate large-scale proteomic data by means of co-expression networks will be discussed presenting some examples of application. Their use to infer biological knowledge will be shown, and a special attention will be devoted to the topological and module analysis.

Although recent advances in synthetic biology allow us to produce biological designs more efficiently than ever, our ability to predict the end result of these designs is still nascent. Predictive models require large amounts of high-quality data to be parametrized and tested, which are not generally available. Here, we present the Experiment Data Depot (EDD), an online tool designed as a repository of experimental data and metadata. EDD provides a convenient way to upload a variety of data types, visualize these data, and export them in a standardized fashion for use with predictive algorithms. In this paper, we describe EDD and showcase its utility for three different use cases: storage of characterized synthetic biology parts, leveraging proteomics data to improve biofuel yield, and the use of extracellular metabolite concentrations to predict intracellular metabolic fluxes.

BackgroundModeling of microbial metabolism is a topic of growing importance in biotechnology. Mathematical modeling helps provide a mechanistic understanding for the studied process, separating the main drivers from the circumstantial ones, bounding the outcomes of experiments and guiding engineering approaches. Among different modeling schemes, the quantification of intracellular metabolic fluxes (i.e. the rate of each reaction in cellular metabolism) is of particular interest for metabolic engineering because it describes how carbon and energy flow throughout the cell. In addition to flux analysis, new methods for the effective use of the ever more readily available and abundant -omics data (i.e. transcriptomics, proteomics and metabolomics) are urgently needed.ResultsThe jQMM library presented here provides an open-source, Python-based framework for modeling internal metabolic fluxes and leveraging other -omics data for the scientific study of cellular metabolism and bioengineering purposes. Firstly, it presents a complete toolbox for simultaneously performing two different types of flux analysis that are typically disjoint: Flux Balance Analysis and 13C Metabolic Flux Analysis. Moreover, it introduces the capability to use 13C labeling experimental data to constrain comprehensive genome-scale models through a technique called two-scale 13C Metabolic Flux Analysis (2S-13C MFA). In addition, the library includes a demonstration of a method that uses proteomics data to produce actionable insights to increase biofuel production. Finally, the use of the jQMM library is illustrated through the addition of several Jupyter notebook demonstration files that enhance reproducibility and provide the capability to be adapted to the user's specific needs.ConclusionsjQMM will facilitate the design and metabolic engineering of organisms for biofuels and other chemicals, as well as investigations of cellular metabolism and leveraging -omics data. As an open source software proje

The reductionist approach of dissecting biological systems into their constituents has been successful in the first stage of the molecular biology to elucidate the chemical basis of several biological processes. This knowledge helped biologists to understand the complexity of the biological systems evidencing that most biological functions do not arise from individual molecules; thus, realizing that the emergent properties of the biological systems cannot be explained or be predicted by investigating individual molecules without taking into consideration their relations. Thanks to the improvement of the current -omics technologies and the increasing understanding of the molecular relationships, even more studies are evaluating the biological systems through approaches based on graph theory. Genomic and proteomic data are often combined with protein-protein interaction (PPI) networks whose structure is routinely analyzed by algorithms and tools to characterize hubs/bottlenecks and topological, functional, and disease modules. On the other hand, co-expression networks represent a complementary procedure that give the opportunity to evaluate at system level including organisms that lack information on PPIs. Based on these premises, we introduce the reader to the PPI and to the co-expression networks, including aspects of reconstruction and analysis. In particular, the new idea to evaluate large-scale proteomic data by means of co-expression networks will be discussed presenting some examples of application. Their use to infer biological knowledge will be shown, and a special attention will be devoted to the topological and module analysis.

Although recent advances in synthetic biology allow us to produce biological designs more efficiently than ever, our ability to predict the end result of these designs is still nascent. Predictive models require large amounts of high quality data to be parametrized and tested, which are not generally available. Here, we present the Experiment Data Depot (EDD), an online tool designed as a repository of experimental data and metadata. EDD provides a convenient way to upload a variety of data types, visualize these data, and export them in a standardized fashion for use with predictive algorithms. In this paper, we describe EDD and showcase its utility for three different use cases: storage of characterized synthetic biology parts, leveraging proteomics data to improve biofuel yield, and the use of extracellular metabolite concentrations to predict intracellular metabolic fluxes.

