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1.  Biomedical research in a Digital Health Framework 
Journal of Translational Medicine  2014;12(Suppl 2):S10.
This article describes a Digital Health Framework (DHF), benefitting from the lessons learnt during the three-year life span of the FP7 Synergy-COPD project. The DHF aims to embrace the emerging requirements - data and tools - of applying systems medicine into healthcare with a three-tier strategy articulating formal healthcare, informal care and biomedical research. Accordingly, it has been constructed based on three key building blocks, namely, novel integrated care services with the support of information and communication technologies, a personal health folder (PHF) and a biomedical research environment (DHF-research). Details on the functional requirements and necessary components of the DHF-research are extensively presented. Finally, the specifics of the building blocks strategy for deployment of the DHF, as well as the steps toward adoption are analyzed. The proposed architectural solutions and implementation steps constitute a pivotal strategy to foster and enable 4P medicine (Predictive, Preventive, Personalized and Participatory) in practice and should provide a head start to any community and institution currently considering to implement a biomedical research platform.
doi:10.1186/1479-5876-12-S2-S10
PMCID: PMC4255881  PMID: 25472554
Biomedical Research; Chronic care; Clinical Decision Support Systems; Integrated Health Care Systems; Patient Decision Support Systems; Personal Health Folder
2.  Workforce preparation: the Biohealth computing model for Master and PhD students 
Journal of Translational Medicine  2014;12(Suppl 2):S11.
The article addresses the strategic role of workforce preparation in the process of adoption of Systems Medicine as a driver of biomedical research in the new health paradigm. It reports on relevant initiatives, like CASyM, fostering Systems Medicine at EU level. The chapter focuses on the BioHealth Computing Program as a reference for multidisciplinary training of future systems-oriented researchers describing the productive interactions with the Synergy-COPD project.
doi:10.1186/1479-5876-12-S2-S11
PMCID: PMC4255883  PMID: 25472654
Biomedical Research; Education; Integrated Health Care Systems; Master; PhD; Professionals; Systems Medicine; Training
3.  Predictive medicine: outcomes, challenges and opportunities in the Synergy-COPD project 
Journal of Translational Medicine  2014;12(Suppl 2):S12.
Background
Chronic Obstructive Pulmonary Disease (COPD) is a major challenge for healthcare. Heterogeneities in clinical manifestations and in disease progression are relevant traits in COPD with impact on patient management and prognosis. It is hypothesized that COPD heterogeneity results from the interplay of mechanisms governing three conceptually different phenomena: 1) pulmonary disease, 2) systemic effects of COPD and 3) co-morbidity clustering.
Objectives
To assess the potential of systems medicine to better understand non-pulmonary determinants of COPD heterogeneity. To transfer acquired knowledge to healthcare enhancing subject-specific health risk assessment and stratification to improve management of chronic patients.
Method
Underlying mechanisms of skeletal muscle dysfunction and of co-morbidity clustering in COPD patients were explored with strategies combining deterministic modelling and network medicine analyses using the Biobridge dataset. An independent data driven analysis of co-morbidity clustering examining associated genes and pathways was done (ICD9-CM data from Medicare, 13 million people). A targeted network analysis using the two studies: skeletal muscle dysfunction and co-morbidity clustering explored shared pathways between them.
Results
(1) Evidence of abnormal regulation of pivotal skeletal muscle biological pathways and increased risk for co-morbidity clustering was observed in COPD; (2) shared abnormal pathway regulation between skeletal muscle dysfunction and co-morbidity clustering; and, (3) technological achievements of the projects were: (i) COPD Knowledge Base; (ii) novel modelling approaches; (iii) Simulation Environment; and, (iv) three layers of Clinical Decision Support Systems.
Conclusions
The project demonstrated the high potential of a systems medicine approach to address COPD heterogeneity. Limiting factors for the project development were identified. They were relevant to shape strategies fostering 4P Medicine for chronic patients. The concept of Digital Health Framework and the proposed roadmap for its deployment constituted relevant project outcomes.
doi:10.1186/1479-5876-12-S2-S12
PMCID: PMC4255885  PMID: 25472742
chronic diseases; co-morbidities; chronic obstructive pulmonary disease; information and communication technologies; modelling; network medicine; training
4.  Synergy-COPD: a systems approach for understanding and managing chronic diseases 
Journal of Translational Medicine  2014;12(Suppl 2):S2.
