grace: the first network of excellence on primary care in europe herman goossens co-ordinator
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GRACE:The First Network of Excellence on
Primary Care in Europe
Herman GoossensCo-ordinator
GRACE
From ‘molecule to management’ in community-acquired LRTI:
GRACE as a model for translating scientific innovation into benefits for patients
GRACE: Aim
• The overall aim of GRACE is to combat antimicrobial resistance through integrating and strengthening centres of excellence for studying the application of genomics with primary care practitioners, to community-acquired lower respiratory tract infections (LRTI), which is the leading reason for seeking medical care and consuming antibiotics.
• GRACE will develop into a “European Lower Respiratory Tract Infection Research Centre” to investigate and improve the bed-site management of community-acquired LRTI.
The Target Community-acquired LRTI in GRACE
• Acute cough syndrome
• Acute bronchitis
• Community-acquired pneumonia (CAP)
• Infective exacerbations of chronic obstructive pulmonary disease (COPD)
• Infective exacerbations of asthma
GRACE: Facts and Figures
• Period of funding: March 1, 2006 – February 28, 2011
• Grant for integration: 11.5 million Euro• Co-ordinating centre: University of
Antwerp, Belgium• Partners from 14 countries:
– Full partners: 24 from 10 countries (including 5 SMEs from 3 countries)
– Primary Care Networks: 13 from 11 countries
GRACE: Four Platforms
• GRACE-COMIT:– WP1: Co-ordination, Organisation, Management– WP2: IT infrastructure
• GRACE-TECH: – WP3, WP4, WP5, WP6, WP7: Technical platform
• GRACE-PAT: – WP8, WP9, WP10, WP11: Patient platform
• GRACE-EDUT: – WP12: Education and Training platform
GRACE-COMIT
WP N° Workpackage Lead Partner
1 Project co-ordination and Herman Goossensmanagement University of Antwerp,
Belgium (and University of
Leiden, Netherlands)
2 Develop IT platform and tools for Robert Veen
information technology University of Utrecht,Netherlands
WP N° Workpackage Lead Partner
3 Microbial genomics for diagnosis of Greet Ievencommunity-acquired LRTI University of Antwerp,
Belgium
4 Human genomics for studying Adrian Hillrisk factors University of Oxford,
United Kingdom
5 Virus discovery Willy SpaanUniversity of Leiden,
Netherlands
6 Pneumococcal genomics Birgitta Henriques-Normark,Swedish Institute for Infectious
Disease Control, Sweden
7 Haemophilus genomics Derrick Crook
University of Oxford,United Kingdom
GRACE-TECH
GRACE-PATWP N° Workpackage Lead Partner
8 Observational study on determinants Christopher Butlerof antibiotic use Cardiff University,
United Kingdom
9 Observational studies on aetiology, Theo Verheijdiagnosis and prognosis University of Utrecht,
Netherlands
10 Randomised control trials Paul LittleUniversity of Southampton,
United Kingdom
11 Economics of resistance Joanna Coast,University of Birmingham,
Richard SmithUniversity of East Anglia,
United Kingdom
GRACE-EDUT
WP N° Workpackage Lead Partner
12 Education and training Francesco BlasiUniversity of Milan,
ItalyRoger Finch
University of Nottingham,
United Kingdom
WP1: Objectives
• To provide a secure framework to ensure that the objectives of the work programme are complied with
• To achieve the expected degree of integration through the joint programme of activities
• To interact with the Commission, press and public• To setup a business centre• To prepare financial contracts and consortium
agreement • To ensure the optimal use of the generated knowledge
within the scientific community and the public• To manage staff mobility within the Network• To manage quality control• To develop a durable network beyond the period of the
Commission’s financial support
WP1: Description of the Work
• Provision of a secure framework for structural decisions
• Management of flow of patient samples and isolates
• Management of quality control • Management of staff mobility • Monitoring the progress of the workpackages• Setting up a business centre• Preparing financial contracts, consortium
agreement• External communication
WP1: Expected Achievements
A high quality organisation and management
WP2: Objectives
• To co-ordinate and harmonise the IT platform. • To develop a Data Processing Centre• To develop a web-based content management system• To develop the GRACE portal• To develop a technical framework access control management• To develop a technical security and privacy concept and framework• To engineer support for the development of database schemata for
repositories• To engineer support for the development of web-based case report
forms (CRFs)• To develop data export functions for statistical evaluation• Technical maintenance of Data Processing Centre
WP2: Description of the Work • Co-ordination and harmonisation of IT platform.• Development of a Data Processing Centre• Development of web-based content management
system.• Development of the GRACE portal• Development of a technical platform for access control
management• Development of a technical security and privacy concept
and framework• Engineering support for the development of database
schemata for repositories• Engineering support for the development of web-based
case report forms• Support of data export functions for statistical evaluation• Technical maintenance of Data Processing Centre
WP2: Expected Achievements
A high quality IT infrastructure
WP3: Objectives
• To develop novel rapid genome based diagnostic tests for the detection of pathogens implicated in community-acquired LRTI
• To develop reference reagents and an external quality assessment programme for molecular diagnostic methods for patients with community-acquired LRTI
• To establish a European repository of specimens and strains linked to a database including microbial and patient information
WP3: Description of the Work
Diagnostics:• Inventory of diagnostic (molecular) methods in the participating