Background: Modeling of microbial metabolism is a topic of growing importance in biotechnology. Mathematical modeling helps provide a mechanistic understanding for the studied process, separating the main drivers from the circumstantial ones, bounding the outcomes of experiments and guiding engineering approaches. Among different modeling schemes, the quantification of intracellular metabolic fluxes (i.e. the rate of each reaction in cellular metabolism) is of particular interest for metabolic engineering because it describes how carbon and energy flow throughout the cell. In addition to flux analysis, new methods for the effective use of the ever more readily available and abundant -omics data (i.e. transcriptomics, proteomics and metabolomics) are urgently needed.Results: The jQMM library presented here provides an open-source, Python-based framework for modeling internal metabolic fluxes and leveraging other -omics data for the scientific study of cellular metabolism and bioengineering purposes. Firstly, it presents a complete toolbox for simultaneously performing two different types of flux analysis that are typically disjoint: Flux Balance Analysis and C-13 Metabolic Flux Analysis. Moreover, it introduces the capability to use C-13 labeling experimental data to constrain comprehensive genome-scale models through a technique called two-scale C-13 Metabolic Flux Analysis (2S-C-13 MFA). In addition, the library includes a demonstration of a method that uses proteomics data to produce actionable insights to increase biofuel production. Finally, the use of the jQMM library is illustrated through the addition of several Jupyter notebook demonstration files that enhance reproducibility and provide the capability to be adapted to the user's specific needs.Conclusions: jQMM will facilitate the design and metabolic engineering of organisms for biofuels and other chemicals, as well as investigations of cellular metabolism and leveraging -omics data. As an open source soft

Efficient redirection of microbial metabolism into the abundant production of desired bioproducts remains non-trivial. Here, we used flux-based modeling approaches to improve yields of fatty acids in Saccharomyces cerevisiae. We combined 13C labeling data with comprehensive genome-scale models to shed light onto microbial metabolism and improve metabolic engineering efforts. We concentrated on studying the balance of acetyl-CoA, a precursor metabolite for the biosynthesis of fatty acids. A genome-wide acetyl-CoA balance study showed ATP citrate lyase from Yarrowia lipolytica as a robust source of cytoplasmic acetyl-CoA and malate synthase as a desirable target for downregulation in terms of acetyl-CoA consumption. These genetic modifications were applied to S. cerevisiae WRY2, a strain that is capable of producing 460 mg/L of free fatty acids. With the addition of ATP citrate lyase and downregulation of malate synthase, the engineered strain produced 26% more free fatty acids. Further increases in free fatty acid production of 33% were obtained by knocking out the cytoplasmic glycerol-3-phosphate dehydrogenase, which flux analysis had shown was competing for carbon flux upstream with the carbon flux through the acetyl-CoA production pathway in the cytoplasm. In total, the genetic interventions applied in this work increased fatty acid production by ~70%.

Technological advances in molecular biology over the past decade have given rise to high dimensional and complex datasets offering the possibility to investigate biological associations between a range of genomic features and complex phenotypes. The analysis of this novel type of data generated unprecedented computational challenges which ultimately led to the definition and implementation of computationally efficient statistical models that were able to scale to genome-wide data, including Bayesian variable selection approaches. While extensive methodological work has been carried out in this area, only few methods capable of handling hundreds of thousands of predictors were implemented and distributed. Among these we recently proposed GUESS, a computationally optimised algorithm making use of graphics processing unit capabilities, which can accommodate multiple outcomes. In this paper we propose R2GUESS, an R package wrapping the original C++ source code. In addition to providing a user-friendly interface of the original code automating its parametrisation, and data handling, R2GUESS also incorporates many features to explore the data, to extend statistical inferences from the native algorithm (e.g., effect size estimation, significance assessment), and to visualize outputs from the algorithm. We first detail the model and its parametrisation, and describe in details its optimised implementation. Based on two examples we finally illustrate its statistical performances and flexibility.