Chronic diseases (CD) are generating a dramatic societal burden worldwide that is expected to persist over the next decades. The challenges posed by the epidemics of CD have triggered a novel health paradigm with major consequences on the traditional concept of disease and with a profound impact on key aspects of healthcare systems.
We hypothesized that the development of a systems approach to understand CD together with the generation of an ecosystem to transfer the acquired knowledge into the novel healthcare scenario may contribute to a cost-effective enhancement of health outcomes. To this end, we designed the Synergy-COPD project wherein the heterogeneity of chronic obstructive pulmonary disease (COPD) was addressed as a use case representative of CD.
The current manuscript describes main features of the project design and the strategies put in place for its development, as well the expected outcomes during the project life-span. Moreover, the manuscript serves as introductory and unifying chapter of the different papers associated to the Supplement describing the characteristics, tools and the objectives of Synergy-COPD
doi:10.1186/1479-5876-12-S2-S2
PMCID: PMC4255903  PMID: 25472826
Chronic Diseases; Chronic Obstructive Pulmonary Disease; COPD; Integrated Care; ICT; Systems Medicine; Predictive Medicine; Telemedicine
5.  Chronic Obstructive Pulmonary Disease heterogeneity: challenges for health risk assessment, stratification and management 
Journal of Translational Medicine  2014;12(Suppl 2):S3.
Background and hypothesis
Heterogeneity in clinical manifestations and disease progression in Chronic Obstructive Pulmonary Disease (COPD) lead to consequences for patient health risk assessment, stratification and management. Implicit with the classical "spill over" hypothesis is that COPD heterogeneity is driven by the pulmonary events of the disease. Alternatively, we hypothesized that COPD heterogeneities result from the interplay of mechanisms governing three conceptually different phenomena: 1) pulmonary disease, 2) systemic effects of COPD and 3) co-morbidity clustering, each of them with their own dynamics.
Objective and method
To explore the potential of a systems analysis of COPD heterogeneity focused on skeletal muscle dysfunction and on co-morbidity clustering aiming at generating predictive modeling with impact on patient management. To this end, strategies combining deterministic modeling and network medicine analyses of the Biobridge dataset were used to investigate the mechanisms of skeletal muscle dysfunction. An independent data driven analysis of co-morbidity clustering examining associated genes and pathways was performed using a large dataset (ICD9-CM data from Medicare, 13 million people). Finally, a targeted network analysis using the outcomes of the two approaches (skeletal muscle dysfunction and co-morbidity clustering) explored shared pathways between these phenomena.
Results
(1) Evidence of abnormal regulation of skeletal muscle bioenergetics and skeletal muscle remodeling showing a significant association with nitroso-redox disequilibrium was observed in COPD; (2) COPD patients presented higher risk for co-morbidity clustering than non-COPD patients increasing with ageing; and, (3) the on-going targeted network analyses suggests shared pathways between skeletal muscle dysfunction and co-morbidity clustering.
Conclusions
The results indicate the high potential of a systems approach to address COPD heterogeneity. Significant knowledge gaps were identified that are relevant to shape strategies aiming at fostering 4P Medicine for patients with COPD.
doi:10.1186/1479-5876-12-S2-S3
PMCID: PMC4255905  PMID: 25472887
Chronic diseases; COPD; Disease heterogeneity; Integrated Care; Predictive Medicine; Redox disequilibrium; Systems Medicine; VO2max
6.  Systems Medicine: from molecular features and models to the clinic in COPD 
Journal of Translational Medicine  2014;12(Suppl 2):S4.
Background and hypothesis
Chronic Obstructive Pulmonary Disease (COPD) patients are characterized by heterogeneous clinical manifestations and patterns of disease progression. Two major factors that can be used to identify COPD subtypes are muscle dysfunction/wasting and co-morbidity patterns. We hypothesized that COPD heterogeneity is in part the result of complex interactions between several genes and pathways. We explored the possibility of using a Systems Medicine approach to identify such pathways, as well as to generate predictive computational models that may be used in clinic practice.