laboratories• Establishing banks of fully characterised respiratory pathogens• Development of reference reagents, calibrated stocks and ‘run
controls’• Development and distribution of proficiency panels for external
quality assessment• Development and optimisation of molecular methods for aetiological
diagnosis • Clinical validation of the novel technology
Repositories:• Development of a bank of clinical materials from well-defined
patients with community-acquired LRTI• Development of a bank of well characterised clinical isolates of
respiratory pathogens
WP3: Expected Achievements
• Novel rapid genome based diagnostic tests for the detection of pathogens implicated in community-acquired LRTI
• European repository of specimens and strains linked to a database including microbial and patient information
WP4: Objectives
• To devise the potential genetic risk profile for community-acquired LRTI
• To assess whether these polymorphisms identify individuals at risk of various presentations and outcomes of community-acquired LRTI in several European populations
• To determine whether these human genetic risk factors interact with each other or with key microbial genetic or other environmental risk factors for community-acquired LRTI
• To identify potential target pathways for new immunomodulatory approaches
WP4: Description of the Work Two case-control studies:
First case-control study (years 1-3)• Genotyping of severe community-acquired LRTI cases and controls
from the UK by Illumina Beadarray high throughput typing for 30,000 coding SNPs with a minimum allele frequency >5% that span the entire human genome
• Define the 30 most strongly associated SNPs• Define the causative variants in these relevant genes
Second case-control study (years 3 - 5)• Retesting of the 30 most strongly associated SNPs in a larger study
of about 6000 cases and locally matched controls from 6 European sites by Sequenom mass spectrometry or microarray
• Genotyping of specific loci of particular interest such as: Ig receptors, cytokines, cytokine receptors, acute phase reactants, collectins, toll receptors, chemokines, inflammatory signalling pathway components, macrophage and neutrophil receptors.
WP4: Expected Achievements
Genetic risk factors for (particular) phenotypes of community-acquired pneumonia (caused by certain pathogens)
WP5: Objectives
• To align RNA viruses to identify conserved domains for primer selection
• To optimise the CODEHOP programme for the selection of degenerated CODEHOP primers
• To construct test systems using amplicons created with consensus and CODEHOP primers
• To validate test systems for screening clinical samples
• To identify the genomes and characterise new viruses
WP5: Description of the Work
Two amplification-based strategies:
• Nested Primers Primagen’s PALM Method: – Generic and specific primers located within the first amplicon– Sequencing of obtained second amplicon of about 500 to 600
nucleotides
• CODEHOP-based approach: – Primers with a non-degenerate 5' end and degenerate 3' end – Primers designed using a method based on the CODEHOP
programme– Bioinformatics-based improvements of the CODEHOP– Principal target: RNA dependent RNA polymerase of three major
genera of the Nidovirales – Validation of the developed techniques– Adaptation to encompass other virus genera
WP5: Expected Achievements
New tools to detect novel or previously unknown viral pathogens in clinical specimens form patients with community-acquired LRTI
WP6: Objectives
• To correlate antibiotic resistance, virulence characteristics and pneumococcal genotype to severity of community-acquired LRTI
• To identify pneumococcal genes important for virulence and for antibiotic resistance development
WP6: Description of the Work • Collection of isolates with resistance profiles and clinical
information through WP9 and WP10• Genotypic determination of new resistance determinants• Serotyping and genotyping of relevant (virulent) pneumococci • Correlating antibiotic resistance profile and genotype to
clinical parameters with the aim of finding certain clones that are more virulent and prone to spread
• Study of known pathogenicity islands as well as horizontally acquired genes important for resistance development by comparative genomics using microarray chips, and correlate to clonality and clinical information.
• Deletion of relevant genes by performing knockout mutants and study for virulence in various models (tissue culture, animal, etc)
WP6: Expected Achievements
Pneumococcal genes important for virulence and for antibiotic resistance development
WP7: Objectives
• To determine the relationship between antibiotic usage and prevalence of resistance in Europe among infecting and colonising haemophili, as determined by resistance genes encoded by: – integrating conjugative mobile elements, and– chromosomal genes
• Determine the phylogenetic relationships between conjugative elements and their host bacteria
• Determine the prevalence and distribution of hypermutable H. influenzae clinical isolates in Europe
• Determine the European variation in the prevalence in clinical settings and carriers of capsulated isolates, their molecular epidemiology and their resistance mechanism
WP7: Description of the Work
• Collection of H. influenzae from clinical samples and Haemophilus species from throat samples, through WP9 (prevalence of resistance) and WP10 (impact of use)
• Determination of species by conventional methods and 16S RNA sequence analysis
• Phenotypic characterisation of antibiotic resistance (MIC)• Genotypic characterisation of antibiotic resistance by
multiplex PCR (conjugative elements), PCR and sequencing (chromosomal elements)
• Multi-locus sequence analysis of the resistance elements and host bacteria
• Study of the prevalence of mechanisms of hypermutability (i.e. mutations in the DNA repair system, mutS and mutL).
