No 8 SEPTEMBER 2012 VPH NoEnewsletternewsletter V IRTUAL P HYSIOLOGICAL H UMAN N ETWORK O F E XCELLENCE
A vision and strategy for the virtual physiological human P.6 What have we achieved so far? P.8 What are the biomedical science challenges? P.12 What are the healthcare challenges? P.17 What are the ICT challenges? P.21 A strategy for the VPH P.27 CONTENTS
Editorial 3
1. A vision and strategy for 6 the virtual physiological human
2. What have we achieved 8 2.1 Standards, tools and services so far? 2.2 Dissemination, training and outreach 2.3 International connections 2.4 VPH-I projects
3. What are the biomedical 12 3.1 The further inclusion of molecular systems biology science challenges? 3.2 Genomic networks – models and databases 3.3 Human metabolic networks – models and databases 3.4 Physiology – models and databases 3.5 Incorporation of ageing into multiscale and multiphysics models 3.6 The VPH as a potential platform for a new drug targeting paradigm 3.7 Phenomics technology – a new innovation arena for European industry?
4. What are the healthcare 17 4.1 The needs challenges? 4.2 Personalised, predictive and integrative healthcare and the ‘Digital Patient’ 4.3 Access to clinical data 4.4 EC regulatory policy 4.5 Impact analysis
5. What are the ICT 21 5.1 Model and data encoding standards: model reproducibility challenges? 5.2 The challenges of model reduction and multi-scale model integration 5.3 Dealing with probabilistic and stochastic processes 5.4 Convergence of image-based integrative prototyping frameworks 5.5 Multiscale simulation and visualization software 5.6 Supercomputing challenges 5.7 Informatics and “big-data” 5.8 Data security
6. A strategy for the VPH 27 6.1 The VPH Institute 6.2 VPH conference series 6.3 Training and dissemination 6.4 Timelines 6.5 The next steps 6.6 Towards a European VPH meta-infrastructure
Acknowledgements 33
References 33
Editor in Chief: Tara Chapman, Researcher, Faculty of Medicine, Université Libre de Bruxelles Production Chief: Katherine Fletcher, University of Oxford Conception & realisation: Photos: IStock / Angelhell, Caracterdesign, Comotion design, Cosmin 4000, Eraxion, Yakobchuk
2 VPHNoE VPH NoE EDITORIAL
The VPH Network of Excellence is close to completing In this eighth and final issue of the VPH NoE newsletter four successful years of achievements and I am delighted we’d like to look at some of the achievements of the project. to announce that the VPH NoE has been granted a six-month The project and its partners have been involved in a total of extension until March 2013. The VPH NoE was set up eight hundred and fifty-three events over the last four years with ‘service to the community of VPH researchers’ as its promoting the concept of the VPH. VPH2012 is the second primary purpose: we believe that our efforts in the creation in the series of international VPH conferences organized by of the VPH NoE ToolKit, the implementation of VPH study the VPH NoE, and is supported by the European Commis- groups, educational meetings and training events, clinic- sion ICT for Health / DG Information Society and Media. We and industry-orientated events and the creation of the VPH are pleased to have four keynote speakers who are interna- conference series has come some way to achieving this tionally acclaimed leading experts in their respective fields: service. Professor Raimond Winslow, Professor Salvador Moncada, Professor Douglas Kell and Professor Hiroaki Kitano. This I would like to thank Tara Chapman for her exceptional year there will be an overall theme of integration of the VPH work as Editor in Chief of the newsletter over the VPH NoE projects with subthemes on: (1) Physiome: multiscale years. The VPH NoE newsletter has been an important way modelling of physiology and pathology; (2) Virtual in which the VPH NoE has connected with the VPH com- Physiological Human: infrastructures and technologies munity. We have given updates on news within the VPH for integrative biomedical research; (3) Systems NoE, highlighted events and provided updates on develop- Medicine/-omics and (4) VPH in Translation. We hope to see ments both within and outside the NoE relevant to the VPH as many of you as possible there! initiative. We featured interviews with leading internatio- nal experts, clinicians, researchers and industry personnel We have been extensively involved in education and trai- in VPH related fields. Each issue of the newsletter also fea- ning. Alongside the study groups, 2013 will see the release tured an update on Exemplar projects in the form of a of the ‘VPH Textbook’ which represents a major effort from ‘Technical report’ discussing their progress. a large number of contributors. In the final year, the VPH NoE will continue to work with AMEE in a major collabo- To look back at the history of the VPH NoE newsletter: the rative effort to deliver effective Virtual Patient teaching first issue highlighted the VPH NoE project and introduced materials. We have also produced a short video of the VPH some of the new VPH Initiative (VPH-I) projects from the and edited five special VPH dedicated issues in Phil. FP7 Virtual Physiological Human Call (ICT-2007.5.3.) Trans. R. Soc. A., and also several articles in newspapers, Issue 2 introduced the VPH NoE Exemplar projects and gave professional association newsletters and others. an update on SuperComputing, whilst issue 3 continued to update on the progress of the VPH-I projects. Issue 4 focused The VPH NoE newsletter and outreach activities have been on clinical trials with VPH-I projects and demonstrated fundamental in fostering the development of a VPH com- some of the new and exciting developments in the VPH munity, but what is the VPH without the necessary tools to field. Issue 5 was dedicated to the 50th anniversary of car- enable different software, built by different laboratories in diac modelling and saw contributions from some of the different universities, towns and countries all over the most promising groups in cardiac modelling. Issue 6 focu- world, to speak to each other? To achieve the aim of a truly sed on the new and exciting virtual physiological human ‘digital patient’ an infrastructure needed to be put in place. projects (Call ICT-2009.5.3) and issue 7 focused on the The VPH NoE has worked hard throughout its lifetime to E-infrastructure for the Virtual Physiological Human whilst create such an infrastructure. The VPH Toolkit is a shared continuing to highlight new projects. and mutually accessible source of tools, research equip-
VPHNoE 3 ment, managerial and research infrastructures, facilities and I would like to thank all the partners of the VPH NoE for services. A great deal of effort has made throughout the VPH their dedication throughout the lifetime of the project. I NoE on building internal – and capturing external – ToolKit would like to thank Joel Bacquet , former VPH NoE project materials to maximise the availability of software resources officer, for his hard work and enthusiasm that was funda- to the VPH community. There were eleven Exemplar pro- mental to the success of the project and to our current jects set up with the VPH NoE to work closely with the VPH project officer, Amalia Vlad for her continuing support. I ToolKit. These individual projects have met with conside- would also like to thank Miriam Mendes (project co-ordina- rable success during the lifetime of the project and tor) and Vanessa Diaz (technical co-ordinator) who have presentations from nine of these projects will take place at brilliantly succeeded in steering the network of excellence. the forthcoming VPH2012 (www.vph-noe.eu/vph2012). I would also like to thank you, the VPH community for your continued support and wish you good luck in all your future We recognise that there needs to be a continuation of the endeavours. knowledge and resources built up after the lifetime of the project. To this end we have been working hard to create a By Peter Coveney, VPH Portal. The portal will house the ToolKit and aims to VPH NoE Project Coordinator be the future source of all VPH resources. This portal will be run by the VPH NoE during its lifetime and will then trans- fer to the VPH Institute. The Virtual Physiological Human (VPH) Institute for Integrative Biomedical Research (or VPH Institute) is an international non-profit organisation, whose mission is to ensure that the Virtual Physiological Human is fully realised, universally adopted, and effectively used both in research and in clinic. The VPH institute will take over from the VPH NoE in many respects, including the running of the VPH conference series and the management of the VPH Portal after the VPH NoE has finished.
The VPH Network of Excellence as a project will end, but its legacy will certainly remain. This legacy includes a roadmap for the future of the field. The ‘VPH Vision and Strategy Paper’ has been coordinated by Prof Peter Hunter and is the combined result of continued input from consultation with VPH projects, experts in relevant fields and yearly strategic consultation public meetings. A previous version of the VPH NoE Roadmap/Vision and & Strategy Paper was edited and published in May 2010 in Phil. Trans. R. Soc., ‘A vision and strategy for the virtual physiological human in 2010 and beyond’ by Hunter et al. Most notably, it was one of the most cited papers of the journal in 2010*. For this final issue it is therefore fitting and appro- priate that this document should be published in the last VPH NoE newsletter.
*http://rsta.royalsocietypublishing.org/site/misc/top_ten.xhtml.
4 VPHNoE VPH NoE
A VISION AND STRATEGY FOR THE VIRTUAL PHYSIOLOGICAL HUMAN
Peter Hunter1,2,*, Tara Chapman3, Peter V. Coveney4, Bernard de Bono5, Vanessa Diaz6, John Fenner7, Alejandro F. Frangi8,9,10,11, Peter Harris12, Rod Hose7, Peter Kohl13,14, Pat Lawford7, Keith McCormack7, Miriam Mendes4, Stig Omholt15, Alfio Quarteroni16,17, Nour Shublaq4, John Skår18, Karl Stroetmann19, Jesper Tegner20, S. Randall Thomas21,22, Ioannis Tollis23,25, Ioannis Tsamardinos24,25, Johannes HGM van Beek26 and Marco Viceconti11,27
1 Department of Physiology, Anatomy & Genetics, University of Oxford, UK 2 Auckland Bioengineering Institute (ABI), University of Auckland, New Zealand 3 Laboratory of Anatomy, Biomechanics and Organogenesis, Faculty of Medicine, Université Libre de Bruxelles, Belgium 4 Centre for Computational Science, University College London, UK 5 European Bioinformatics Institute, European Molecular Biology Laboratory, Cambridge, UK 6 Department of Mechanical Engineering, University College London, UK 7 Department Cardiovascular Science (Medical Physics Group), Faculty of Medicine, Dentistry and Health, University of Sheffield, Sheffield, UK 8 Center for Computational Imaging & Simulation Technologies in Biomedicine (CISTIB), Universitat Pompeu Fabra, Barcelona, Spain 9 Networking Biomedical Research Center on Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Barcelona, Spain 10 Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain 11 Department of Mechanical Engineering, University of Sheffield, Sheffield, UK 12 Department of Physiology, Faculty of Medicine, Dentistry and Health Sciences, The University of Melbourne, Australia 13 National Heart and Lung Institute, Imperial College, London, UK 14 Department of Computer Science, University of Oxford, Oxford, UK 15 Centre for Integrative Genetics, Department of Animal Science, Norwegian University of Life Sciences, Norway 16 Ecole Polytechnique Fédérale de Lausanne, Switzerland 17 Politecnico di Milano, Milan, Italy 18 Department LIME, Karolinska Institutet, Stockholm, Sweden 19 empirica Communication & Technology Research, Bonn, Germany 20 Department of Medicine, Unit for Computational Medicine, Center for Molecular Medicine, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden 21 IR4M CNRS UMR8081, Institut Gustave-Roussy, Dept Imagerie/Echographie, Orsay, France 22 Université Paris-Sud, CNRS, Orsay, France 23 Computational Medicine Laboratory, Institute of Computer Science, Foundation for Research and Technology (FORTH), Hellas 24 Bioinformatics Laboratory, Institute of Computer Science, Foundation for Research and Technology (FORTH), Hellas 25 Computer Science Department, University of Crete, Greece 26 Section Medical Genomics, Department of Clinical Genetics, VU University Medical Centre, Amsterdam, The Netherlands 27 Laboratorio di Tecnologia Medica, Istituto Ortopedico Rizzoli, Bologna, Italy
SUMMARY
European funding under Framework 7 (FP7) for the Virtual Physiological Human (VPH) project has been in place now for five years. The VPH Network of Excellence (NoE) has been set up to help develop common standards, open source software, freely accessible data and model repositories, and various training and dissemination activities for the project. It is also wor- king to coordinate the many clinically targeted projects that have been funded under the FP7 calls. An initial vision for the VPH was defined by the FP6 STEP project in 2006 [6]. In 2010 we wrote an assessment of the accomplishments of the first two years of the VPH in which we considered the biomedical science, healthcare and ICT challenges facing the project [9]. We proposed that a not-for-profit professional umbrella organisation, the VPH Institute, should be established as a means of sus- taining the VPH vision beyond the time-frame of the NoE. Here we update and extend this assessment and in particular address the following issues raised in response to [9]: (i) a vision for the VPH updated in the light of progress made so far, (ii) biomedical science and healthcare challenges that the VPH initiative can address while also providing innovation opportu- nities for European industry, and (iii) external changes needed in regulatory policy and business models to realise the full potential that the VPH has to offer to industry, clinics and society generally.
KEYWORDS
Virtual physiological human, physiome, computational physiology, systems biology, multi-scale modelling.
*Author for correspondence ([email protected]).
