VPH NoE Exemplar Projects and the VPH ToolKit PDF | Print | E-mail

VPH NoE seed Exemplar Projects

1. A multi-organ Core Model of arterial pressure and body fluids homeostasis

Lead: CNRS, This e-mail address is being protected from spambots. You need JavaScript enabled to view it

Long-term regulation of arterial blood pressure (BP), which necessarily involves several organ systems and regulatory feedback loops, is determined essentially by the balance between fluid and salt intake and their excretion, the latter being characterised by the relation between BP and urinary output, manifested in the renal function curve (RFC). This paradigm serves as the basis not only for understanding normal BP regulation but also for treatment of hypertension (necessarily due to modification of the RFC), and was developed by Arthur Guyton and colleagues based importantly on their quantitative control-theory based models, which were firmly grounded in experimental results (mainly from animal experiments) and several decades of clinical experience.

For the VPH, it is appropriate to build a core modelling environment inspired by the Guyton models but implemented as a set of basic open source modules for the various functional components (not only organs, such as heart, kidney, lung, and muscle mass, but also the relevant nervous and hormonal regulatory systems), each of which can be replaced as appropriate by higher resolution mechanistic models (or even nested sets of models) allowing the exploration of specific, gene-to-organism predictive scenarios. This is the goal of the SAPHIR project at CNRS, funded by the French ANR (National Research Agency). Also included will be the computation of virtual magnetic resonance images of the multi-organ model (SIMRI). The ultimate aim is to work towards patient- customisation of the generic core model set, which should serve as a valuable aid to the clinician for design of therapeutic regimens.

Within this seed EP, the SAPHIR modelling environment will, first, inform the WP3 ToolKit development team of specific requirements for this type/level of model integration, and, subsequently, be explicitly adapted to the protocols of the VPH ToolKit (WP3) as they become available. In particular, this will involve adaptation of inter-module I/O connection protocols, cross-discipline ontology integration (and development where necessary), and possibly integration or link-up of the SAPHIR quantitative parameter database with a more generic VPH DB (to be implemented under WP3). This EP will thus serve as a prototype VPH "core model" providing an open collaborative working environment. In this way, it will be straightforward for interested laboratories to contribute their detailed mechanistic models at any scale as new sub-modules, thus extending with no a priori limit the number of "services" available for customised model construction.

2. Integrated multi-level modelling of the musculoskeletal system

Lead: ULB, This e-mail address is being protected from spambots. You need JavaScript enabled to view it

A number of problems met in daily clinical practice relating to the musculoskeletal system still call for the development of new integrative approaches. For example, cerebral palsy requires clinicians to handle and mentally combine numerous types of inhomogeneous data: electromyography, motion data, medical imaging, etc. Furthermore, clinical interventions and observations for this kind of pathology typically occur at the organ level (i.e., injection of Botox in the spastic muscle), while the real problem is located at the cellular level (i.e. spasticity of the muscle fibre, action of the Botox on the neuromuscular junction). Additional complexity arises in the musculoskeletal system due to the interaction of multiple organs (several muscles, several ligaments, the hyaline cartilage) in the overall functioning of the system. Solving this kind of problem will not only require multi-level integration, but will also require the development of multi-organ and multi-tissue modelling based on robust optimisation algorithms and advanced visualisation tools. Such an approach has been the focus of several EC-funded projects (VAKHUM, Multimod, LHDL), whose main results are the availability of a shared ICT technology, called MAF2, aiming to perform the required integrative research.

3. The Vertical and Horizontal Atherome (WHAM)

Lead: KI, This e-mail address is being protected from spambots. You need JavaScript enabled to view it

Coronary artery disease (CAD) is a major (50 %) killer of the western population. Atherosclerosis is a main driver of CAD and it would be advantageous if the suffering from this disease could be reduced. Due to the western life style there are however no indications that atherosclerosis will become less important in the future. Yet, our limited mechanistic understanding of the disease in terms of the identity of the disease related genes, polymorphisms, proteins, and their interactions, within and between cells and organs, constitute a severe bottleneck in preventing and developing efficient drugs which can regress the development of atherosclerosis.