Efficient redirection of microbial metabolism into the abundant production of desired bioproducts remains non-trivial. Here, we used flux-based modeling approaches to improve yields of fatty acids in Saccharomyces cerevisiae. We combined 13C labeling data with comprehensive genome-scale models to shed light onto microbial metabolism and improve metabolic engineering efforts. We concentrated on studying the balance of acetyl-CoA, a precursor metabolite for the biosynthesis of fatty acids. A genome-wide acetyl-CoA balance study showed ATP citrate lyase from Yarrowia lipolytica as a robust source of cytoplasmic acetyl-CoA and malate synthase as a desirable target for downregulation in terms of acetyl-CoA consumption. These genetic modifications were applied to S. cerevisiae WRY2, a strain that is capable of producing 460 mg/L of free fatty acids. With the addition of ATP citrate lyase and downregulation of malate synthase, the engineered strain produced 26% more free fatty acids. Further increases in free fatty acid production of 33% were obtained by knocking out the cytoplasmic glycerol-3-phosphate dehydrogenase, which flux analysis had shown was competing for carbon flux upstream with the carbon flux through the acetyl-CoA production pathway in the cytoplasm. In total, the genetic interventions applied in this work increased fatty acid production by ~70%.

Recent progress in high-throughput data acquisition has shifted the focus from data generation to the processing and understanding of now easily collected patient-specific information. Metabolic models, which have already proven to be very powerful for the integration and analysis of such data sets, might be successfully applied in precision medicine in the near future. Context-specific reconstructions extracted from generic genome-scale models like Reconstruction X (ReconX) (Duarte et al., 2007; Thiele et al., 2013) or Human Metabolic Reconstruction (HMR) (Agren et al., 2012; Mardinoglu et al., 2014a) thereby have the potential to become a diagnostic and treatment tool tailored to the analysis of specific groups of individuals. The use of computational algorithms as a tool for the routinely diagnosis and analysis of metabolic diseases requires a high level of predictive power, robustness and sensitivity. Although multiple context-specific reconstruction algorithms were published in the last ten years, only a fraction of them is suitable for model building based on human high-throughput data. Beside other reasons, this might be due to problems arising from the limitation to only one metabolic target function or arbitrary thresholding. The aim of this thesis was to create a family of robust and fast algorithms for the building of context-specific models that could be used for the integration of different types of omics data and which should be sensitive enough to be used in the framework of precision medicine. FASTCORE (Vlassis et al., 2014), which was developed in the frame of this thesis is among the first context-specific building algorithms that do not optimize for a biological function and that has a computational time around seconds. Furthermore, FASTCORE is devoid of heuristic parameter settings. FASTCORE requires as input a set of reactions that are known to be active in the context of interest (core reactions) and a genome-scale reconstruction. FASTCORE uses

Recent progress in high-throughput data acquisition has shifted the focus from data generation to the processing and understanding of now easily collected patient-specific information. Metabolic models, which have already proven to be very powerful for the integration and analysis of such data sets, might be successfully applied in precision medicine in the near future. Context-specific reconstructions extracted from generic genome-scale models like Reconstruction X (ReconX) (Duarte et al., 2007; Thiele et al., 2013) or Human Metabolic Reconstruction (HMR) (Agren et al., 2012; Mardinoglu et al., 2014a) thereby have the potential to become a diagnostic and treatment tool tailored to the analysis of specific groups of individuals. The use of computational algorithms as a tool for the routinely diagnosis and analysis of metabolic diseases requires a high level of predictive power, robustness and sensitivity. Although multiple context-specific reconstruction algorithms were published in the last ten years, only a fraction of them is suitable for model building based on human high-throughput data. Beside other reasons, this might be due to problems arising from the limitation to only one metabolic target function or arbitrary thresholding. The aim of this thesis was to create a family of robust and fast algorithms for the building of context-specific models that could be used for the integration of different types of omics data and which should be sensitive enough to be used in the framework of precision medicine. FASTCORE (Vlassis et al., 2014), which was developed in the frame of this thesis is among the first context-specific building algorithms that do not optimize for a biological function and that has a computational time around seconds. Furthermore, FASTCORE is devoid of heuristic parameter settings. FASTCORE requires as input a set of reactions that are known to be active in the context of interest (core reactions) and a genome-scale reconstruction. FASTCORE uses