VPHNoE 5 1.A VISION AND STRATEGY FOR THE VIRTUAL PHYSIOLOGICAL HUMAN
pecialisation, in both clinical putational modelling of the human patient’s condition across multiple and scientific practice, has sup- body and physiology is poised to revo- organ systems and length scales, and S ported the most rapid growth in lutionise 21st century bioscience by across time and environment. This is medical knowledge ever known. Yet fundamentally shifting the basis for the the vision for future patient care that drug discoveries are faltering, health- diagnosis and treatment of disease. drives the personalised Virtual Physio- care budgets are unsustainable and Medical innovation should therefore logical Human (VPH) project. patients are sometimes falling between now be directed towards optimising the cracks of medical specialists who treatments using integrated functional The Physiome, Systems Biology, the cannot treat the patient holistically. simulation in silico, assembling a cus- Virtual Physiological Human, Personal Meanwhile, biophysically-based com- tomised computer model of the Health Systems, Biomedical Informa-
6 VPHNoE VPH NoE
tics, Life Science e-Infrastructures, Sys- complexities are significant, not least tomy and function at the cell, tissue tems Pharmacology; these domains in areas of privacy and security; a few and organ levels. share one issue: the need for integra- examples of the consequences of buil- tion. To implement the outputs of ding the Digital Patient expose the The success of this opportunity is biomedical research in clinical practice complexities: highly dependent on the development, and within the healthcare industry, we • Biomedical professionals require adoption and integration of ICT and need to integrate data, information, approved secure access to my per- eHealth infrastructures throughout knowledge and wisdom. As in [21] we sonal data, routinely and in Europe [21], and on the coordination of need to integrate emergencies; this effort with other related interna- • Data for the same patient stored • My wearable and implanted techno- tional initiatives such as the IUPS4 across different systems, across diffe- logy must update my Digital Patient Physiome Project. The NoE is concer- rent hospitals, across different mem- routinely with status data; ned primarily with ICT infrastructure, ber states and in clinical research da- • An alarming event, detected by coordination and training, and the tabases [19]; device or Digital Patient computa- VPH-I projects themselves are prima- • Patient-specific knowledge with tion, must inform me, my family and rily focused on developing and domain-specific knowledge; friends, and my trusted healthcare implementing biophysically-based • Information related to various parts providers of the need for an inter- computational models into clinical and processes of the human body vention; environments via industrial partners. into a systemic understanding of • The infrastructure must support the The success of these endeavours is pathophysiology; collaboration of trusted specialists significantly dependent on the conti- • Knowledge digitally captured via around my complex systemic nued progress of biomedical science in metadata, ontologies and models in diseases; revealing the biophysical mechanisms order to respond to the combinatorial • Models must be able to employ the underlying structure and function at explosion of complexity that integra- totality of my data to predict the all spatial scales, and the continued tive research is producing; and future development of my health; development of the integrated struc- • Wisdom produced in the research • Models must be able to access a tures established by the VPH Initiative. laboratories and in clinical practice, wealth of anonymised reference data, which will be formalised in guide- routinely amassed from patients; A Roadmap5 for the VPH project was lines, standards and protocols and • My goals are fully self-aware lifestyle laid out in 2006 by the STEP coordina- used to promote translation of basic and health management, disease pre- ted action [6]. The outcome of the first science and integrative models into vention, and optimised intervention FP7 VPH funding round in 2007 (Call healthcare benefits. at any time. 2) was the VPH Network of Excellence, The FP7 VPH Network of Excellence is three Integrated Projects (IPs), nine Our vision for the VPH/Physiome ini- addressing these challenges by promo- Specific Targeted Research Projects tiative is therefore: ting and facilitating the use of (STREPs) and two Cooperative Actions • To establish an ICT1 and computa- computational models, software tools (CAs), all of which formed the initial tional science framework for digital, and web services, and this work is core of the European VPH Initiative personalised, predictive medicine. being extended and exemplified by the (VPH-I). The second and third funding • To link discoveries in molecular bio- FP7 Call 6 Infrastructure projects rounds (Calls 4 & 6) added four more logy with clinical imaging and other P-MEDICINE2 and VPH-Share3, which IPs and six more STREPs, and Call 9 is technologies using computational are developing frameworks under about to introduce a further series of physiology, based on the mathemati- which the VPH community can projects. With nearly six years of expe- cal and engineering sciences. streamline developments. Stability and rience behind us, and with Horizon • To link genotype to phenotype for overarching authority has been added 2020 taking shape, it is time to assess humans and other animals through to the initiative with the establishment our achievements and plan for the anatomical and biophysical multis- of the VPH Institute, an international short, medium and long term future of cale models of physiological structure non-profit body whose mission is to the VPH. ■ and function, at the levels of proteins, ensure that the Virtual Physiological cells, tissues, organs and systems. Human is fully realised, universally adopted, and effectively used both in The concept of a fully-informed ‘Digi- research and clinical practice. In ano- tal Patient’, maintained with each ther significant move the biomedical person’s current healthcare data, is community has now adopted a new powerful and compelling, and in mee- model for data standards and a com- ting the challenge of its design we will mon set of reference ontologies with make a significant impact on the lives which to understand genotype-pheno- of our citizens and on the economy. Yet type relationships by linking databases the range of application means the of genetic and proteomic data to ana-
1 Information & Communications Technology 2 http://www.vph-noe.eu/vph-projects/74-eu-fp7-vph-projects/502-p-medicine 3 http://www.vph-noe.eu/vph-projects/74-eu-fp7-vph-projects/506-vph-share 4 International Union of Physiological Sciences. 5 http://www.europhysiome.org/roadmap
VPHNoE 7 2.WHAT HAVE WE ACHIEVED SO FAR?
he importance of establishing a top priority targets. These goals are dis- NoE ToolKit [7,15]). Most content of the solid foundation for the VPH by cussed below, along with proposals for NoE ToolKit is open source. More Tcreating model and data standards, the identification and use of additional recently, the NoE’s preoccupation with together with mechanisms for achieving resources and engagement needed to standards has precipitated support for model reproducibility and reuse, was establish digital, personalised, and pre- high quality ToolKit submissions. This recognised in the STEP Roadmap. This, dictive medicine in Europe. has involved the development of forma- together with the development of plans lised, ‘best practise’ guidelines. These for dissemination, training and outreach 2.1 Standards, tools and services outline the nature of 'desirable’ ToolKit to the communities of researchers, phy- content, encouraging submissions that sicians, patients, students, industry and The first stage of the NoE project was lar- offer maximum utility to the end user. the public in general, was the primary gely concerned with recognising the Currently, eight guidelines have been focus for the first year of the NoE. Direct need and establishing standards for released and demonstrate the breadth of engagement with the other VPH projects models and data, as well as building interests pursued within the NoE. Their and clear examples of how standards- model and data repositories for publi- titles are: based models, software tools and web shed models, and assembling a toolbox based services can be used to facilitate of existing software programmes that are • Tool Characterisation clinical outcomes, have now become the relevant to the VPH (known as the VPH- • Model Characterisation
8 VPHNoE VPH NoE
• Data Characterisation Dissemination and training is therefore for on-line access focus on core VPH • Ontological Annotation a major responsibility and one that is topics including; multiscale and multi- • Interoperability being tailored separately for these physics modelling, data fusion/ • Ethico-Legal and Provenance Issues various audiences. The initial focus for workflows, the role of experimental • Licensing the NoE was the website containing des- work in the VPH and ethical and pri- • Usability and Training criptions of the various VPH-I projects vacy considerations. and giving access to the VPH modelling An essential and urgent step identified in A high priority for the NoE is that all and data resources and training pro- the last Vision Document was the imple- efforts must be considered in the light of grams, suitable for the first target mentation of workshops and summer sustainability. The latter refers to community. The NoE website receives schools to train researchers in the use of mechanisms and strategies that enable 13,000 visits per month and the news- the VPH models and software. Such acti- the VPH to continue to profit from the letters, which mainly focus on the vities were recognised as an important legacy of the NoE, even beyond the offi- progress of VPH projects, are published part of a wider, pan-European process di- cial lifetime of the project. This at six monthly intervals, and continue to rected towards the introduction of syste- influences every corner of its activities. be well received by the VPH community. matic educational activities with the aim The production of the guideline docu- The average number of downloads for of ensuring that academia, medicine and ments is one example and the each electronic version is 2500. Interest industry throughout Europe have a work- sustainability of the NoE model/data in the VPH continues to grow as eviden- force that is appropriately equipped to repositories is another. This denotes ced by the successful VPH-Industry Day meet the possibilities offered by this new transitional mechanisms that have been hosted in Barcelona in September 2010, and important discipline. This initiative negotiated and are currently being put and the VPH2010 conference in Brussels is well in line with the EU agenda for re- in place, to secure the longevity of the also in September 2010, The conference search and growth. The European level model/data repositories that have been was the first of a series of scientific mee- document6 Europe 2020 “A strategy for nurtured within the NoE. Links with tings intended to be held every two smart, sustainable and inclusive growth” FP7 Call6 infrastructure projects have years to showcase the best of VPH indicates the need to generate not just proven particularly productive in this research with a clear remit to reach excellent convergent scientists but scien- regard. Population of these repositories junior VPH-related researchers and tists who are flexible, who can work on continues to be an explicit outreach those from neighbouring knowledge different problems at different stages in function of the NoE, overseen by wor- fields. There are new, developing, colla- their careers and who can move easily king groups from partners responsible borations with other communities such between sectors. Also, according to the for the ToolKit. This is an inclusive exer- as the International Association for document7 ‘An Agenda for new skills cise that forages beyond the badged VPH Medical Education (AMEE). and jobs: A European contribution to- projects to include globally sourced bio- wards full employment’, serious deficits medical tools and data (eg. BIRN, JSim Training remains a fundamental part of in qualified professionals, in management etc). This expands the ToolKit, and also the dissemination strategy, where the and technical, job-specific skills are ham- helps to forge wider VPH/Physiome col- VPH NoE will target young and expe- pering Europe’s sustainable growth ob- laborations. Complementary to this rienced researchers alike. VPH training jectives with shortages in areas critical for effort, is development and support for should be embedded in basic and innovation, in particular Science, Tech- workflows. Links between the NoE and applied research methods courses for nology, Engineering and Mathematics. the FP7 Call6 infrastructure projects are higher degree students and as part of An additional 1 million researchers are key to the success of these activities. informatics education and training for needed to meet the EU ambition to esta- the healthcare workforce. The impor- blish an Innovation Union. Many of these Finally, a specific strand of effort tant contribution that education and scientists will be engaging with biological addresses training and dissemination, training can make in the context of the and medical research. Two study groups which is particularly important if the long-term sustainability of the VPH has and one workshop have been success- reach of the ToolKit and its contents is to been recognised by the VPH Commu- fully convened and a third study group is be maximised. Here a fresh cooperation nity, leading to a number of successful planned for mid-2012. In study groups, with the education community is pro- initiatives. For example, a consortium individuals (including clinicians) with ving valuable, and details of this area are of core and associate VPH NoE partners different levels of experience and types of presented more fully below. have secured external funding, under expertise, focus on a collective problem. the ERASMUS life-long learning pro- In contrast, the workshop brought toge- 2.2 Dissemination, training and gramme (LLP), to develop joint ther modellers and tool developers to ad- outreach educational resources for generic VPH dress interoperability and strategies for activities. This project, the VPH Masters combining models developed by diffe- Many communities will benefit from the Initiative Programme (VPH-MIP), will rent groups. VPH, including: in the short term, bio- extend beyond the life-time of the NoE medical researchers and students; in the and it is envisaged that students will Aside from training initiatives many medium term, healthcare workers and access the educational materials deve- other efforts are contributing to the for- European industry; and, in the longer loped as part of a VPH community mation of the VPH community: the Bio- term, patients and the general public. resource. Modules under development medTown on-line community, which
6 http://ec.europa.eu/europe2020/index_en.htm 7 http://ec.europa.eu/education/news/news2675_en.htm
VPHNoE 9 hosted the consensus process of the STEP of the VPH-I projects have international embryonic stage of the Toolkit, it is clear action, now has 2000 members. Also, the partners and the NoE itself has ‘Interna- that the community is nurturing a larger VPH projects are contributing to the tional General Members’. This formal wealth of potentially powerful and rele- dissemination of the VPH vision. In ad- recognition of international membership vant tools (e.g. [26,29]). The Toolkit dition to their project web sites, projects is also important for VPH-linked co-fun- portal - in conjunction with its require- like preDICT, VPHOP or euHEART are - ding arrangements in countries outside ment to annotate content with limited or have been during their tenure - publi- Europe. The five ‘International Coopera- metadata - can usefully bring some order shing periodic newsletters that reach tion projects’ funded under VPH are; and structure into this collection, with thousands of stakeholders worldwide. RICORDO, TUMOR, NMS, Sim-e-Child the NoE clarifying direction and recom- and MSV (see below under VPH-I pro- mending strategies that promote Industry outreach has been facilitated jects for further details). The ARGOS interoperability and sustainability. by the joint activities of the VPH com- project, to promote common methods for munity with the Pistoia Alliance, a responding to global eHealth challenges Example tools range from software for 45-member organisation conceived by in the EU and the US14, is another oppor- data exchange (e.g. ArchFTP client) to informatics experts at AstraZeneca, tunity to encourage US input to the VPH physiological modelling (e.g. the GSK, Novartis, and Pfizer to lower bar- as well as VPH input to IMAG [28]. euHeart software framework) and also riers to innovation by improving the include database and analysis support. interoperability of R&D business pro- 2.4 VPH-I projects Many imaging related tools are being cesses through precompetitive developed, which reflects the impor- collaboration. The VPH NoE co-organi- The goals of the current 30 VPH projects tance of imaging to the VPH community, sed a very well attended workshop on (not including the VPH Network of but perhaps, also increases the danger of biomedical data and model interopera- Excellence) are summarised briefly overlapping functionality. Standards are bility at the Sanger Centre in Hinxton below. There are major technological still not widely adopted, but at least they on the 28-29 March 2011 with the Pis- achievements in various areas, inclu- are in evidence, from the use of XML to toia Alliance in collaboration with the ding: data collection, management and structure data (e.g. HAMAM) to the use Innovative Medicines Initiative8 (IMI), integration; processing and curation of of CellML/FieldML/SBML in the model- and Computational Modeling in Biology data; reductionist and integrative model- ling work. Also, there appears to be Network9 (COMBINE) communities. ling of pathophysiological processes; active uptake of underpinning techno- presentation, deployment and end-user logy frameworks like MAF15, GIMIAS16, 2.3 International connections applications. It is also notable that there ITK17, VTK18, CMGUI19 and OpenC- is already an active involvement of com- MISS20. Deployment of these tools helps Internationally, the WIRI agreement10 panies participating in VPH consortia, to consolidate the respective user com- and the Osaka Accord11 have established both at the level of SME and large corpo- munities, accelerates tool development a worldwide agenda for physiome rations, and that the involvement is and encourages standardisation. Some research under the patronage of the Euro- moving from their R&D departments to of these frameworks, although initiated pean VPH initiative and the IUPS their strategic management as the first before the VPH-I was started, are being Physiome Project [10,11,14,30]. Other business scenarios emerge. Clinical part- actively adopted and used in running important recent events have been the ners are providing a vital contribution to VPH-I projects (e.g. MAF in VPHOP, participation of a European delegation at many of the VPH projects, participating MSV and NMS Physiome; GIMIAS, the IMAG12 symposium in Washington enthusiastically and with considerable CMGUI and OpenCMISS in euHeart, in 2010; the annual CellML meetings13 commitment. Note that the NoE advisory RICORDO, MSV and VPHShare; (2007-2012), and the Virtual Tissue board is now playing a more active role ITK/VTK underpinning both MAF and conference organised by the USA Envi- and provides a mechanism for generali- GIMIAS). ronmental Protection Agency and the sing the lessons learned from clinical European Commission in Spring 2009. partners of the individual VPH-I projects. Various centres of expertise are emer- These and similar earlier events have ging, focused around expert groups that been of considerable political relevance, The VPH-I projects have made signifi- can assist new users, helping those in and have strengthened the role of the cant contributions to the NoE Toolkit, difficulty and clarifying the merits of the European VPH community on the inter- providing a wide range of content rele- technologies to potentially interested national research scene. Note that many vant to the VPH community. Even at this parties. This might be considered a prag-