The WHAM program requires both a vertical and horizontal integration. Available vertical data ranges from molecular information (gene-expression, protein-protein interactions data) to angiograms (imaging) reflecting degree of disease from patients undergoing by-pass surgery. Horizontal molecular information is obtained from tissue biopsies (liver, muscle, fat, affected and unaffected aorta). Similar data-types are available from the aorta from a mouse model prone for atherosclerosis. Molecular data from macrophages a key cell-type involved in atherosclerosis are also available.

To analyze these data from different organs, and model systems of different complexity a blend of pattern detection techniques (statistics, machine learning), network identification algorithms and mathematical modelling is required.

This seed EP will aim to harness the development of the VPH ToolKit (WP3) and accelerate the success of WHAM, since such features have not been developed within the WHAM project itself, this being a clinical and experimental project that was launched and run without these considerations in mind. Therefore, VPH tools enabling "simple" things like storing different types of data (patient descriptions, experimental protocols, expression, SNPs etc) are urgently needed. At the other end of the spectrum the issue of integrating the molecular information obtained across different model systems and imaging is most likely a central methodological problem for a VPH ToolKit addressing clinical needs. This includes visualisation but also how molecule X affects the tissue and 3D properties etc., interaction between flow (blood) and expression of various molecules.

4. Multi-scale simulation and prediction of the drug safety problems related with hERG

Lead: IMIM, This e-mail address is being protected from spambots. You need JavaScript enabled to view it

URL: http://multiscalelab.org/VPH

An important field of application of the VPH concept is the drug development process since multi-scale simulations can be extremely useful for the understanding of the physiological mechanisms related with the therapeutic efficacy of the drugs, as well as with their adverse events (drug safety problems). In order to get useful in-silico predictions of the efficacy and safety of drugs, we require computational models that have to be sensitive to the differential molecular characteristics of the drugs, which, on the other hand, have to be coupled with models simulating the biological system or organ in which the therapeutic effectiveness or adverse events are observed. The hERG-related cardiac adverse effects of drugs are a paradigmatic example of this approach. Although other potential targets for cardiac adverse effects exist, the vast majority of drugs associated with pathological prolongations of the QT segment of the electrocardiogram are known to interact with the hERG potassium channel. The differential interaction of series of drugs under development with the hERG potassium channel can be simulated at the molecular scale by means of atomistic simulations coupled to drug discovery tools based on quantitative structure activity relationships. In this way one will be able to obtain quantitative predictions of electrophysiological parameters of each drug that could be used in both mesoscopic simulations dealing with macromolecular behaviour of the channels and, more importantly, macroscopic electromechanical simulations of the hearth with the aim of predicting the change in the QT segment generated by the drugs under study.

This approach will be based on tools developed in several projects that are focused on the multiscale processes modelling and their computational implementation (PS3Grid and EC-STREP QosCosGrid) as well as on the translational research aspects of such a multilevel problem (EC-STREP BioBridge). This seed EP will aim at integrating existing software tools dealing with the several levels of complexity of the QT elongation. The expected outcome of the next step will be the standarisation of formats for easy integration of simulation scales and the computational implementation of the different levels of detail.

5. Digital Patient Working Group: Modelling and visualising brain function and pathophysiology

Lead: DPWG/FORTH, This e-mail address is being protected from spambots. You need JavaScript enabled to view it

The ERCIM project models brain function based on clinical data in order to better understand the causality of brain diseases such as epilepsy, dementia, schizophrenia, and alcoholism. At the first functional level, linear and nonlinear synchronisation methods are applied to study neuronal dynamics. The latter have been increasingly recognised to be an important mechanism by which specialised cortical and sub-cortical regions integrate their activity to form distributed neuronal assemblies that function in a cooperative manner. Synchronous oscillations of certain types of such assemblies in different frequency bands relate to different perceptual, motor or cognitive states and may be indicative of a wider range of cognitive functions or brain pathologies. At a second level, source estimation models and graph theoretic measures will be applied to better describe and understand the functional characteristics of brain networks.