Objective and method
Our overarching goal is to generate clinically applicable predictive models that characterize COPD heterogeneity through a Systems Medicine approach. To this end we have developed a general framework, consisting of three steps/objectives: (1) feature identification, (2) model generation and statistical validation, and (3) application and validation of the predictive models in the clinical scenario. We used muscle dysfunction and co-morbidity as test cases for this framework.
Results
In the study of muscle wasting we identified relevant features (genes) by a network analysis and generated predictive models that integrate mechanistic and probabilistic models. This allowed us to characterize muscle wasting as a general de-regulation of pathway interactions. In the co-morbidity analysis we identified relevant features (genes/pathways) by the integration of gene-disease and disease-disease associations. We further present a detailed characterization of co-morbidities in COPD patients that was implemented into a predictive model. In both use cases we were able to achieve predictive modeling but we also identified several key challenges, the most pressing being the validation and implementation into actual clinical practice.
Conclusions
The results confirm the potential of the Systems Medicine approach to study complex diseases and generate clinically relevant predictive models. Our study also highlights important obstacles and bottlenecks for such approaches (e.g. data availability and normalization of frameworks among others) and suggests specific proposals to overcome them.
doi:10.1186/1479-5876-12-S2-S4
PMCID: PMC4255907  PMID: 25471042
Chronic diseases; COPD; Disease heterogeneity; Systems Medicine; Predictive Modeling; Co-morbidity
7.  The COPD Knowledge Base: enabling data analysis and computational simulation in translational COPD research 
Journal of Translational Medicine  2014;12(Suppl 2):S6.
Background
Previously we generated a chronic obstructive pulmonary disease (COPD) specific knowledge base (http://www.copdknowledgebase.eu) from clinical and experimental data, text-mining results and public databases. This knowledge base allowed the retrieval of specific molecular networks together with integrated clinical and experimental data.
Results
The COPDKB has now been extended to integrate over 40 public data sources on functional interaction (e.g. signal transduction, transcriptional regulation, protein-protein interaction, gene-disease association). In addition we integrated COPD-specific expression and co-morbidity networks connecting over 6 000 genes/proteins with physiological parameters and disease states. Three mathematical models describing different aspects of systemic effects of COPD were connected to clinical and experimental data. We have completely redesigned the technical architecture of the user interface and now provide html and web browser-based access and form-based searches. A network search enables the use of interconnecting information and the generation of disease-specific sub-networks from general knowledge. Integration with the Synergy-COPD Simulation Environment enables multi-scale integrated simulation of individual computational models while integration with a Clinical Decision Support System allows delivery into clinical practice.
Conclusions
The COPD Knowledge Base is the only publicly available knowledge resource dedicated to COPD and combining genetic information with molecular, physiological and clinical data as well as mathematical modelling. Its integrated analysis functions provide overviews about clinical trends and connections while its semantically mapped content enables complex analysis approaches. We plan to further extend the COPDKB by offering it as a repository to publish and semantically integrate data from relevant clinical trials. The COPDKB is freely available after registration at http://www.copdknowledgebase.eu.
doi:10.1186/1479-5876-12-S2-S6
PMCID: PMC4255911  PMID: 25471253
8.  Oxygen Pathway Modeling Estimates High Reactive Oxygen Species Production above the Highest Permanent Human Habitation 
PLoS ONE  2014;9(11):e111068.
The production of reactive oxygen species (ROS) from the inner mitochondrial membrane is one of many fundamental processes governing the balance between health and disease. It is well known that ROS are necessary signaling molecules in gene expression, yet when expressed at high levels, ROS may cause oxidative stress and cell damage. Both hypoxia and hyperoxia may alter ROS production by changing mitochondrial Po2 (). Because depends on the balance between O2 transport and utilization, we formulated an integrative mathematical model of O2 transport and utilization in skeletal muscle to predict conditions to cause abnormally high ROS generation. Simulations using data from healthy subjects during maximal exercise at sea level reveal little mitochondrial ROS production. However, altitude triggers high mitochondrial ROS production in muscle regions with high metabolic capacity but limited O2 delivery. This altitude roughly coincides with the highest location of permanent human habitation. Above 25,000 ft., more than 90% of exercising muscle is predicted to produce abnormally high levels of ROS, corresponding to the “death zone” in mountaineering.
doi:10.1371/journal.pone.0111068
PMCID: PMC4222897  PMID: 25375931
9.  Compartmentation of glycogen metabolism revealed from 13C isotopologue distributions 
BMC Systems Biology  2011;5:175.