8 http://www.imi.europa.eu/ 9 http://sbml.org/Events/Forums/COMBINE_2010 10 http://www.biomedtown.org/biomed_town/LHDL/Reception/lhpnews/wiri 11 http://www.biomedtown.org/biomed_town/VPH/wiri/OsakaAccord 12 The Interagency Modelling and Analysis Group (IMAG) coordinates multi-scale modelling initiatives from various United States agencies including the National Institutes of Health, National Science Foundation, National Aeronautics and Space Administration, Department of Energy, Department of Defence, United States Department of Agriculture, and Unites States Department of Veteran Affairs. 13 http://www.cellml.org/community/events/workshop 14 http://argos.eurorec.org/ 15 http://www.biomedtown.org/biomed_town/MAF/Reception 16 http://www.gimias.org 17 http://www.itk.org 18 http://www.vtk.org 19 http://www.cmiss.org/cmgui 20 http://www.opencmiss.org
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matic approach to standardisation gineering multiscale modelling principles treatment decisions for an individual pa- because experts tend to offer opinions INTEGRATE (STREP) is developing tient by matching a patient’s individual that are necessarily biased towards data flexible infrastructure components and data with the injury’s characteristics formats that have been effective for their tools for data and knowledge sharing and THROMBUS (CA) is developing a quan- own use. Naturally, this encourages large-scale collaboration in biomedical titative model of thrombosis in intracra- uptake of a subset of available formats. research nial aneurisms MSV (STREP) is developing visualiza- TUMOR (STREP) is an interoperable, cli- The current VPH projects21 (listed here in tion of multiscale data through open- nically oriented, semantic-layered cancer alphabetical order) are targeted as follows: source extension to the visualization digital model repository toolkit (vtk) VIGOR++ (STREP) is about research and ACTION-Grid (CA) is promoting col- MySPINE (STREP) is establishing a pro- development of ICT tools for the analysis, laboration in medical/biomedical Infor- totype computing platform with a gra- modelling and simulation of human phy- matics and grid technologies to promote phical user interface for clinical settings siology and disease processes of the GI tract the interface between ICT and nano- and a patient-specific database of the VPH2 (STREP) is developing decision technology lumbar spine support tools for heart disease AirPROM (IP) is building an airway mo- NeoMARK (STREP) is implementing col- VPHOP (IP) is developing a patient-spe- del validated by omic data and ex vivo laborative research networks and tools cific, multiscale modelling framework models at the nome-transcriptome-cell- for the early detection of oral squamous for predicting osteoporotic fracture in el- tissue scale and by CT and functional cell carcinoma derly patients MRI imaging NMS Physiome (STREP) is a transconti- VPH-SHARE (IP) is developing of an or- ARCH (STREP) is developing clinical nent NeuroMusculoSkeletal physiome ganizational framework for the wides- decision support tools based on patient- activity in pursuit of personalized, pre- pread integration of VPH services specific predictive modelling of vascular dictive and integrative musculoskeletal Several other FP7 projects funded out- pathologies medicine side the VPH Call are very relevant to the ARTreat (IP) is developing an interven- PASSPORT is developing an open source VPH Initiative and involve close colla- tional decision support system for sten- multiscale framework for diagnostics and borations with VPH researchers: ting procedures based on multiscale pa- surgical training in the liver, based on mo- EUDAT – is working to develop a per- tient specific models of atherosclerotic delling liver cell regeneration sistent data storage infrastructure for Eu- disease p-Medicine (IP) is creating an infrastruc- ropean researchers CONTRACANCRUM (STREP), now ture that will facilitate the translation from CRESTA – brings together supercompu- completed, used multiscale modelling current practice to personalized medi- ting centres, vendors, software providers techniques to simulate patient specific cine. The project is designed to bring VPH and researchers to address the challenges cancer treatment outcomes methods to three sets of clinical trials trea- on the path to exascale computing euHeart (IP) is developing open source ting various cancers (leukaemia, breast ITFoM – is a proposed FET (Future and codes and multiscale/multi-physics mo- cancer, Wilm’s tumour) Emerging Technologies) initiative to de- dels of heart electromechanics for clini- preDiCT (STREP) is developing models velop a new ICT infrastructure to link cal cardiac diagnostic and device deve- of cardiac electrophysiology for drug des- bioinformatics at the genomic and pro- lopment applications ign and toxicity testing teomic scale to improved health care FUSIMO (STREP) is developing patient PredictAD (STREP) is developing an evi- specific modelling and simulation of fo- dence based statistical framework for Nearly all of these projects deal with chal- cused ultrasound in moving organs diagnosis of Alzheimer’s disease lenges relating to patient-specific, mul- GRANATUM (CA) is a social working RADICAL (CA) is investigating security tiscale modelling and the implementa- space semantically interlinking biome- and privacy issues for VPH applications tion of models and software in clinical dical researchers, knowledge and data and best practices for medical and gene- environments. A broader analysis of the for the design and execution of in-silico tic data protection in distributed envi- VPH-I indicates that strengths include si- models and experiments in cancer che- ronments mulation, data handling, scientific visua- moprevention RICORDO (STREP) aims to support VPH lisation (although not yet sufficiently HAMAM (STREP) is establishing a data- resource sharing by providing a seman- user-friendly in general) and an appre- base of curated and annotated imaging tic interoperability framework that links ciation of community. Previously identi- data and software tools for breast cancer physiology-related data and model re- fied limitations in ontology annotation diagnosis sources and inadequate infrastructure for the se- INBIOMEDVision (CA) aims to become a Sim-e-Child (STREP) is a grid-enabled cure and wider sharing of models and European-wide initiative intended to platform for large-scale simulations in data (authentication, authorisation etc) monitor the evolution of the Biomedical paediatric cardiology are being addressed, for example through Informatics field and address its scienti- SYNERGY (STREP) is a modelling and the RICORDO project. Similarly, the new fic challenges by means of collaborative simulation environment for systems me- VPH-Share project has particular rele- efforts performed by a broad group of dicine and decision support for clini- vance to the commercial and health sec- experts with complementary perspec- cians using chronic obstructive pulmo- tors of the VPH, both of which are vulne- tives on the field nary disease as a demonstration case rable to legal uncertainty (e.g. lack of IMPPACT (STREP) is developing mini- TBIcare (CA) is creating an objective and harmonization of EU law across member mally invasive, patient-specific treatment evidence-based solution for management states), evolving quality standards and strategies for liver cancer based on bioen- of TBI by improving diagnostics and inadequate provenance. ■
21 http://www.vph-noe.eu/vph-projects
VPHNoE 11 3.WHAT ARE THE BIOMEDICAL SCIENCE CHALLENGES?
he VPH project is achieving we must now instigate projects to fill genomic networks with multiscale important outcomes within the identified gaps in the necessary know- physiological models, such that one Tlifetime of the current NoE by how and infrastructure. can address and understand the geno- introducing computational modelling mic networks of complex diseases in a into the diagnosis and treatment of Many challenges in personalized medi- population context, defines a large and some diseases (with an initial emphasis cine reflect a lack of understanding of ambitious research topic that needs to on cardiovascular, orthopaedic and res- what is called the genotype-phenotype be given specific attention in the piratory diseases), but the real impact in map (GP map), i.e. the aggregated phe- coming years if personalized clinical the long term will be to transform notypic effects across different length treatments based on simulation studies healthcare into a more personalised, and time scales of different constella- that take into account the genetic pro- predictive, and preventative process tions of genetic networks, related file of the individual patient are to (see next section). The resources needed epigenetic information on the DNA, become a reality [22]. The biomedical to achieve this long term goal must be RNA and protein level, and the envi- genetics community is now facing realistically assessed and, in particular, ronment. The challenge of relating serious challenges concerning the overall
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applicability of the genome wide asso- lenge that awaits technological, concep- and also by the rapid improvement in ciation study (GWAS) approach when tual and methodological breakthroughs computing hardware performance that it comes to drug development and per- [8]. Only large-scale systematic and has enabled the new discipline of com- sonalized medicine. The VPH initiative concerted efforts by a wide range of putational physiology to emerge. This may be of substantial help by provi- scientific communities are capable of discipline invokes the mathematical ding mechanistic model descriptions realizing this vision. equations representing the conservation of the phenotypic effects originating laws of physics, themselves the great from genomic network variation. Such One major challenge is to account for the achievement of 19th century science and causally cohesive genotype- phenotype fact that age is the dominant risk factor on which, along with the law of evolu- (cGP) models are very advanced mul- for most complex diseases. The making tion, all life is based. Mathematics is the tiscale physiological models with an of multiscale physiological models cap- language of quantitative science and pre- explicit link to molecular information turing the ageing process defines a very dictive models based on biophysical and with the capacity to describe, for ambitious long-term theoretical-experi- principles are essential for understan- example, how genetic variation mani- mental research programme of vital ding complex phenomena. The fests in phenotypic variation at various importance to the VPH vision. equations, incorporating multiple cou- systemic levels up to the tissue, organ pled physical processes, are solved and whole-organism level. Further development and use of multis- numerically on anatomically realistic cale and multiphysics modelling as geometries with models that include To facilitate the construction of such envisioned above will be very much both tissue structure and the link to cel- models an important task is to identify dependent on the development of new lular function. As elsewhere, the key to and connect with other communities high-throughput phenotyping technolo- progress in the biomedical field is the who are already working on standards gies (phenomics). This provides a right combination of data-driven, phy- and data-repositories within their fields. tremendous opportunity window for sics-driven and computationally-driven This is most pressing for molecular data new innovations and subsequent Euro- science. The “bottom up” molecular sys- such as protein-protein interactions, pean industrial developments with a tems biology approach has been largely protein structure databases, gene expres- worldwide market potential. On the data-driven, while the “top down” com- sion and metabolic databases. New other hand, without guidance from mul- putational physiology has been largely technologies based on second and third tiscale models such technology physics-driven. These are complemen- generation sequencing instruments development and subsequent large-scale tary approaches and it is time they were (DNAseq, RNAseq, CHiPseq, etc) are phenotyping programmes will risk to more integrated. now producing terabytes of data. VPH become highly unfocused and unneces- models increasingly incorporate the sarily costly. This synergistic relation Most of the models being developed by signalling, metabolic and gene regula- between the VPH initiative and a new the VPH-I projects deal with struc- tory networks that underpin a innovation arena for European high-tech ture/function relations at the tissue, mechanistic explanation of physiologi- industry should be given attention organ or organ system level, with cal function at the molecular level. within Horizon 2020. applications primarily to clinical diag- Given the large role of signalling, meta- nosis, surgical planning and the bolism and gene regulation in human Below we discuss in more detail the development of medical devices. Some disease processes such as cancer, dia- challenges outlined above requiring spe- link to proteins - for example, pre- betes, neurodegeneration, heart failure, cific attention in the years to come. DICT22 examines the influence of etc, a description of these networks cardiac drugs on ion channel models, within multiscale VPH models is vital. 3.1 Further inclusion of and euHeart23 includes a number of To this end there are a number of active molecular systems biology cellular protein mechanisms in whole communities outside the VPH commu- heart models, but there is very little nity that possess experimental and The last 50 years have seen a revolution linkage to molecular systems biology theoretical competences of vital impor- in our understanding of the molecular in many of the VPH projects. The sys- tance, and it is important for scientific basis of life, much of it driven by the tems biology projects in Europe, on the advancement of the VPH vision to faci- development of new imaging and mea- other hand, are providing a compre- litate better communication with surement technologies. As molecular hensive data-driven framework for communities dealing with different data were accumulated in web-accessible understanding cellular physiology in types of data, from the molecular level databases, the new discipline of molecu- terms of signalling pathways, metabo- and up to the clinical level [10]. lar systems biology emerged to make lic networks and gene regulatory sense of the enormously complex inter- networks that are linked to molecular It should be acknowledged that gaining actions underpinning life [13,16]. These mechanisms. They seldom, however, a quantitative understanding of the phe- developments have been accompanied interpret these molecular pathways in notypic variation in humans as a by an equally important revolution in the context of structure-function rela- function of genes and environment in a our ability to image and measure physio- tions at the cell, tissue or organ level. mechanistic sense, i.e. understanding logical-scale structure and function with The first project that is attempting to the GP map, in both the explanatory and confocal microscopy, MRI, CT, PET and bridge this gap comprehensively is the predictive sense, is a tremendous chal- other such clinical imaging technologies, Virtual Liver Network24, funded by the
22 http://www.vph-noe.eu/vph-projects/74-eu-fp7-vph-projects/47-predict-strep 23 http://www.vph-noe.eu/vph-projects/74-eu-fp7-vph-projects/44-euheart-ip