The project also investigates brain tumours (especially glioblastoma) and normal brain tissue behaviour at the cellular and higher levels of biocomplexity. Such models will be individualised, therefore requiring pertinent image analysis, data processing and visualisation techniques in order to extract the necessary information, which will be the input to the cancer simulator. In particular, image analysis tasks (such as image registration fusion, segmentation, etc) will be applied in different scales (e.g. tissue 3DMRI images, microarray data, etc). Most of these activities are already being funded (e.g. ACGT for simulation tasks, BIOP ATTERN NoE for Brain Disorders). FORTH is additionally investing its own funds to brain network visualisation algorithms (and relevant clinical applications) development, etc. Significant progress has been made in the action lines mentioned both in R&D (cancer simulation has already gained significant attention and respect within ACGT and the EC), as well as in the purely scientific/academic area (e.g., a number of papers demonstrating the clinical value of brain networks to understand and model function, microarray analysis, etc.).

As a seed EP, functional modelling of the brain will require certain VPH ToolKit elements that are already generically described in WP3. However, some "fine-tuning" will be needed in order to meet the brain's specific needs. What will be needed from the VPH ToolKit includes: web-accessible repositories for data, annotations, patient information etc.; the DICOM waveform standard; model solutions to the inverse or forward brain source localisation problems; patient-specific customisation of models; data fitting; and GUIs specifically tailored to visualise causal and functional relations between different brain lobes. As an added value, the VPH NoE through this EP will also address the CNS (central nervous system).

6. Establishing ontology-based methods for the VPH ToolKit to improve interoperability between data and models: the Guyton case study

Lead: EBI Cambridge, This e-mail address is being protected from spambots. You need JavaScript enabled to view it

This Exemplar Project will investigate an interoperability framework for physiology models and gene expression data. In particular, this EP sets out to achieve the following goals:

i) the design and implementation of representational classes for the annotation of anatomy and physics in physiology model parameters and gene expression data;

ii) the demonstration and verification of such an approach via the annotation of (a) the parameters of a classic model that represents blood pressure regulation (namely, the Guyton model), implemented in the SAPHIR project (from the VPH NoE seedEP1) and marked up in the CellML repository, as well as (b) related human gene expression datasets in ArrayExpress that correspond to the anatomical locations these parameters address;

iii) the contribution of the outcomes of this work to the VPH toolkit effort, as a reference example of the role of a communal anatomical and physics framework for resource interoperability.

7. CIGENE: Integrating genetic theory and genomic data with multiscale models in a population context

Coordinator: Stig Omholt, Norwegian University of Life Sciences

Partners: University of Auckland, King’s College London

One of the central goals of the VPH is to link genotype to phenotype through multiscale models of physiological structure and function, at the levels of cells, tissues, organs and organ systems. The vertical integration is a major challenge, from both ends of the spectrum. Given the serious challenges for the effectiveness of genome-wide association studies (GWAS) for drug development, and since mathematical models represent a rigorous compendium of the knowledge about biological processes at many scales, the time is ripe to begin using them as a platform for multi-parametric in silico studies aimed at understanding the functional implications of genome-level perturbations, i.e., to work towards modelling-based genome-to-phenotype maps.

The group of Stig Omholt in Norway has been moving in this direction for the last several years. They call it "causally cohesive genotype-phenotype (cGP) models" (Rajasingh et al. 2008),  and they will now, in the context of an NoE Exemplar Project, team up with Universities of Auckland and Oxford to connect genetic information with multiscale and multiphysics models in a population context, with specific application to dynamic multiscale modelling of the heart.