En els últims anys han sorgit noves tecnologies d’alt rendiment que han permès la generació de grans quantitats de dades biològiques.Fet que ha motivat a la interconnexió de la bioinformàtica amb diferentes disciplines.La possible anàlisi d’aquestes dades ha conduït a nous grans reptes en la biologia molecular i les ciències de la salut en general. En aquest context, aquest treball proposa un nou algorisme d’aprenentatge automàtic per a la classificació multinivell, efectuant una aplicació del mètode en una base de dades genòmica per a l’obtenció de biomarcadors.Finalment es proposa una aplicació web interactivaperpermetrel’accessibilitatdelmètode.

Efficient redirection of microbial metabolism into the abundant production of desired bioproducts remains non-trivial. Here, we used flux-based modeling approaches to improve yields of fatty acids in Saccharomyces cerevisiae. We combined 13C labeling data with comprehensive genome-scale models to shed light onto microbial metabolism and improve metabolic engineering efforts. We concentrated on studying the balance of acetyl-CoA, a precursor metabolite for the biosynthesis of fatty acids. A genome-wide acetyl-CoA balance study showed ATP citrate lyase from Yarrowia lipolytica as a robust source of cytoplasmic acetyl-CoA and malate synthase as a desirable target for downregulation in terms of acetyl-CoA consumption. These genetic modifications were applied to S. cerevisiae WRY2, a strain that is capable of producing 460 mg/L of free fatty acids. With the addition of ATP citrate lyase and downregulation of malate synthase, the engineered strain produced 26% more free fatty acids. Further increases in free fatty acid production of 33% were obtained by knocking out the cytoplasmic glycerol-3-phosphate dehydrogenase, which flux analysis had shown was competing for carbon flux upstream with the carbon flux through the acetyl-CoA production pathway in the cytoplasm. In total, the genetic interventions applied in this work increased fatty acid production by ~70%.

In modern Life Sciences, high dimensional correlated data matrices are often dealt with. Ordinary linear regression fail and PCA does not take into account the outcome variable(s). Also there might be large amount of orthogonal variation present. To deal with this, the O2PLS model (which is based on the PLS model) is derived. O2PLS is symmetric and predictive, with the covariance matrix playing an important role. The algorithm is given, and important remarks are made. A simulation study and real data analysis is conducted. A derivation for Probabilistic O2PLS is made, the estimation method being maximum likelihood. All calculations were done in R, code is available on request., Applied Mathematics, Statistics, Electrical Engineering, Mathematics and Computer Science

application/pdf, Moonlighting proteins perform two or more cellular functions, which are selected based on various contexts including the cell type they are expressed, their oligomerization status, and the binding of different ligands at different sites. To understand overall landscape of their functional diversity, it is important to establish methods that can identify moonlighting proteins in a systematic fashion. Here, we have developed a computational framework to find moonlighting proteins on a genome scale and identified multiple proteomic characteristics of these proteins.

Moonlighting proteins perform two or more cellular functions, which are selected based on various contexts including the cell type they are expressed, their oligomerization status, and the binding of different ligands at different sites. To understand overall landscape of their functional diversity, it is important to establish methods that can identify moonlighting proteins in a systematic fashion. Here, we have developed a computational framework to find moonlighting proteins on a genome scale and identified multiple proteomic characteristics of these proteins., journal article