VPHNoE 13 German Federal Ministry for Education sequencing technologies are currently metabolism are not separated but inter- and Research (BFBM), which is in the producing whole genome digital trans- act strongly, regulating each other. first year of a five year programme. criptomic data which also include Modelling human physiology requires splicing variants and non-coding RNA. not only consideration of the large meta- Integrating molecular systems biology At this level there is an abundance of bolic networks inside the cell, but also into the higher scale modelling has data about how different protein pro- the exchange of metabolites among always been the goal of the VPH/Phy- ducts, as well as non-coding RNA, can various cell types in a tissue (for ins- siome project but it is an enormously provide feedback and affect transcrip- tance between astrocytes and neurons in challenging task and establishing the tion. This includes transcription factor the brain). Transport processes of meta- link to clinical outcomes was the higher binding sites, histone modification, bolites between organs in the body priority. However, achieving this inte- methylation sites, and chromosomal including transport in the blood, across gration is clearly essential if we are to interactions, all relevant for epigenetic blood vessel walls and cell membranes understand and diagnose human modifications. This is one of the fastest must be included in physiological disease, exploit personalised pharma- developing areas in biomedicine and models. ceutical interventions, and improve raises significant challenges on standar- many other aspects of 21st century disation regarding storage, annotation A large body of biochemical literature on healthcare. A white paper published in and analysis. human metabolism is available, and January 2012 [22], addresses the oppor- metabolic genes in the human genome tunities and obstacles that confront us as Protein-protein interactions and protein have been partially characterized. There Europe explores the translational role of structure provides the third level of data are several sources available for recons- bioinformatics and systems biology in of relevance for genomic networks. Dif- truction of metabolic networks including drug discovery and clinical medicine. ferent proteins can interact with DNA KEGG27 and BioCyc28. A consortium of and thereby affect the transcription as almost fifty scientists from about twenty 3.2 Genomic networks – models indicated above. In addition, experi- academic departments worldwide, inclu- and databases mental and computational analysis of ding members of the VPH, has produced protein-protein networks in different a reconstruction of the human metabolic The term ‘genomic networks’ often species has been a most active research system which integrates data from seve- includes three levels of data: First, at the field in systems biology during the last ral prominent, already existing DNA level, there is the raw DNA decade. Interactions between DNA and databases. This reconstruction is captu- sequence, promoter regions, enhancer proteins have been studied using hybri- red in a database containing more than regions and genetic variants (SNPs and dization methods such as Chip-Chip but six thousand biochemical reactions for- CNVs25). A major effort within the bio- are now being replaced with sequencing ming a descriptive model of metabolism medical community during the last 5 based methods such as Chip-seq. in the human body. years has been the use of genome wide association study (GWAS) designs to There are significant challenges in how While data on human metabolism are identify a select set of putative SNPs. to integrate this variety of molecular perhaps somewhat more ambiguous The requirements for standards and information as well on standards and than genome sequences, the benefits of databases are active research areas in storage. It is important that the VPH having a well-organised database of bioinformatics that, within Europe, are community establish links to these human metabolic pathways is substan- exemplified by efforts such as ELIXIR26 ongoing efforts in one of the most active tial. The metabolites in this database are (a European effort to develop an infra- areas in biomedical research of clear linked to (bio)chemical databases such structure for the life sciences), and relevance for understanding diseases as CheBI29 and HMDB30. The reactions recommendations that make full use of and therefore important for the health. are linked to the Enzyme Commission the integration of genome-based data nomenclature and to databases with cor- resources with resources detailing 3.3 Human metabolic networks responding genes and genomic loci. This disease-based and other human pheno- – models and databases effort, which has adopted an open types [23]. source approach and is supported by an Metabolism provides the energy for all informal consortium consisting of most The second level of information refers to physiological processes, and biochemi- of the leading scientific groups in this transcription or the RNA level. Here cal processes are therefore closely field, will require ongoing cycles of there are large databases on gene expres- coupled to the physiological functioning updating and improvement in the sion based on ‘classical’ technologies of cells and organs. Molecular networks future. This may therefore constitute a developed during the last decade that for intracellular signalling link extracel- de facto standard for metabolic recons- represent only a subsampling of the lular stimuli such as hormones to truction of human metabolism. This annotated genome. Recent develop- adaptive responses of the cell. Intracel- recent development forms an excellent ments of second and third generation lular signalling networks and basis for physiological modelling in the
24 http://www.virtual-liver.de 25 Single Nucelotide Polymorphism and Copy Number Variation 26 http://www.elixir-europe.org 27 http://www.genome.jp/kegg 28 http://biocyc.org 29 http://www.ebi.ac.uk/chebi/ 30 http://www.hmdb.ca/
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VPH. In addition to the reconstruction of Exemplar projects. The tools for inter- more prone to develop pathophysiologi- the human metabolic system, an inven- preting these data are being developed by cal conditions. Frailty is generally tory and standardization of modelling the VPH and Physiome Projects. These viewed as the accumulation of deficits approaches and modelling tools espe- data resources have to be aligned to cor- affecting various organ systems that ren- cially suited for metabolic network responding efforts on physiological ders the individual vulnerable to simulation, analysis and visualization models (Section 5.1). functional decline. There currently useful for physiological modelling Note also that an important, yet gene- exists no mathematical-physical concep- should be undertaken. An example to be rally overlooked, aspect of cell tion of frailty for any organ system, and included is the COBRA 2 package for modelling is the fact that cells represent proper handling of this key biogeronto- constrained-based metabolic model ana- ‘crowded environments’. Not only does logical phenomenon brings a new layer lysis. In addition a completely open this affect the way in which proteins of complexity to the field of multiscale source package with some similar func- form and interact, but the pronounced modeling of physiological systems. tionalities, using approaches more compartmentalisation, common in par- There is no better framework than what common in genomics and ecology, was ticular to mammalian cells, both enables is offered by the VPH to pursue this inte- developed by a VPH-linked group. The and restricts the extent of network inter- gration. adoption of generally accepted stan- actions that are possible within a cell. dards for metabolite nomenclature and Therefore, nano-resolution three-dimen- We foresee that the development of identification, reaction stoichiometry, sional (3D) reconstruction of individual drugs that make us less prone to com- kinetic equations, etc, should form the cells is likely to be as important for lin- plex diseases (see below) by reducing basis of databases of all metabolites, king the challenges described above as it frailty will in mathematical terms have reactions, kinetic equations and analysis has been for organ-level multiscale to focus on how to impose controls that tools relevant to human metabolism. models to incorporate micro-resolution expand the operational regimes of parti- Metabolic models could be readily 3D information. cular mathematical behaviours (i.e. exchanged and interlinked if based on physiological functions) of dynamic sys- these standards and databases. The Techniques are emerging to provide tems, where age-dependent underlying recent efforts to develop metabolic connected 3D volume data of membrane changes in the control structure might models mostly aimed for a general data- and filament compartments in the entire otherwise cause radical changes in base covering all of human metabolism. cell, including electron-microscopic robustness and resilience features. For the VPH effort, models specific for (EM) tomography or focussed ion beam cell type and tissue must be developed. approaches that are combined with EM As ageing due to its stochastic nature is observation of progressively shaved cell phenotypically manifested in so many 3.4 Physiology – models and surfaces. These approaches are, by and different ways and places, a quantitative databases large, still relatively time-consuming, understanding of ageing physiological and the associated image analysis and systems will demand dramatically more A further significant gap is the lack of mesh-generation techniques still require spatiotemporal data than will be needed comprehensive web-accessible databases significant amounts of user-interaction. for understanding the physiology of of physiological data, encoded with well- young and non-diseased individuals, established data and metadata standards Computational integration of nano-to- and thus become a major driver behind [20,24]. Such data provides numerical micro structure-function relations will the development of advanced phenoty- parameters for use in computational benefit from multi-scale tools and ping technologies (see below). models. This need was expressed in sec- approaches developed for the micro-to- tion 3.2.3 of the VPH STEP roadmap. macro ranges. In fact, the computational In summary, if we are to create indivi- One standard, DICOM, does exist for challenge of reconstructing one cell with a dualised models describing the deve- medical image data. Others such as 1nm voxel resolution is no different from lopment and maintenance of complex C3D31 are well established binary data reconstructing the heart with para-cellular diseases on given genetic backgrounds formats for specialist communities (bio- detail. At the same time, many aspects of in a way that is of broad practical utility mechanics, animation and gait analysis biological and biophysical behaviour for medicine, we have to incorporate in the case of C3D). A more general pur- undergo step-changes as you approach the the effects of ageing in multiscale and pose metadata standard (BioSignalML) is single molecule level, and new modelling multiphysics models. being developed for annotating physio- techniques will be required to build logical time-dependent signals encoded bridges across molecular dynamics, 3.6 The VPH as a potential in a wide variety of existing specialist coarse-grained protein, and reaction-dif- platform for a new drug standards. But even this represents a fusion modelling approaches. targeting paradigm small fraction of what is needed. A major effort is now needed by the physiology 3.5 Incorporation of ageing in Even though model-based drug deve- community to identify the types of phy- multiscale and multiphysics lopment is gaining acceptance as a vital siological data that are available and to models approach in understanding patient begin the development of a broad range risk/benefit and attrition, current drug of data standards and data repositories; The somatic damage that accumulates as targeting research typically aims to iden- as a first step, example datasets are being we age (i.e. senescence of tissues and tify a key molecule involved in a parti- collected from the VPH-I and VPH NoE- organs) makes us more frail and thus cular metabolic or signaling pathway that
31 http://www.c3d.org
VPHNoE 15 is specific to a disease condition or pa- values of other "background" parameters, sive efforts by highly trained personnel. thology. Treatment then focuses on inhi- one may be able to identify multiple pu- This laborious “business-as-usual” phe- biting or enhancing particular pathways tative drug targets in terms of different notyping provides a very modest amount or processes. This paradigm has been parameters to manipulate as well as nu- of information compared to the high-di- one of the major drivers behind the de- merous ways of manipulating a particu- mensional spatiotemporal phenotypic velopment of genomics and other –omics lar parameter. Furthermore, if a drug per- data from several individuals that is really platforms. In particular, it was thought turbs a biological process that cascades needed for making fast progress. Second, that large genome-wide association stu- into a stable change of the value of a fo- because model parameters are really phe- dies would provide a plethora of putative cal parameter, it is evident that the para- notypes, phenomics may open up com- drug targets for complex diseases. Ho- meter itself can be considered a state va- pletely new ways of using multiscale mo- wever, despite huge investments almost riable in a lower-level dynamic system dels for uncovering functional genetic all such studies to date show that the richer in biological detail. One may thus and environmental variation across the number of determinants (genes and non- foresee layers of models that finally bring whole phenotypic hierarchy. In a well-va- coding DNA sites) can be very high, such us to a resolution level allowing us to lidated model describing one or more that each determinant does not account glean molecular clues about how to ma- phenotypic features and capable of ac- for more than a small fraction of the to- nipulate a given parameter. If this scena- counting for observed variation in a po- tal phenotypic variation, and that the to- rio turns out to be feasible, we will be in pulation, the genetic and environmental tal variation explained by the cumulative a unique position to link this drug targe- variation influencing these features have effects of the identified determinants is ting approach to drug design, i.e. the in- to be manifested in the parametric varia- much less than would be expected from ventive process of finding appropriate tion of the model. Genetic mapping to the estimated heritabilities of the actual medications based on the knowledge of such parameters are likely to provide diseases. This strongly suggests that the the biological target. This in turn allows much stronger genotype-phenotype si- relationship between genetic variation for more rapid drug discovery, cycling gnals and make us able to identify more and complex diseases is such that geno- between model refinements and experi- causative variation. If we could rapidly mics alone is not likely to provide the so- mental testing of drug candidates. obtain reliable measurements of parame- rely needed rejuvenation of pharmaceu- ters across a wide range of resolution le- tical R&D, and calls for radically new In summary, this suggested ICT-intensive vels, this would have a dramatic impact drug targeting approaches. and VPH-based approach has the poten- on our understanding of the GP map. tial to transform drug-targeting R&D into It may be argued that if we do not take a highly structured enterprise capable of The engineers have a major responsibility the full consequence of the fact that making the best of genomic and pheno- for the very fast improvements in genome complex diseases are characteristics of mic information and targeted experi- sequencing technology we are now wit- complex dynamic systems and thus mental research. Even though this is a nessing. Considering the diversity of tech- being phenomena that in principle are daunting undertaking, the potential gains nologies needed, the development of a amenable for mathematical description, in terms of innovation and better health- mature phenomics technology will have analysis and control, drug-targeting R&D care are so high that feasibility studies to engage much broader parts of the engi- will not make much headway. ought to be supported in coming years. neering community in academia as well Multiscale mathematical representations as in industry than what has been the of what causes and maintains complex 3.7 Phenomics technology – case for genomics. Phenotype space is a disease may thus become a very impor- a new innovation arena for vast place, however, and the development tant tool for rejuvenating drug-targeting European industry? of a mature phenomics will always de- research. In a multiscale model capable mand prioritizing what to measure. If we of describing a pathophysiological phe- Even though very advanced models of want to avoid misspending enormous hu- notype, the major determinants of this e.g. human physiology are now emer- man and financial resources, the major phenotype will manifest in the model ging, for this modelling work to really guide for this prioritization will have to be parameters. A particular value of a given become transformative, it is mission cri- mathematically formulated conceptions parameter may be due to numerous low- tical that it becomes nourished and (or models) of how phenotypes are crea- level processes, but in terms of control, confronted by massive amounts of data ted and maintained in causal terms. Thus the parameter is key. This means that that only a mature phenomics techno- the VPH is ideally suited to provide mis- instead of a head-on single-molecule logy can provide. The modelling of sion critical guidance for the develop- drug targeting approach, one may step human heart function may be used to ment of a European phenomics techno- back and focus on the relationship bet- illustrate two major ways a mature phe- logy development. ■ ween parameter variation and phenoty- nomics may support the development of pic variation predicted by multiscale mo- a comprehensive causal and quantitative dels. As parameters are lower-level understanding of phenotypic variation. phenotypes themselves, we can focus on exploiting a causally cohesive mapping First, phenomics may quantitatively and between low-level phenotypes and high- qualitatively enrich the intimate rela- level ones for which we have a mathe- tionship that exists between experimental matical representation. By identifying measurement and quantitative model parameter changes that can cause a phe- construction and validation. In the case of notypic change from the disease regime the heart, much of the experimental data to the normal regime, conditional on the needed requires time-consuming, expen-
16 VPHNoE VPH NoE
4.WHAT ARE THE HEALTHCARE CHALLENGES?