Background
Stable isotope tracers are used to assess metabolic flux profiles in living cells. The existing methods of measurement average out the isotopic isomer distribution in metabolites throughout the cell, whereas the knowledge of compartmental organization of analyzed pathways is crucial for the evaluation of true fluxes. That is why we accepted a challenge to create a software tool that allows deciphering the compartmentation of metabolites based on the analysis of average isotopic isomer distribution.
Results
The software Isodyn, which simulates the dynamics of isotopic isomer distribution in central metabolic pathways, was supplemented by algorithms facilitating the transition between various analyzed metabolic schemes, and by the tools for model discrimination. It simulated 13C isotope distributions in glucose, lactate, glutamate and glycogen, measured by mass spectrometry after incubation of hepatocytes in the presence of only labeled glucose or glucose and lactate together (with label either in glucose or lactate). The simulations assumed either a single intracellular hexose phosphate pool, or also channeling of hexose phosphates resulting in a different isotopic composition of glycogen. Model discrimination test was applied to check the consistency of both models with experimental data. Metabolic flux profiles, evaluated with the accepted model that assumes channeling, revealed the range of changes in metabolic fluxes in liver cells.
Conclusions
The analysis of compartmentation of metabolic networks based on the measured 13C distribution was included in Isodyn as a routine procedure. The advantage of this implementation is that, being a part of evaluation of metabolic fluxes, it does not require additional experiments to study metabolic compartmentation. The analysis of experimental data revealed that the distribution of measured 13C-labeled glucose metabolites is inconsistent with the idea of perfect mixing of hexose phosphates in cytosol. In contrast, the observed distribution indicates the presence of a separate pool of hexose phosphates that is channeled towards glycogen synthesis.
doi:10.1186/1752-0509-5-175
PMCID: PMC3292525  PMID: 22034837
10.  A Systems Biology Approach Identifies Molecular Networks Defining Skeletal Muscle Abnormalities in Chronic Obstructive Pulmonary Disease 
PLoS Computational Biology  2011;7(9):e1002129.
Chronic Obstructive Pulmonary Disease (COPD) is an inflammatory process of the lung inducing persistent airflow limitation. Extensive systemic effects, such as skeletal muscle dysfunction, often characterize these patients and severely limit life expectancy. Despite considerable research efforts, the molecular basis of muscle degeneration in COPD is still a matter of intense debate. In this study, we have applied a network biology approach to model the relationship between muscle molecular and physiological response to training and systemic inflammatory mediators. Our model shows that failure to co-ordinately activate expression of several tissue remodelling and bioenergetics pathways is a specific landmark of COPD diseased muscles. Our findings also suggest that this phenomenon may be linked to an abnormal expression of a number of histone modifiers, which we discovered correlate with oxygen utilization. These observations raised the interesting possibility that cell hypoxia may be a key factor driving skeletal muscle degeneration in COPD patients.
Author Summary
Chronic Obstructive Pulmonary Disease (COPD) is a major life threatening disease of the lungs, characterized by airflow limitation and chronic inflammation. Progressive reduction of the body muscle mass is a condition linked to COPD that significantly decreases quality of life and survival. Physical exercise has been proposed as a therapeutic option but its utility is still a matter of debate. The mechanisms underlying muscle wasting are also still largely unknown. The results presented in this paper show that diseased muscles are largely unable to coordinate the expression of muscle remodelling and bioenergetics pathways and that the cause of this phenomena may be tissue hypoxia. These findings contrast with current hypotheses based on the role of chronic inflammation and show that a mechanism based on an oxygen driven, epigenetic control of these two important functions may be an important disease mechanism.
doi:10.1371/journal.pcbi.1002129
PMCID: PMC3164707  PMID: 21909251
11.  Reactive Oxygen Species Production by Forward and Reverse Electron Fluxes in the Mitochondrial Respiratory Chain 
PLoS Computational Biology  2011;7(3):e1001115.