In a well-validated multiscale model describing one or more phenotypic features and capable of accounting for observed variation in a population, the effects of genetic and environmental variability on the phenotypic features are manifested in the parametric variations of the model. To the extent that model parameters represent phenotypes, the phenotypic variation that emerges from a multiscale model when its parameters are varied is an in silico manifestation of how lower-level phenotypic variation causally contributes to higher-level phenotypic variation; a deep enough sensitivity analysis of the model will provide valuable insight into how this lower-level variation percolates up to the higher level. By producing large populations of "virtual individuals" through randomization of selected parameter values, the models thus become a testbed for the possible roles of low-level parameters (e.g., cell- or molecular-level phenotypes affected directly by genetic variation) in determining high-level physiological behavior. Since the in silico models are not subject to the same limitations facing experimental models such as mice, the two could be combined in a powerful new approach.  The modeling could thus serve as a companion and guide to directed GWA studies, in which the contributions of individual genetic variants all too often seem to contribute little to macro phenotypic variation. This EP will explore this new territory.

8. USFD: The NoE, Infrastructure and the Challenge of Call6

Coordinator: John Fenner, University of Sheffield (UK)

Partners: University College London, Universitat Pompeu Fabra (Spain)

The sustainability of the VPH vision beyond the lifespan of the NoE clearly will depend on the establishment of a robust data infrastructure and digital repository. While it may be argued that examples of such an infrastructure exist in other fields (e.g. high energy physics), the special problems faced in biomedicine, not only technical but also ethical and legal, represent a daunting challenge. The EC recognises this, and has consequently incorporated it as a focus of FP7 Call 6, announced last spring.

Given the role of the VPH NoE to orchestrate the interactions and cooperation among the various VPH-Initiative projects, it was logical to select the Sheffield proposal as an Exemplar Project, to give the NoE a voice in important infrastructure decisions.

The stated objective of this EP is the "development of infrastructure for the NoE, based on consultation with the VPH Initiative [VPH-I], ultimately leading to implementation of a federated Distributed File System (DFS) and a pilot demonstrator." The project will follow a three-fold plan of action to:

• Characterise candidate technologies of the infrastructure landscape, complemented by an infrastructure platform appropriate to the NoE, demonstrated through interaction with a VPH-I project;
• Characterise the architectures, infrastructure needs and workflow tools of the VPH-I and engage with wider infrastructure interests beyond the VPH-I; and
  • Engage in discussion with infrastructure protagonists to deliver a coherent and authoritative message that can influence strategies for VPH infrastructure implementation under Call 6.

The team at Sheffield has already made progress towards these goals, demonstrated in a report submitted a little over one month after hiring their EP postdoc. The requirements of an adequate Data Hosting Environment (DHE) have been proposed, they are conducting an extensive survey of the landscape, and they have identified key technologies capable of supporting these requirements and their suitability, strengths and weaknesses. Since no single solution may serve the NoE, they are also undertaking a performance benchmark of the systems under consideration, with the results included in an infrastructure report.

9. VIP for VPH : Execution of medical image simulation workflows on DEISA through workflow interoperability between the Virtual Imaging Platform and the VPH toolkit

Coordinator: Denis Friboulet, CNRS Créatis, Lyon

Partner: University College London

The main motivation behind EP9, "VIP for VPH", was to offer imaging scientists a convenient mechanism to access the DEISA High- Performance Computing (HPC) resources and to ensure the sustainability of image simulation workflows beyond a particular computing infrastructure and workflow technology. To this end, they will build on workflow interoperability solutions. This EP is backed by a national French ANR project and by partnership in the EU SHIWA project ("SHaring Interoperable Workflows for large-scale scientific simulations on Available DCIs"), whose purpose is to leverage existing workflow-based solutions and enable cross-workflow and inter-workflow exploitation of DCIs (Distributed Computing Infrastructures) by applying both coarse- and fine-grained strategies (http://shiwa-workflow.eu).