ajor diseases like cancer, neuro- power and associated information tech- and technological development com- logical and cardiovascular nology offers the potential to deliver ponent, is a huge, complex, and Mdiseases are complex in nature tailored clinical treatments based on highly articulated system. Due to the involving environmental, life style, simulation studies that take account of peculiar political history of the Euro- ageing and genetic components. A major the genetic profile and clinical indica- pean Union, it is not a surprise that challenge for the future is to integrate the tors (interpreted via physiological such a system is highly fragmented, knowledge of all these different compo- models) of the individual requiring treat- not only between members states, nents into robust and reliable computer ment. but also between regions, districts, models and in silico environments that and even single hospitals. However, will help the development and testing of 4.1 The needs in spite of this extreme heteroge- new therapies and better disease predic- neity, common requirements are tion and prevention tools in healthcare. The European healthcare system, emerging in a number of analysis The progressive advance in computing including its biomedical research documents produced by very diffe-
VPHNoE 17 rent sources32,33,34,35,36,37. Such requi- both population and patient-specific munity has long championed this mes- rements can be summarised in three information. sage, and as identified even in the keywords: Personalised, Predictive, The Digital Patient is a vision of a cohe- original STEP roadmap, there is a need and Integrative healthcare. A fourth rent digital representation of each for… keyword, affordable, is implicit, as patient that is used to provide an inte- “Global VPH security that makes possi- the sustainability of healthcare sys- grative framework for Personalised, ble the federation of clinical databases tems is becoming the number one Predictive, and Integrative Medicine. located behind hospital firewalls into issue in member states dealing with This vision and the currently open call the VPH framework.” (VPH Research a constantly ageing population. for a support action targeting the so-cal- Roadmap section 12.1.5). led ‘Digital Patient’, include three major More specific common needs are: to challenges: In a recent report38, Deloitte writes: maximise the yield of biomedical research expenditure; to achieve per- a) To provide medical professionals and “Most Life Sciences (LS) Research and sonalised healthcare for individuals biomedical researchers with advan- Development functions are under and groups (women, children, etc); to ced user interfaces based on the increasing pressure to improve innova- improve the reliability, repeatability, digital patient metaphor, that make it tion, reduce development inefficiencies and the timeliness of medical deci- easier to cope with large amounts of and advance product safety. Patient- sions; to integrate digital health information related to different organ level data, collected through Electronic information on a global scale; to systems, different space-time scales, Health Record (EHR) systems, offers resolve the individual-society conflict and different diagnostic imaging one promising avenue for redefining around the privacy of health data. It modalities. Research and Development and revo- should be noted that at this stage these b) To provide healthcare providers with lutionizing the LS value chain. needs are very hard to quantify an ICT layer capable of recovering Globally–aggregated, patient-level data because the information is fragmented and integrating all health information could support the identification of over dozens of reports produced by available for each patient into a cohe- disease mechanisms and new disco- different medical specialities, and rent whole. very areas, accelerate the termination much effort is required to elaborate c) To provide to biomedical researchers of unsuccessful compounds, decrease into a single coherent framework a and to clinical research settings the patient recruitment cycle times for cli- detailed and quantifiable description technology to capture existing know- nical trials, and improve drug safety of needs. To address these issues it ledge into digital artefacts in the form surveillance through continuous moni- might be appropriate for the European of predictive models, and to compose toring”. Commission to consider funding a such digital quanta of knowledge into specific support action to collect, orga- integrative models of complex syste- There is clearly agreement that signifi- nise, and compose all this evidence mic mechanisms, thus generating new cant value would attach to the federation into a fully justified and quantified insight. of these databases. Yet it is important to needs analysis. recognize that from an ICT perspective From this description, one might see a there are multiple shortcomings to be 4.2 Personalised, predictive and risk of overlapping with the VPH overcome: integrative healthcare and the Research roadmap, but this risk is only • The majority of the ‘clinical databases’ ‘Digital Patient’ apparent. In our opinion the Digital behind the firewalls are poorly struc- Patient roadmap should focus on pro- tured and inconsistently annotated. A new generation of medical technolo- blems closer to the deployment of the This remains a serious hurdle for gies is needed to integrate the data VPH vision, i.e. on problems such as medical informatics in realising the available about a patient to support a user interface, information systems full potential of the VPH vision. more personalised diagnosis, prognosis, interoperability and integrability, gene- • Interoperability is the key to the effec- treatment planning, and monitoring, as ralisation and wide use deployment of tive re-use of clinical data. Currently, well as to develop new drugs, therapies, the concept of integrative model. data exchange tends to be ad hoc, and medical devices, assistive, and diagnos- no facility exists to support organised tic technologies that are optimised for 4.3 Access to clinical data data exchange between multiple inde- specific groups of patients (age, gender, pendent repositories (clinical, co-morbidity, etc). Diagnostic work- The re-use of clinical data remains a key industrial and research). flows are required, not on pre-defined challenge, and [21] is an important pre- • Candidate technologies capable of pro- general protocols, but on the prediction cursor for an EU digital vision and viding a data infrastructure that can of risk obtained by models that combine agenda for the next 5-10 years. The com- facilitate VPH-wide data exploration,
32 Dobrev, A., Jones, T., Stroetmann, V.N., Stroetmann, K.A. Interoperable eHealth is Worth it - Securing Benefits from Electronic Health Records and ePrescribing. Luxembourg: Office for Official Publications of the European Communities, 2010 33 Apoteket and Stockholm County Council, Sweden, “eRecept, an ePrescribing application”, ec.europa.eu/information_society/activities/health/docs/events/opendays2006/ehealth-impact-7-2.pdf 34 “The benefits from translating biomedical research into the health care system” Report to Bio21 Australia 2007 35 “Personalized health care: opportunities, pathways, resources” US DHHS 2007 36 “Pharma 2020: Virtual R&D”, PWC 2008 37 http://www.inbiomedvision.eu/PDF/D4.1_INBIOMEDvision_First%20think-tank%20report_v5_Final.pdf [21] 38 “Secondary uses of Electronic Health Record (EHR) data in Life Sciences”, Deloitte Development LLC, 2009
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exchange and interoperability need to be explored and evaluated. A viable data infrastructure must support many activities (curation etc) giving data prospectors the freedom to revolutio- nise clinical procedures from the data they obtain, and yet issuing data pro- viders with necessary assurances that their data will not be abused. • Facilities for secure download/ upload must be supported and data providers require further assurances that data users are appropriately authenticated and authorised to use the data. • There are important legal issues to be addressed. By its very nature, the VPH crosses scientific and national boundaries. Differing interpretations of data protection law (e.g. EU direc- tive 95/46/EC) between member states discourage collaborative sha- ring of data for patient benefit. This is compounded by jurisdictional uncertainty due to a lack of legal pre- cedents in this area. The ethical considerations relating to sharing of patient data are also formidable and require management if they are not to become a stumbling block to the pro- gress of the VPH.
Note that the following three initiatives are relevant:
The FP7 Call 6 Infrastructure projects, though not specifically aimed at tackling these issues, are nonetheless addressing their impact as part of their remit to pro- and will provide an important plat- The VPH Institute is well-placed to offer vide community-wide facilities for the form for the dissemination and a mechanism by which formal authori- construction, development and testing acquisition of intelligence relating to sation procedures can be managed and of simulation-based methods. In parti- clinical data-sharing. policed, whilst also providing guidance cular they are examining the changing on recommended procedures (e.g. ano- ethical and legal landscape as it affects Call 7 project INBIOMEDvision is a nymisation) that are important to the potential users of their infrastructures, Coordination Support Action bringing clinic. The Institute is also well-suited to and in doing so will not only expose the together the scientific community, advise on standardisation, since it is issues in a consistent, structured way, healthcare and industry representatives well-informed on community needs and but will identify and liaise with experts to discuss challenges and opportunities able to identify strategies maximising across Europe with both insight and in the area of biomedical informatics, data interoperability; indeed it is already influence. and come up with various strategies and concerned with other fundamental recommendations to better integrate cli- efforts including the harmonisation of Call 7 project DISCIPULUS is a Sup- nical data, exploit this data in research, nomenclature through ontologies, port Action bringing together translate innovation in research to recommendations for data formats and community and public representatives improved clinical outcomes, and data interchange, and representation on to identify and optimise the strategy achieve a better mapping of genotype- international standards committees. for the introduction of the Digital phenotype resources. In addition, the Standards activities are necessarily mul- Patient, the healthcare avatar that will project promotes the dissemination of tifaceted, with the need to recognise the accompany all citizens in their jour- knowledge, training of new generation competing demands of research, indus- ney through healthcare, indeed of scientists and medical practitioners in try and the clinic and to avoid the through life. In consulting widely, and new ways of thinking, and the consoli- dangers of over-regulation. informing significantly, the project dation of a community of experts with will come into contact with a large this unified approach to personalised In summary, increasing and consistent diaspora of relevant opinion-holders, medicine. interaction between projects, regulators
VPHNoE 19 and users is required to further the cause from the FDA, the DICOM standards human physiology have rarely, if ever, of increased access to clinical data, and working group and COCIR the trade been applied. Whereas conventional each project has a responsibility to par- association, representing European health technology assessment (HTA) is ticipate in the collective endeavour to Radiological, Electromedical and Health- usually applied only to incremental, improve the data landscape on behalf of care IT Industry. COCIR is particularly almost established, technological inno- all stakeholders. active in the context of EU software regu- vations (which are studied as a lation and has set up a Medical Software well-defined alternative intervention at 4.4 EC regulatory policy Task Force. Continued involvement with specific decision-points in a treatment these groups is a strategic aim and will algorithm), VPH technology may lead to Translation of predictive modelling tech- help to guide researchers through the the complete transformation of diagno- nology to the clinic is an exciting regulatory minefield. sis and treatment pathways and thereby prospect and a leading driver for many of the respective clinical guidelines. researchers. However, clinical uptake is VPH technology will have to meet two The assessment of such complex, multi- associated with greatly increased res- further key challenges en route to rou- faceted health technology innovations ponsibility and, necessarily, tight tine clinical application: it has to prove already during their early phases of regulation. Few basic researchers have both its clinical and socio-economic development requires innovations also the knowledge and experience required benefits, and it needs sustainable busi- in clinical and socio-economic impact to undertake this final step. The VPH ness models. More and more, funding assessment [25]. A new, multilevel gene- should plan the development of an envi- agencies require such activities as an ric methodological framework should be ronment to foster translation. Industry integral part of ongoing research to developed, built on a method-mix of will be a critical partner in the transla- ensure that the output will indeed meet socio-economic cost benefit analysis, the tion process but, whilst industry is used the needs of clinical users, the health comparative analysis of healthcare path- to accessing regulatory guidance in sup- system, industry and society. ways, and disease cost simulation port of the introduction of a new models based on health economic pharmaceuticals or medical devices to 4.5 Impact analysis theory. In order to guide the research market in the EU, this is not necessarily process itself, and to help focus it on the the case for software. The emergence of In biomedical research, methods asses- most promising and realistic develop- VPH technology in the clinic comes at a sing the clinical and socio-economic ment path, a prospective, formative time of significant regulatory change; impact of complex technologies such as approach is mandatory [12,18,19]. ■ since the revision of the European Medi- multiscale computer modelling of cal Device Directive which came into force in March 2010, the definition of a Medical Device now includes software used for diagnostic and medical pur- poses. Such software, if intended for sale or distribution for clinical use, must first be CE marked. Only software produced and used in a clinical institution is exempt from CE marking, although in practice all issues of conformity should still be addressed. The Commission has published a guidance document to help identify software which is categorised as a Medical Device, but at this early stage of implementation, many European States differ in their interpretation of the Directives. In addition to the changes already implemented, a re-cast of the Medical Devices Directives is currently underway with a draft expected to be released by the Commission in Spring/ Summer 2012. As yet the potential impact of the re-cast remains unclear.
The VPH Community has a responsibi- lity to raise awareness of these issues and, towards this goal, is extending its current programme of industrial engage- ment to include the regulatory community. As a first step, the NoE orga- nised a regulatory and standards event as part of the September 2010 Industry Day. Invited speakers included representation
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5.WHAT ARE THE ICT CHALLENGES?
he VPH-Physiome Project aims to ducibility and reuse, was recognised in cal meaning. The languages encourage provide a systematic framework for the STEP Roadmap. The framework in- modularization and have import mecha- Tunderstanding physiological pro- cludes modelling languages for encoding nisms for creating complex models from cesses in the human body in terms of systems of differential-algebraic equations modular components. Model reposito- anatomical structure and biophysical me- - CellML39 and SBML40 - and the spatially ries have been established, together with chanisms at multiple length and time varying fields used with systems of par- freely available open source software scales. The importance of establishing a tial differential equations - FieldML41. In tools to create, visualize and execute the solid foundation for the VPH by creating both cases the parameters and variables models. The CellML repository42 now in- model and data standards, together with in the mathematical models are annotated cludes models for a wide variety of sub- mechanisms for achieving model repro- with metadata that provides the biologi- cellular processes.