Reactive oxygen species (ROS) produced in the mitochondrial respiratory chain (RC) are primary signals that modulate cellular adaptation to environment, and are also destructive factors that damage cells under the conditions of hypoxia/reoxygenation relevant for various systemic diseases or transplantation. The important role of ROS in cell survival requires detailed investigation of mechanism and determinants of ROS production. To perform such an investigation we extended our rule-based model of complex III in order to account for electron transport in the whole RC coupled to proton translocation, transmembrane electrochemical potential generation, TCA cycle reactions, and substrate transport to mitochondria. It fits respiratory electron fluxes measured in rat brain mitochondria fueled by succinate or pyruvate and malate, and the dynamics of NAD+ reduction by reverse electron transport from succinate through complex I. The fitting of measured characteristics gave an insight into the mechanism of underlying processes governing the formation of free radicals that can transfer an unpaired electron to oxygen-producing superoxide and thus can initiate the generation of ROS. Our analysis revealed an association of ROS production with levels of specific radicals of individual electron transporters and their combinations in species of complexes I and III. It was found that the phenomenon of bistability, revealed previously as a property of complex III, remains valid for the whole RC. The conditions for switching to a state with a high content of free radicals in complex III were predicted based on theoretical analysis and were confirmed experimentally. These findings provide a new insight into the mechanisms of ROS production in RC.
Author Summary
Respiration at the level of mitochondria is considered as delivery of electrons and protons from NADH or succinate to oxygen through a set of transporters constituting the respiratory chain (RC). Mitochondrial respiration, dealing with transfer of unpaired electrons, may produce reactive oxygen species (ROS) such as O2− and subsequently H2O2 as side products. ROS are chemically very active and can cause oxidative damage to cellular components. The production of ROS, normally low, can increase under stress to the levels incompatible with cell survival; thus, understanding the ways of ROS production in the RC represents a vital task in research. We used mathematical modeling to analyze experiments with isolated brain mitochondria aimed to study relations between electron transport and ROS production. Elsewhere we reported that mitochondrial complex III can operate in two distinct steady states at the same microenvironmental conditions, producing either low or high levels of ROS. Here, this property of bistability was confirmed for the whole RC. The associations between measured ROS production and computed individual free radical levels in complexes I and III were established. The discovered phenomenon of bistability is important as a basis for new strategies in organ transplantation and therapy.
doi:10.1371/journal.pcbi.1001115
PMCID: PMC3068929  PMID: 21483483
12.  Knowledge management for systems biology a general and visually driven framework applied to translational medicine 
BMC Systems Biology  2011;5:38.
Background
To enhance our understanding of complex biological systems like diseases we need to put all of the available data into context and use this to detect relations, pattern and rules which allow predictive hypotheses to be defined. Life science has become a data rich science with information about the behaviour of millions of entities like genes, chemical compounds, diseases, cell types and organs, which are organised in many different databases and/or spread throughout the literature. Existing knowledge such as genotype - phenotype relations or signal transduction pathways must be semantically integrated and dynamically organised into structured networks that are connected with clinical and experimental data. Different approaches to this challenge exist but so far none has proven entirely satisfactory.
Results
To address this challenge we previously developed a generic knowledge management framework, BioXM™, which allows the dynamic, graphic generation of domain specific knowledge representation models based on specific objects and their relations supporting annotations and ontologies. Here we demonstrate the utility of BioXM for knowledge management in systems biology as part of the EU FP6 BioBridge project on translational approaches to chronic diseases. From clinical and experimental data, text-mining results and public databases we generate a chronic obstructive pulmonary disease (COPD) knowledge base and demonstrate its use by mining specific molecular networks together with integrated clinical and experimental data.
Conclusions
We generate the first semantically integrated COPD specific public knowledge base and find that for the integration of clinical and experimental data with pre-existing knowledge the configuration based set-up enabled by BioXM reduced implementation time and effort for the knowledge base compared to similar systems implemented as classical software development projects. The knowledgebase enables the retrieval of sub-networks including protein-protein interaction, pathway, gene - disease and gene - compound data which are used for subsequent data analysis, modelling and simulation. Pre-structured queries and reports enhance usability; establishing their use in everyday clinical settings requires further simplification with a browser based interface which is currently under development.
doi:10.1186/1752-0509-5-38
PMCID: PMC3060864  PMID: 21375767
13.  Bistability of Mitochondrial Respiration Underlies Paradoxical Reactive Oxygen Species Generation Induced by Anoxia 
PLoS Computational Biology  2009;5(12):e1000619.