for further details on EP9 please visit the dedicated website

10. "Environment for Sexually Transmitted Infection Modeling"

Coordinator: Martin Nelson, University of Nottingham, Centre for Mathematical Medicine & Biology

Partners: Queensland University of Technology, Australia.; Norwegian University of Science & Technology,Trondheim, Norway; Chlamydia Research Group, Arkansas Children’s Hospital Research Institute, Little Rock, Arkansas,USA

EP10 is developing an environment for mathematical/computational modeling of sexually transmitted infections (STIs). As a representative case study, the project focuses on mark-up and simulation of three existing “within-host” models of Chlamydia trachomatis infection – the most common sexually transmitted pathogen of humans, with over 90 million new adult cases occurring worldwide each year. These models deploy multiscale approaches to describe the spatial progression of C. trachomatis infection in the female genital tract, coupling a continuum description of extracellular Chlamydial particle motion to cell-scale and tissue-scale models of infection of the genital epithelium. Model simulations will be compared to experimental data for Chlamydia caviae infection in guinea pigs, a bacterial infection highly representative of C. trachomatis infection in humans. The study will demonstrate application of existing VPH toolkit software to the reproductive system, with a focus placed upon demonstrating the interoperability of tools across different spatial scales. While a focus upon C. trachomatis is proposed, the modeling approach should be extensible to other STIs, including gonorrhea and syphilis. The project will develop a computational tool for simulation of a range of STIs, coding each component of the proposed models independently to facilitate future uptake in the study of other infections. This STI modeling environment will facilitate efficient comparison of models and results, and will be deployable in identification of suitable vaccines.

11: "Vascular Tissue Modeling Environment (VTME)"

Coordinator: Markus Owen, University of Nottingham

Partners: Oxford University; CRM, Barcelona; Charité, Berlin; Physiology, U of Arizona, Tucson; Textensor Ltd., Edinburgh; Arizona State, Tempe; Neuroscience, Physiol. & Pharmacol, UCL

Throughout life, almost all tissues require a blood supply to deliver nutrients and remove waste products. Problems with blood vessel development can lead to severe birth defects. Later, vascular growth and remodeling play a key role in pathologies including diabetes, macular degeneration and rheumatoid arthritis. In addition, tumor growth is crucially dependent on the host blood supply, and this has made the vascular system a major target for anti-cancer therapies. These features make patient-specific computer models of vascular tissues a natural target for the VPH. Over a number of years a multiscale model for vascular tissues has been developed by the EP11 team as part of projects funded by the EU (FP5, FP6), the UK (BBSRC, EPSRC), German (BMBF) and US (NCI/NIH) research councils. The model combines (A) fluid flow in a vessel network; (B) PDEs for the transport, release and uptake of diffusible substances such as oxygen; (C) cell division and reinforced random walks of cells on a regular lattice; (D) ODEs for subcellular networks that regulate the cell cycle and growth factors such as VEGF; and (E) integration of angiogenic and vasculogenic endothelial cells into the vascular network. The model (Owen et al. 2011, Cancer Research 71(8); Perfahl et al. 2011, PLoS ONE 6(4)) is at a stage of maturity that makes it ideal for a VPH NoE Exemplar Project, in order to reinforce these developments, and to enable re-use, integration and sharing of the model and relevant data.

EP11 will implement a user-friendly Vascular Tissue Modeling Environment (VTME) within the "Cancer, Heart and Soft Tissue Environment" tool (CHASTE, http://web.comlab.ox.ac.uk/ chaste/), already part of the VPH ToolKit (http://toolkit.vph-noe.eu/). VTME will enable sustainable curation of published vascular tissue simulations within the Chaste environment. It will be standards-based and infrastructure-supportive, adopting existing standards where they exist (SBML, CellML, MIRIAM, MIASE), and contributing to the development of new VPH standards (e.g., for vascular networks).