39 http://www.cellml.org 40 http://www.sbml.org 41 http://www.fieldml.org 42 http://www.cellml.org/models
VPHNoE 21 We have recently seen the first public in clinical application of these VPH mo- 2. Develop application programming sharing of models expressed in the dels, a range of new challenges have ari- interfaces (APIs) based on the MLs. FieldML standard, under the auspices of sen [21]: In order to be used in clinical 3. Develop libraries of open source tools the euHeart project. As well as a range of decisions, models must be verified (e.g. that can read and write the ML enco- anatomies, these include descriptions of are the units consistent and are physical ded files. functional benchmarks. One criticism of laws obeyed?), reproducible (can so- 4. Develop data and model repositories many of the models exposed by the meone other than the author generate based on MLs. community is that they do not adequa- the model outputs from specified in- 5. Develop reference descriptions to tely represent physiological variations puts?), validated (how accurately and demonstrate model reproducibility. and uncertainties. A first step is to under what conditions does the model 6. Implement web services for a variety ensure that variation and uncertainty match reality) and available (is the model of tasks including access to automated can be represented in the modelling lan- encoded in a standard form? Is it availa- scripts to run the models and compare guages. We need to learn how to ble as open source?). The functional results against experimental data, represent the physiological envelope of benchmarks mentioned in the previous optimize parameter values for new the individual in our simulations, and section are an important component of experimental data and provide sensi- how to inform the parameters in this verification and validation strategies for tivity analyses for changes in model envelope from the rich information in sophisticated numerical codes develo- parameters. the electronic health record of the ped by the VPH community. There are patient. other less essential but highly desirable A useful way of viewing the develop- aspects such as parameter sensitivity ment of standards is shown in Table 1, 5.1 Model and data encoding (how sensitive are the model outputs to where progress in developing a specifi- standards: model particular parameter values?), modula- cation of the minimal requirements for reproducibility rity (can the model be incorporated as data, models and the simulation experi- one component of a more comprehensive ment are shown, along with the Mathematical models for the VPH-I are model?) and usability (is there freely standards for the syntax of the data, developed by bioengineers, biomathe- available software to run the model, dis- models or simulation experiments and maticians and experimental physiolo- play results and if necessary modify pa- the ontologies for annotating the seman- gists to quantitatively describe complex rameters? does it have a good user inter- tic meaning of terms in the data, models biological processes. When these models face?). The understanding of parameter or simulation experiments [2,3,4,7]. are based on biophysical mechanisms sensitivities is also important in the and, where appropriate, incorporate ana- context of the interpretation of the phy- Note that the best example of an eHealth tomical detail, their predictive capability siological envelope of the individual. technology that is already in widespread can provide physical insights into the use is the Picture Archiving Communi- interpretation of experimental data and The general strategy for developing the cations Systems (PACS), usually based can help formulate experimental hypo- modeling standards is as follows: on use of the DICOM image encoding theses. In fact, the most powerful appli- standard. Others close to maturity are cation of modelling occurs when there is 1. Develop markup languages (MLs) for Electronic Transfer of Prescriptions a close interplay between modelling and encoding models, including metadata, (ETP), Computer based Patient Records experiment. With the increasing interest and data. and Electronic Medical Records (CPR/EMR) and Electronic Health Records (EHR). Data Models Simulation Minimal requirements MIAME43, MICEE44, etc MIRIAM45 MIASE46 The VPH Initiative is also represented in the EUDAT project via partner UCL. 47 48 Standard formats PDB , DICOM SBML, CellML EUDAT is an FP7 project launched to 49 50 BioSignalML FieldML SED-ML target a pan-European solution to the Ontologies GO51, Biopax52, FMA53 GO, Biopax, FMA challenge of data proliferation in SBO54, OPB55 SBO, OPB KiSAO56 Europe's scientific and research com- munities. The project, coordinated by Table 1.The minimum information standards, syntax and semantics being developed for CSC Finland, aims to work towards the data, models and simulation experiments. development of a collaborative data 43 http://www.mged.org/Workgroups/MIAME/miame.html infrastructure for Europe, driven by the 44 http://www.micee.org [17] needs of researchers. VPH is a core 45 http://www.ebi.ac.uk/miriam research community in the project, and 46 http://www.ebi.ac.uk/compneur-srv/miase a major activity within the project is to 47 http://www.rcsb.org/pdb/home/home.do examine how to store VPH data on the 48 http://medical.nema.org 49 http://www.embs.org/techcomm/tc-cbap/biosignal generic data infrastructure being deve- 50 http://www.ebi.ac.uk/compneur-srv/sed-ml loped, and link that underlying 51 http://www.geneontology.org infrastructure with specific VPH data 52 http://www.biopax.org storage systems, such as those being 53 http://sig.biostr.washington.edu/projects/fm/AboutFM.html 54 http://www.ebi.ac.uk/sbo developed by VPH-Share and p-medi- 55 http://bioportal.bioontology.org/ontologies/46667 cine. 56 http://www.ebi.ac.uk/compneur-srv/kisao
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A concerted effort will move us closer dent manner, the user may choose either diovascular system or the airways: both towards reproducibility, interoperability to embed annotations directly in the ori- systems can be seen as networks of and the re-use of VPH models, inclu- ginal DMR files or to maintain such repeating units with decreasing spatial ding both future models and legacy, associations independently. This separa- scale. An effective approach to handle published models. This requires adop- tion of annotation from DMR also allows this kind of complexity relies on the tion of the above consensus set of VPH users to serve annotations via a application of geometrical multi-scale standards for metadata that describe the separate repository service that does not models, where the reference scale is models and of markup languages for require the public availability of the treated with the most accurate model at their mathematical description. An inte- DMR to which these annotations were hand, i.e. Navier-Stokes equations for gral aspect of interoperability will be the originally applied. In practice, therefore, blood or air flow, while the contribution tagging of model variables and parame- this system allows users to make well- of smaller scales is described with redu- ters with identifiers from reference defined details of their work known to ced spatial dimension models, such as ontologies such as the Foundational the community at large, while satisfying one-dimensional models or lumped Model of Anatomy (FMA), Gene Onto- the operational constraints and obliga- parameter models. In the framework of logy (GO), and appropriate ontologies tions of confidentiality that sensitive VPH, the development of a general for- for units, physics-based quantities, phy- clinical/industrial work often entails. malism to extend such model reduction siological processes, etc, as described and integration techniques to different above. These must be adopted not only Model curation and annotation is a long- applications (i.e. venous system, lym- by the VPH community but also by the term task that spans a wide spectrum of phatic system, spinal flow…) would be curators of the massive existing gene-, disciplines and will require a major particularly effective. protein- and metabolic-databases in effort but it is crucial to the success of order to enable vertical multi-scale lin- the VPH vision. Sustainability of model A distinguishing feature of the multis- king of models at the physiological scale repositories and software (including ver- cale challenge is the property that the (organs, tissues, cells) to the wealth of sion control, archiving, technical reference problem and the underlying medically relevant molecular data. upgrades, and provision for updating physical laws are homogeneous and In VPH practice, there are two key types and expansion) will also be a major known with satisfactory exactness, even of obstacle to resource sharing and re- expense and limiting factor in the com- though the problem is not immediately use, namely: munity acceptance of VPH models. prone to discretization. In such cases, the role of model reduction and multi- 1) operational restrictions such as legal, 5.2 The challenges of model scale integration is to increase the ethical and competitive constraints, reduction and multi-scale efficacy of computations while maintai- and model integration ning comparable accuracy with respect 2) the lack of functional interoperability to the original model. On the other hand, between data or modelling systems. Biological systems are characterized by VPH objectives address biological sys- A key contributor to the latter is the multiple space and time scales. New tems that are characterized by the heterogeneity of formats that data and multi-scale modelling techniques are interaction of many different physical model resources (DMRs) are encoded in. needed to help connect the large range processes at each spatial scale. In this A second interoperability problem of spatial and temporal scales involved situation, a unifying macroscopic model relates to the lack of consistent annota- in the VPH. To attempt a description and is seldom available and multi-scale tion of DMRs: for example, it may not be planning of such complex activity, it is model integration appears to be the fun- possible to discover all datasets in a VPH useful to start from a preliminary classi- damental tool for modelling the repository that are relevant to the study fication of problems that typically need theoretical input to a macroscopic/ of a specific disease (e.g. diabetes) the application of model reduction stra- coarse-grained model from a collection because such DMRs were not annotated tegies and multi-scale integration of more detailed microscopic models, using a standardized vocabulary of techniques in order to be efficiently bypassing the necessity of empirical des- terms (e.g. instead free-text annotation addressed by computational methods. cription, when available. One example using phrases like ‘glycaemic response’, is the fact that the macroscopic proper- FBG, ‘blood glucose’, OGT, etc). Models such as the PKPD addressed ties of a tissue, such as the bone above, combine phenomena featuring stress-strain curve, or the diffusion coef- To this end, the VPH-I project RICORDO very heterogeneous characteristic time ficient of a drug or chemical in the is developing a toolkit, and an associated scales. From the mathematical point of interstitial space of skeletal muscle, are set of ontology standards, that allows view, they can be seen as large dynami- related to microscopic effects. Here, community users to (i) apply semantic cal systems with multiple time scales. In homogenization and volume averaging annotation to data and models in a this case, the model reduction challenge methods can be used to obtain the strain consistent manner, and then to (ii) query is to automatically identify the most energy function for bone tissue starting and reason logically over distributed relevant eigenmodes of the system. from basic information about a ‘repre- repositories that share such annotations. sentative’ microscopic cell. Similarly, Apart from improving VPH DMR seman- A different model reduction strategy can mass transfer in biomaterials or within tic interoperability, RICORDO be applied to manage geometrical com- polymeric scaffolds for tissue growth, methodology will also contribute to over- plexity. This is a fundamental issue in can be effectively described at the coming other obstacles to resource the solution of biomedical problems macroscale by using macroscopic para- sharing. For example, as annotations are involving the human body. An example meters that are obtained on the basis of applied to DMRs in a format-indepen- is the development of models for the car- a microscopic ‘cell problem’ (i.e. on the
VPHNoE 23 reference elementary volume describing both for the definition of input and Although they are frequently used as the scaffold). boundary parameters, and as a test-bed synonyms, ‘probabilistic’ and ‘stochastic’ for the validation of model-based pre- have different meanings. Probabilistic Another example at the organ/tissue dictions. The anatomically and models assume that each random quan- level is the analysis of the beating heart, biophysically based approaches of the tity can be described with a single where large deformation mechanics of VPH project are being designed to link distribution, whereas stochastic models the myocardium are coupled to the reac- these approaches. The model reposito- accept that such probability can change tion-diffusion equations governing the ries based on the CellML and SBML over time and/or space. For example we spread of electrical excitation, as well as standards already contain many models can account for the aleatory uncertainty with the equations of fluid mechanics of both types. A particularly relevant of the average module of elasticity of for blood flow both within the ventricles challenge will be the nanoscopic repre- bone tissue using a probabilistic model and within the coronary vasculature. At sentation of intra-cellular structures, that where this input is represented with a the sub-cellular level, the simulation of will allow the linking of molecular level Gaussian distribution of values. Howe- cardiac myocyte function requires the pathway models to realistic spatial ver, if we notice that the variance of the coupling of ion channel electro-physio- constraints, thereby providing the cur- measure increases as the porosity logy, calcium transport, myofilament rently missing link to project between decreases, we should have a different mechanics, pH regulation and complex sub-cellular mechanisms and (patho-) probability distribution in each point of networks for signal transduction, meta- physiological function as it manifests the bone, as the bone tissue porosity bolism and gene regulation. This shows itself at the cellular and supra-cellular changes from point to point, in which that multi-scale model integration is a levels. Thus, the question is not 'top- case we would need a stochastic model. challenging problem where multiple down' or 'bottom-up', but how to link the In the VPH we need both approaches, scales are simultaneously interacting, two, in particular from nano to micro (as depending on the particular biological such as the nano-scale (interaction of the micro- to macro-domain already property or behavior in question. chemical species, ions and proteins), the forms an active part of present VPH acti- micro-scale (cardiac myocytes) and the vities). There are a number of mathematical macro-scale (the cardiac tissue, usually methods for probabilistic and stochastic treated as a continuum). 5.3 Dealing with probabilistic modelling, but only a few are adopted in and stochastic processes biomedical modelling, and only to a More generally, when addressing bio- limited extent. However, there are phy- medical phenomena featuring multiple Another modelling challenge, that has siological processes that are inherently time and/or space scales, suitable so far received relatively little attention, stochastic, e.g. in neuromotor control. In mathematical techniques need to be is that of incorporating stochastic beha- addition the clinical application of VPH developed to identify a correct scale vior into the multiscale VPH models. At integrative models, where rarely are all separation, to model each of them and to a molecular level stochastic behavior the inputs properly identified for each express the interactive/coupling mecha- can be a reflection of Brownian (thermal) individual patient, requires in many nism among them. This development, motion, but at higher spatial scales it can cases that the population-based inputs accompanied by the necessity to set up be a reflection of extreme sensitivity to are modelled as random variables of efficient multiscale numerical algo- initial conditions (usually called chaotic known frequency distribution. The use rithms, represents a major challenge for behavior) or simply unknown mecha- of simpler approaches, such as Monte integrative multi-scale modeling [1]. nisms – i.e. ignorance. It is very Carlo methods, primarily poses a pro- important that the consequences of this blem of computational weight, since Note that the VPH needs to encompass uncertainty, for example in parameter every model must be run hundreds or ‘top-down’, ‘bottom-up’, and 'middle- value estimation, are quantified. thousands of times to get a single, pro- out' approaches. A good example of babilistic answer. The use of more top-down is the Pharmaco-Kinetic-Phar- There are two types of uncertainty: complex approaches, for example invol- maco-Dynamic (PKPD) modelling ving Bayesian modelling, are still largely community. PK deals with the advec- Aleatory Uncertainty arises because of territory for fundamental mathematical tion, distribution, metabolism and natural, unpredictable variation in the and numerical research. excretion of drugs and PD deals with the performance of the system under study. dynamics of how the drugs affect recep- In our context, this involves the uncer- The identification and quantification of tors. PKPD models accommodate tainty we have on measuring (or more uncertainties is crucial in order to obtain human variability in an empirical frequently estimating) the input para- more realistic results from biomedical fashion and treat body compartments meters of our model. numerical models. Many strategies to with highly lumped approximations. describe uncertainties, based for exam- The ‘bottom-up’ approach of modelling Epistemic Uncertainty: is due to a lack ple on fuzzy set theory, worst scenario molecular mechanisms at the sub-cellu- of knowledge about the behaviour of the analysis, and probability representation, lar level is the realm of the molecular system. In our context this might also have been experimented with. Among systems biology community. The 'mid- represent our inability to measure or those, characterization of uncertainty by dle-out' approach is exemplified by even estimate the patient-specific value probability distribution function inclu- simulations of biological behaviour that of an input parameter, which forces us to ding random variables, random target those levels at which we have par- replace it with a range of possible values processes, and random fields are applied ticularly good insight, using lower and observed in a representative population. in combination with deterministic higher levels of structural complexity models and is considerably stimulating