Increased production of reactive oxygen species (ROS) in mitochondria underlies major systemic diseases, and this clinical problem stimulates a great scientific interest in the mechanism of ROS generation. However, the mechanism of hypoxia-induced change in ROS production is not fully understood. To mathematically analyze this mechanism in details, taking into consideration all the possible redox states formed in the process of electron transport, even for respiratory complex III, a system of hundreds of differential equations must be constructed. Aimed to facilitate such tasks, we developed a new methodology of modeling, which resides in the automated construction of large sets of differential equations. The detailed modeling of electron transport in mitochondria allowed for the identification of two steady state modes of operation (bistability) of respiratory complex III at the same microenvironmental conditions. Various perturbations could induce the transition of respiratory chain from one steady state to another. While normally complex III is in a low ROS producing mode, temporal anoxia could switch it to a high ROS producing state, which persists after the return to normal oxygen supply. This prediction, which we qualitatively validated experimentally, explains the mechanism of anoxia-induced cell damage. Recognition of bistability of complex III operation may enable novel therapeutic strategies for oxidative stress and our method of modeling could be widely used in systems biology studies.
Author Summary
The levels of reactive oxygen species (ROS) that are generated as a side product of mitochondrial respiratory electron transport largely define the extent of oxidative stress in living cells. Free radicals formed in electron transport, such as ubisemiquinone, could pass their non-paired electron directly to oxygen, thus producing superoxide radical that gives rise to a variety of ROS. It is well known in clinical practice that upon recommencing oxygen supply after anoxia a tissue produces much more ROS than before the anoxia, and the state of high ROS production is stable. The mechanism of switching from low to high ROS production by temporal anoxia was unknown, in part because of the lack of detailed mathematical description of hundreds of redox states of respiratory complexes, which are formed in the process of electron transport. A new methodology of automated construction of large systems of differential equations allowed us to describe the system in detail and predicts that the mechanism of paradoxical effect of anoxia-reoxygenation could be defined by the properties of complex III of mitochondrial respiratory chain. Our experiments confirmed that the effect of hypoxia-reoxygenation is confined by intramitochondrial processes since it is observed in isolated mitochondria.
doi:10.1371/journal.pcbi.1000619
PMCID: PMC2789320  PMID: 20041200
14.  The Role of External and Matrix pH in Mitochondrial Reactive Oxygen Species Generation* 
The Journal of Biological Chemistry  2008;283(43):29292-29300.
Reactive oxygen species (ROS) generation in mitochondria as a side product of electron and proton transport through the inner membrane is important for normal cell operation as well as development of pathology. Matrix and cytosol alkalization stabilizes semiquinone radical, a potential superoxide producer, and we hypothesized that proton deficiency under the excess of electron donors enhances reactive oxygen species generation. We tested this hypothesis by measuring pH dependence of reactive oxygen species released by mitochondria. The experiments were performed in the media with pH varying from 6 to 8 in the presence of complex II substrate succinate or under more physiological conditions with complex I substrates glutamate and malate. Matrix pH was manipulated by inorganic phosphate, nigericine, and low concentrations of uncoupler or valinomycin. We found that high pH strongly increased the rate of free radical generation in all of the conditions studied, even when ΔpH = 0 in the presence of nigericin. In the absence of inorganic phosphate, when the matrix was the most alkaline, pH shift in the medium above 7 induced permeability transition accompanied by the decrease of ROS production. ROS production increase induced by the alkalization of medium was observed with intact respiring mitochondria as well as in the presence of complex I inhibitor rotenone, which enhanced reactive oxygen species release. The phenomena revealed in this report are important for understanding mechanisms governing mitochondrial production of reactive oxygen species, in particular that related with uncoupling proteins.
doi:10.1074/jbc.M801019200
PMCID: PMC2570889  PMID: 18687689

Results 1-14 (14)