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the activity on uncertainty quantifica- vision has naturally emerged that the IPR and service models, around the tion by stochastic models. effort during the next period should go issues of transfer of the data to the ser- In forward problems, uncertain inputs to defining a reference architecture that vice or the service to the data. are explicitly represented as probability is generic enough to encompass the distribution functions. The goals is to scope and diversity of current applica- 5.5 Multiscale simulation and compute the probability distributions (or tion frameworks to adopt it while, at the visualization software statistical quantities) of the output of the same time, is prescriptive enough to biomedical system in order to assess the ensure the adherence to best practices, Visualisation of the output of complex way uncertainties propagate into the the compliance to certain standards, and systems models and the human compu- system, as well the output sensitivity to the access to and/or interoperability bet- ter interface issues inherent in user uncertainties. ween data formats and resources, interaction with such models is a new software components, physiological and significant area of research. Com- In backward problems, the probability models and computational resources. plex systems models are likely to have distribution functions for the uncertain Over the last two years and within spe- many input and output variables and input are to be determined in order to cific VPH-I projects, several partners may produce non-intuitive data repre- fulfill specific requirements on the within the VPH-I community develo- senting, for example, emergent observed output, yielding optimal ping image-based prototyping behaviours that are not easily represen- control problems, inverse problems, or frameworks, together with institutions ted by classical graphical or text-based data assimilation problems, all of them outside the VPH-I promoting similar ini- methods. This is a rapidly moving area featuring a high level of complexity (see tiatives, have started efforts to share, of cross-disciplinary research that may also [27]). identify and adopt best practices and need specific funding under future calls discuss architectural implications of a for VPH project proposals. 5.4 Convergence of image-based common toolkit57, which could become integrative prototyping the basis for interoperability. Additio- The above challenges provide worth- frameworks nally, a number of other practical while and challenging problems for the experiences have been started, whereby mathematics and computational science Biomedical imaging data, and by exten- certain application frameworks have communities and some VPH funding sion multidimensional biomedical shown interoperability and reusability should be directly targeted to attract signals, are key data elements in the of components from other frameworks. their expertise. construction and personalization of sub- For instance, several communications at ject-specific models of anatomy and the VPH2010 Conference demonstrated VPH is also working with the FP7 MAP- physiology. At the same time, these data the interoperability between GIMIAS, PER project58, which seeks to develop a sources are both intensive (high-dimen- MAF, cmGUI and Slicer3D. persistent, generic infrastructure for sional, large-volume) and extensive multiscale modelling, on top of the (multi-modal, multi-scale, multi-source) The integrated project VPH-Share is lower level infrastructures provided by resources with associated challenges in constructing an ‘infostructure’ to facili- PRACE, EGI and other National Grid Ini- their processing, integration, analysis tate sharing of tools, models and data tiatives (NGIs). VPH is a constituent user and visualization. Additionally, the across the community. One of its targets community of MAPPER, and work is requirements associated with the speci- is to promote the idea of ‘virtual colla- already underway to port VPH applica- fic application domains where they are borations’, so that, for example, a tion scenarios to run on the initial utilized (as a research tool, to derive research group with expertise in com- MAPPER infrastructure. diagnostic biomarkers, to develop inter- putational fluid dynamics can test their ventional plans, or for real-time algorithms and code in a fully develo- 5.6 Supercomputing challenges guidance or navigation in interventional ped workflow that includes those procedures) do impose additional requi- processes (such as image segmentation) A major challenge for VPH-I researchers rements on the underpinning IT that they might not be expert in. To sup- remains the need to secure access to systems. It is therefore not surprising port this effort some of the complex computing resources of a sufficient scale that a number of IT toolkits and frame- workflows developed in earlier projects to support their simulation work. The works have emerged with partially are being decomposed into a series of VPH-NoE has built a relationship bet- overlapping functionalities but also with atomic services that can be re-assem- ween the NoE and the VPH-I research complementary focuses and characteris- bled, with new components, into new projects through the development of a tics. Given this context, it is highly workflows. A concomitant issue is that DEISA59 VPH Virtual Community. The unlikely, and possibly undesirable, that of access to these services through a Virtual Community, applied for and a single framework could be conceived community computational infrastruc- managed by the VPH-NoE on behalf of that would address all the challenges, ture. There are many interesting the VPH-I, provides access to high per- satisfy all the requirements, and meet all questions, some associated with data formance computing facilities for any the needs for every application domain. protection, data security and ethical VPH-I research and allied projects Based on a number of consultation exer- issues, some associated with the which require such a facility. The Virtual cises performed by the VPH NoE, the volumes of data, some associated with Community was renewed by DEISA on
57 http://www.commontk.org 58 http://www.mapper-project.eu 59 http://www.deisa.eu
VPHNoE 25 a year by year basis, until the end of initiatives it will be necessary to track breaches and data losses are frequent DEISA in late 2011. During that time, relevant developments and to determine headline news, the protection of medi- over 50% of VPH-I projects were sup- the most useful information for any spe- cal patient data is of critical importance ported, as well as additional EU funded cific application. The extent, location for VPH. The EU Data Protection Direc- projects working in e-Health related and linkages of research, publication tive makes it a legal requirement for domains are also being supported and health service activities will form VPH-I projects to collect, hold and pro- very substantial metadata sets and allow cess patient data in a secure way. The end of DEISA has created a vacuum monitoring of the effectiveness of invest- Hence, there is a need for VPH security in terms of available compute support ments in health-related programs. solutions not only to protect the data for VPH-I researchers. DEISA has been itself, but also to protect VPH-I resear- replaced by PRACE Tiers 1 and 2, which In addition to published information chers from the consequences of do not currently support community there will be extraordinary accumula- unauthorised disclosure of medical based allocations similar to the DEISA tion of primary data for individuals and information including negative publi- Virtual Community programme. Howe- populations. It has been estimated that city, legal liabilities and fines; and from ver, PRACE have issued a call for for one individual the combined output unauthorised modification of patient expressions of interest in whether such from the common imaging, biochemical data, which may lead to incorrect an allocations programme is required, to and genetic modes of analysis will gene- patient treatment and results in a loss of which the VPH NoE responded. We rate approximately one terabyte of life, or identity theft that is currently hope that such a community based allo- information. When multiplied by the creating a considerable concern. cation mechanism will become available total population of Europe the challenge in the near future and allow us to pro- of “big-data” in health science is abun- There are many security issues that can vide further support to VPH-I dantly clear. arise when sharing data within VPH-I researchers. projects, including: The VPH is well placed to address the Through the MAPPER project, VPH challenges and opportunities posed by (I) How to give information owners researchers also have access to select EGI ‘big data’ including the use of appro- assurance that their data are ade- resources. MAPPER has signed a memo- priate information visualization tools. quately protected when it is randum of understanding with EGI to These will offer researchers and health transferred to VPH research deploy software components onto EGI professionals a technology platform with groups? resources. VPH can use its relationship capabilities to rapidly discover and gain (II) How to give data owners and VPH with MAPPER to help deploy multiscale insights from the copious amounts of scientists assurances that patient VPH simulations on EGI nodes. information being made available from records used in the research are the wide variety of publication sources. appropriately protected? 5.7 Informatics and “big-data” The VPH community needs to recognise (III) How to give data owners assu- the ‘connections’ linking bio-medical rances that the process of sharing Health research and health services pro- and life sciences research and resear- data does not increase the risk of vision faces many of the challenges chers around the world, and to visualise compromising their own already evident in “big-science” such as those linkages through interactive ‘infor- resources? (i.e. opening firewall astro-physics and particle physics and in mation communities’ for exploration, ports to access data) a wide variety of data-rich domains such analysis, and education. (IV) How does a VPH scientist get as global economics, meteorology and access to shared data? How do we environmental monitoring. Rapid It is envisioned that through the VPH assess the security requirements sequencing technologies and the wides- Institute and its European and interna- for derivative data that arises from pread use of diagnostic imaging are tional partners the VPH teams will privileged access of a VPH resear- examples of “big-data” generation in describe and specify the range of ICT cher? research and hospital settings, but when infrastructures required to match the (V) How does one determine whether considered as an integrated international generation of health data with the needs a VPH researcher is allowed to per- process it is already clear that new and capacity of the social environments. form a task on shared patient data? approaches will be needed to allow Development of appropriate tools will (VI) Who decides what the access effective storage, discovery, analysis and build upon the standards already rights of VPH researchers are? application of the knowledge being encompassed by previous VPH initia- (VII) How much change to the data pro- accumulated across Europe and by its tives under the structure of the next viders' IT infrastructure is required international partners. health program frameworks” to provide secure access to patient data? What are the hardware, soft- The extent of the challenge is clear when 5.8 Data security ware and support costs? we consider that there are already over 20 million published papers in the One of the main challenges for VPH-I Some of these issues will be addressed National Library of Medicine PubMed researchers is to provide seamless and by the p-Medicine and VPH-Share pro- database and many more in digital libra- secure access to shared patient data for jects, which in turn should lead to a set ries collected in other relevant domains the benefit of clinicians, and academics of open source tools and best practice such as scientific, medical, engineering, for the purposes of patient care, as well guidelines that can be applied throu- social and legal studies. In the proposed as for scientific and translational ghout the VPH-I community. ■ integrated, predictive models of the VPH research [21]. As high profile security
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6.A STRATEGY FOR THE VPH
urrently, coordination of the structure for common use; European ‘VPH Institute’ with a man- VPH-I projects is via the VPH • monitor the development, adoption, date to support the maintenance of CNoE, which is also pursuing and impact of VPH technologies; VPH databases and the continued additional specific goals such as the • sustain the global adoption of VPH- development of standards and busi- VPH toolkit. In order to transform the based protocols that have proved ness-friendly open source software. VPH vision into a reality for European effective; stakeholders, a long-term coordination • provide training in the use of VPH 6.1 The VPH Institute action is needed in order to: technologies. • coherently strategise and periodi- The need for a non-profit organisation cally revise the concrete research and These activities cannot be maintained capable of representing the whole VPH technological development goals that in the long term by the NoE or by any research community, in itself highly should make the vision come true; other initiative that has funding for a heterogeneous and spread over a large • sustain the standardisation and inter- limited period. They require the atten- number of traditional academic do- operability efforts; tion of a permanent organisation, mains, was first mentioned in the 2009 • further the development, mainte- capable of ensuring continuity over update of this document. The 2010 up- nance and provision of tools, actions that may last for decades. We date described the constitutive process services, databases and other infra- have therefore established a non-profit that has now been completed. On
VPHNoE 27 March 2011 the “Virtual Physiological VPH2010, took place in the Université Work is currently in progress for the Human (VPH) Institute for Integrative Libre de Bruxelles in Belgium on 30th second conference of the series Biomedical Research” was incorpora- September to 1st October, 2010. The ‘VPH2012: Integrative approaches to ted as an international non-profit orga- meeting, which was opened by Zoran computational biomedicine’ which nisation according to Belgian law. Ten Stancic, Deputy Director General (DG will be held in London in September institutions, including one from the Information), was devoted to the VPH 2012. VPH2012 will have a focus on USA and one from New Zealand, for- Initiative and attracted 250 participants the integrative aspects of VPH and med the founding supporting member- from VPH groups, Industry and Clinics. aims at reaching outside of the VPH ship. Representatives from these ten There were also representatives from community to other relevant commu- founding members formed the Board countries such as Australia, Japan, New nities including systems biology. The of Directors to manage all institute ope- Zealand, Singapore and South Korea. vision is to have a conference that truly rations. Marco Viceconti was appointed encompasses all possible scales to as first Executive Director of the VPH Over 95% of respondents stated that model physio/pathology with a clear Institute during the first Board meeting. VPH2010 met with their primary ob- ICT focus. jectives and 90% stated that VPH2010 On September 2011, following the was relevant to their practice, research Four parallel sessions will be held on all annual VPH NoE meeting, the VPH Ins- or work. 73% of respondents stated that days with talks and dedicated poster titute held its first general assembly. they came to VPH2010 because of net- sessions. Additionally, there will be pa- During that meeting 42 applications for working opportunities, which demons- rallel workshops in relevant areas not membership were ratified. Thus, inclu- trates a real need to continue with dis- addressed in the main scientific tracks. ding the founding members, 52 semination activities. The VPH NoE There are two types of workshops organisations joined the VPH Institute will continue to host VPH events until which will be held in VPH2012. Hands- in its first year of activity. the end of the project in November on workshops have invited speakers, 2012. their aim is to give attendees a deeper Soon after the General Assembly the membership elected the first President of the VPH Institute (Denis Noble from the University of Oxford) and two financial auditors (Randy Thomas, Uni- versity of Evry and Isabelle Wartelle, University of Amsterdam). The Presi- dent and the financial auditors together form the Board of Trustees of the VPH Institute.
The VPH Institute has since produced a position paper on the European Com- mission’s Green Paper on Horizon 2020, the next framework programme. In this document an “in silico medi- cine” follow-up project to the FP7 VPH is proposed and three new research priorities named Digital Patient, In silico clinical Trials, and Personalized Health Forecasting are advocated.
6.2 VPH conference series
The ICT-Bio meeting60 held in Brussels in October 2008 was the kick-off mee- ting for the VPH. The ICCB2009 meeting61 held in Bologna in Septem- ber 2009 was a second integrative biosciences VPH meeting. The NoE steering group is now planning a VPH conference series that will provide an annual event for the VPH community and also help to coordinate internatio- nal physiome activities. The first conference of the series,
60 http://ec.europa.eu/information_society/newsroom/cf/itemdetail.cfm?item_id=3956 61 http://www.iccb2009.org
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knowledge and familiarity of a specific the audience in discussion and industry, healthcare, and professional set of tools or concepts, and will have an debate. Importantly, a new sophistica- bodies. The mechanism by which this interactive format. Sessional workshops ted approach to the generation of would be achieved is still under dis- are those which focus on a particular interactive project-related educational cussion, but the BiomedTown VPH theme with keynote speakers and will materials aimed at medical trainees portal, using Web 2.0 technologies and also have an open call for abstracts. Si- was announced, and joint work on approaches, could be used to engage milar to the format of VPH2010, the best this concept is well underway. and build these communities. VPH2012 papers will be published in Consideration should also be given to Interface Focus in a special themed is- the provision of a web-based facility, 6.4 Timelines sue on Integrative Approaches to Com- accessed by a portal, to provide a focus putational Biomedicine. for interaction between training provi- A timeline for the STEP project (an FP6 ders, course developers, young initiative), the NoE, and other VPH pro- 6.3 Training and dissemination researchers wishing to develop a career jects funded under the first Call 2 of in physiological modelling, established FP7 and the international Call 4 pro- Training will continue to be an researchers seeking training as part of a jects, is shown in Figure 1 together with important VPH activity. The results of commitment to Life-Long Learning, and the anticipated future calls. The esta- a survey carried out amongst Indus- representatives from the major employ- blishment of the VPH Institute is also trial, Clinical and Academic partners ment sectors. VPH training will need to indicated. The anticipated impact that emphasised the importance of a qua- be responsive to the changing needs of the VPH activities will have is also lified VPH-formed workforce to employers, and an on-line resource illustrated, first on biomedical research, provide future professionals for would provide an environment to then on industry and finally on the highly-skilled jobs in the pharma and engage with and obtain feedback from general public. medical devices industry as well as in regulatory bodies.
It thus follows that the development of educational systems within the VPH community is an essential part of enlarging the skilled workforce availa- ble to develop clinical care through simulation and, as described, the NoE has made significant efforts to extend the scope and quantity of appropriate facilities. It is now the case that, as VPH technology begins to have an increasing impact on patients, clini- cians and medical institutions, internal community activities have become insufficient, and engagement beyond the VPH, with the wider, established world of medical education becomes a requirement.
The VPH community has now forged a successful relationship with the EU’s largest community of medical educators, the Association of Medical Educators in Europe (AMEE), which boasts a membership in excess of 30,000 practising educators and an annual conference attended by over 3,000 members. The collaboration has so far seen the engagement of all NoE partners and many of AMEE’s leading institutions in collaborative planning, grant applications, projects and publi- cations and, at the AMEE 2011 conference in Vienna, an entire ses- sion was devoted to showcasing VPH concepts, projects, plans and collabo- rative opportunities, at which seven Figure 1. Timelines for VPH funding calls, the VPH projects and their impact on various VPH-I and NoE project teams presen- communities. Sustainability of the NoE, and hence ongoing support for the VPH and the ted their outputs and engaged with healthcare industries that depend on it, will be achieved through the VPH Institute.
VPHNoE 29 The figure below shows how the VPH initiative is positioned in this regard to date.
Figure 2. The VPH in relation to other related initiatives.
6.5 The next steps 2010-2012: definition and quantification We proposed that these actions of needs should have been sustained by other The VPH is a grand challenge. Here we units of the European Commission identify some current and future specific The STEP experience showed that when (namely DGINFSO FET Proactive, actions: properly managed by a motivated consor- DGRTD Systems Biology, and tium, and when embraced by a lively and DGINFSO e-infrastructures as part of 2009-2011: Establish a collective identity receptive community, a road-mapping the Capacities program) and should exercise could be of great value to capture involve significant portions of the It is important that the multitude of and quantify needs and to develop a traditional constituencies of these players involved be able to speak with a vision around them. In the 2009 version units, as it is necessary to include in single voice in a few strategic situations. of this document we recommended three the action complementary expertise This requires the creation of a collective additional road-mapping exercises: that is well represented in these identity around the VPH brand name. constituencies. We also recommen- This process was completed in late • Road-mapping CSA62 on VPH FET ded that similar actions should have 2011 with the full activation of the VPH (‘Future and Emerging Technologies’) been undertaken to push the VPH Institute. From now on the VPH com- • Road-mapping CSA in integrative agenda as high as possible in those munity will have a collective identity health research European institutions that fund fun- represented by this democratic and par- • Road-mapping CSA in health e-infra- damental research such as the ESF or ticipative non-profit organisation. structures the ERC.
62 Coordinated Support Action
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The VPH Research roadmap produced the VPH community should adopt Digital Patient program should begin by the STEP Action, and the annual toward these neighbourhood commu- from targeted research, followed by update elaborated by the VPH NoE nities should be inclusive, not invasive innovation and deployment pilots as remains the primary source of strategic or elitist. We need to make clear that as the framework develops. vision for the entire VPH initiative. In VPH researchers we do not want to start terms of recommendations, this roadmap designing e-infrastructures, running In silico Clinical Trials: the use of VPH focuses on targeted research, which is wet-bench biology experiments, or modelling to provide the biomedical where most VPH funding has been direc- developing fundamental research in industry an personalised, predictive, ted so far. computer science, mathematics, or and integrative approach to the assess- physics. We recognise that our neigh- ment of medical devices and The VPH-FET support action, funded bourhood communities can do this pharmacological products. In silico cli- by the FET Proactive unit, has produ- much better than we can. What we offer nical trials research targets the use of ced an extensive research roadmap is a common goal toward which all ICT to simulate how large cohorts targeting the ‘blue sky’ technological these skills and those we represent as a would react to new drugs, medical research needs of the VPH community. VPH community can join forces. In the devices, biotech and tissue engineered Three strategic reports with specific continuum of skills and interests, we products. If proved effective these new recommendations relevant to the EU need to find among VPH researchers technologies could be positioned before and beyond, are: "Re-use of Clinical those who are working closer to the real animal and clinical trials, in order Information in Research" [21], "Geno- intersection of each of these communi- to increase the efficacy of their design, type-Phenotype Resources" [22], and ties, and support them as ambassadors reduce the size of the cohorts, the risks "Translational Systems Biology and toward the formation of mixed consor- for the patients (or the invasiveness for Bioinformatics" [23]. tia that can run these road-mapping the animals), and the costs for the bio- exercises in a qualified and representa- medical industry (which could turn into No calls for VPH e-infrastructure road- tive way. It is equally clear that in each a reduction of costs for these products). mapping were made, but the ARGOS of these neighbourhood communities It could also open an entirely new mar- observatory63 has elaborated a policy brief we need to find the experts who are fas- ket, for In Silico Clinical Research for transatlantic cooperation on VPH cinated by the challenges, and who are Organisations, a new type of CRO that Research. The recommendations focus on not afraid of the change that this would would conduct these simulated clinical the need to establish coordinated policies necessarily require to their research trials on the next-generation computing between Europe and the USA in order to practice. cloud. ensure the interoperability and integrabi- lity of VPH infrastructures, as well as the 2013-2020: the VPH in Horizon 2020 Personal Health Forecasting: the use of long-term sustainability, in the current VPH modelling to provide personalised, perspective of a research infrastructure, as The structure of Horizon 2020 is cur- predictive, and integrative services to the well as in the future perspective of clini- rently being defined. In the first patients/citizens. What we propose is to cal and industrial infrastructure. As part document elaborated by the European develop personalised VPH models (inte- of this action the VPH community is rea- Commission for the Europarliament to grative predictive models) that ching out to those neighbourhood describe Horizon 2020, under societal constantly elaborate all the data trans- communities that operate large biomedi- challenges is identified a priority named mitted by personal health systems, cine-related cyberinfrastructures, i.e. in silico medicine. wearable sensors, ambient assisted living molecular biology, biomedical imaging, technologies, mobility monitors, etc, and cancer research, neuroscience, etc. There Following the recommendation of the predict how specific aspects of our is still a hole in the area of blue-sky VPH Institute, discussed and approved health will evolve in a near or not-so- research for VPH infrastructures; the VPH during the last VPH NoE Annual mee- near future. Such models should account community should consider positioning ting, this general priority should be for chronic diseases, recurrent prescrip- this specific challenge in the context of divided into three streams of research tions, or specific disabilities and could be future ESFRI Roadmaps, possibly in funding targeting: further personalised with clinical data consultation with these neighbourhood such as medical imaging, biomedical ins- communities. Digital Patient: the use of VPH model- trumentation, biomarkers, etc. ling to provide personalised, predictive, In October 2011 a support action called and integrative technologies to the 6.6 Towards a European VPH Discipulus began, aimed at developing a medical professionals. The Digital meta-infrastructure research roadmap for the first of the new Patient is intended to be a framework of strategic objectives identified in the VPH information technologies that enable a We conclude this review with a brief des- Institute position paper: the digital more integrative, predictive, personali- cription of other European Research In- patient. The action expected to complete sed, and patient-centric medicine, frastructures (or e-infrastructures) that are in March 2013, will provide a first following the indications that will currently being established or considered: important piece in the definition of the emerge from the specific research road- • Biobanking and Biomolecular VPH research agenda in Horizon 2020. map the Discipulus support action is Resources Research Infrastructure In all these actions, the general strategy expected to produce. By its nature the (BBMRI)
63 http://argos.eurorec.org/
VPHNoE 31 • European Life Sciences Infrastructure • Integrated Structural Biology Infra- services (sequencing, imaging, etc) for biological information (ELIXIR) structure (INSTRUCT) across many fields of biological science. • European Clinical Research Infrastruc- The rationale for many of these initia- tures Network (ECRIN) There are also complementary e-infra- tives is to understand high level • European Research Infrastructure for structures that are aimed at managing phenotypes from genomic, metabolo- Imaging Technologies in Biological very large databases, networking ser- mic, proteomic, imaging and other types and Biomedical Sciences (Euro-BioI- vices, and high-performance computing of data. But establishing high level phe- maging) systems. In all recent roadmaps for Euro- notypes from lower level data requires • European Advanced Translational pean biomedical infrastructures multiscale models. The multiscale Research InfraStructure in Medicine computer modelling, multiscale models modelling framework being developed (EATRIS) and simulation are repeatedly cited, but by the VPH project is an ideal environ- • Biological NMR infrastructure (Bio- it is not clear who or where these activi- ment for guiding this endeavour NMR) ties are going to happen. because, as in all other fields of science, • The European Mouse Mutant Archive mathematical models based on physical (EMMA) We are in the midst of an explosion of principles provide the only method for • European Infrastructure for phenoty- online biological and medical data. guiding experimental measurement and ping and archiving of model Moreover, the European Strategy Forum integrating and interpreting large mammalian genomes (INFRAFRON- on Research Infrastructure64 (ESFRI) amounts of heterogeneous data. ■ TIER) will be providing new data production
64 http://www.ugent.be/nl/onderzoek/financiering/int/ESFRI.htm#biological-and-medical-sciences
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ACKNOWLEDGMENTS
Many people have contributed to this document, which formed the core of a report to the European Commission in 2009 that was updated in 2010 and again in 2011. The main task of drafting the document and seeking feedback for the 2009 and 2010 versions was undertaken by Peter Hunter and Marco Viceconti, and for the 2011 version by Peter Hunter, Peter Kohl, Pat Law- ford and Stig Omholt. All the other authors have made substantive contributions in the form of corrections, suggested improvements or additional text. We are also grateful to members of the NoE Steering Committee and Scientific Advisory Board for their suggestions. We sought feedback on earlier drafts of both this document and its predecessor from the VPH-I community generally, including the project leaders for all the currently funded VPH projects. REFERENCES
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VPHNoE 33 VPH NOE PROJECT FACTS AND CORE PARTNERS
SWEDEN
UNITED KINGDOM
GERMANY
BELGIUM
CENTRE NATIONAL DE LA RECHERCHE SCIENTIFIQUE
FRANCE
SPAIN
ITALY
NEW ZEALAND
VPH NoE project facts and core partners Core Partners: VPH NoE is a network of excellence funded by the European Commission’s Seventh Framework The VPH NoE is comprised of 13 Core Project Partners and an extended Associate (for industrial bodies and organisations) Programme. It contributes to the Virtual Physiological and General (for academic institutions) Membership. Human initiative. University College London, United Kingdom The Chancellor, Masters and Scholars of the University of Oxford, EC Project No: FP7-2007-IST-223920 United Kingdom Instrument: Network of Excellence Centre National de la Recherche Scientifique, France Start Date: June 1st, 2008 Université Libre de Bruxelles, Belgium Institut National de Recherche en Informatique et en Automatique, Duration: 4.5 years France Project Management: UCL/UOXF The University of Nottingham, United Kingdom Workpackage Leaders : UCL, CNRS, UOXF, UPF University Pompeu Fabra, Spain The University of Auckland, New Zealand Core Project Members: EMBL, KI, IMIM, ULB, UNOTT, European Molecular Biology Laboratory, Germany UOA, USFD, INRIA, IOR The University of Sheffield, United Kingdom Total Project Cost: 9.65 million euros Karolinska Institutet, Sweden Institut Municipal d’Assistencia Sanitaria, Spain 8 million euros EC Funding: Istituto Ortopedico Rizzoli, Italy Further Information: www.vph-noe.eu
For additional information and to take and active part in the VPH NoE activities, please visit: http://www.vph-noe.eu