• Capsular typing of representative H. influenzae isolates by molecular procedures
WP7: Expected Achievements
• Relationship between antibiotic usage and prevalence of antibiotic resistance encoded by a conjugative and chromosomal genes
• Phylogenetic relationships between conjugative elements and their host bacteria
• Prevalence of hypermutable H. influenzae clinical isolates in Europe
• Prevalence and characterisation of capsulated H. influenzae isolates
Flow of Specimens and Isolates among Academic Participants and SMEs
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University of Antwerp
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University of Oxford
WP4A. Hill
University of
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WP5W. Spaan
Swedish Institute forInfectious Disease
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WP6B. Henriques-Normark
University of Oxford
WP7D. Crook
Project Managemant OfficeUniversity of Antwerp
WP1
H. Goossens
National Co-ordinating Diagnostic Laboratories
WP9, WP10Hospitals Primary Care Networks
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WP8: Objectives
• To establish a collaboration of primary care research networks in Europe
• To describe current presentation, investigation, management and outcomes for patients with community-acquired LRTI in primary care in Europe
• To achieve a deep understanding of the micro-level determinants and contextual factors that influence antibiotic prescription/management for community-acquired LRTI
• To develop evidence-based definitions for community-acquired LRTI
Primary Care Networks
Primary Care Networks Participating in WP8 (I)
Country N° practices/ Co-ordinator Facilitator
N° GPs
Belgium 25/50 Samuel Coenen Samuel Coenen
Finland 5-10/50-150 Ulla-Maija Rautakorpi Ulla-Maija Rautakorpi
Germany 15-25/15-25 Tom Schaberg Konstanze Voigt
Hungary 25/20 Bernadette Kovacs Bernadette Kovacs
Italy 20/15 Francesco Blasi Francesco Blasi
Netherlands 7/35 Theo Verheij Eelko Hak
Primary Care Networks Participating in WP8 (II)
Country N° practices/ Co-ordinator Facilitator N° GPs
Norway 8/32 Carol Pascoe Hasse Melbye
Poland 5/10 Maciek Godycki-Cwirko Maciek Godycki-Cwirko
Spain 20/6 Jordi Almirall Jordi Almirall
15/6 Antoni Torres Ruano Nuria Sanchez
Sweden 10/40 Bo-Eric Sigvard MölstadMalmvall Futurum
UK 25/60 Christopher Butler Richard Hibbs
8/24 Michael Moore Michael Moore
WP8: Description of the Work Quantitative, registration study
• 13 PC networks in 11 countries have been selected (minimum of 20,000 patients)
• Computerised or paper standardised formats
• Consecutive enrolment of 300 patients/network consulting with acute cough
• Data collection (patients and primary care clinicians) over two one-month periods (February and September)
WP8: Description of the WorkQualitative in depth study
• Stratification of practices and samples to maximise variation
• Training of researchers in qualitative interviewing• Interview study, exploring:
– PC Clinicians’ accounts of management of patients with community-acquired LRTI
– Patients’ accounts of their experiences and beliefs about medical management of LRTI
• Data analysis according to the procedures of Grounded Theory
WP8: Description of the Work Developing definitions
Multi-step evidence-based development of definitions withinternationally agreed clinical (signs and symptoms) and technical(radiological and microbiological) criteria for the target diseases:
Empirical research (the quantitative study will provide the platform todescribe syndromes and clinical presentation)
↓Literature searching
↓Expert opinion to enhance the empirical research and literaturesearching
↓Consensus groups (using modified Delphi technique)
↓Face validity (the qualitative study will provide the platform to confrontthe definitions with clinical reality)
WP8: Expected Achievements• Description and a deep understanding of the variation in presentation,
investigation, management and outcomes of community-acquired LRTI• Pilot specimen collection, procedures and inform study methods for
WP9, WP10, WP11• Identification of good practice and factors which predispose and
maintain this good practice, that may be generalised in later intervention studies (WP10) and education and training initiatives (WP12)
• Areas in which practice could be enhanced and targets for interventions aimed at improving antibiotic prescribing/management, and inform the prioritising, the nature and location of the intervention studies (WP10)
• An instrument to measure change in attitude, knowledge and beliefs about common infections and their management (WP10)
• Provide data for modelling studies (WP11)• Definitions on which to base later observational, intervention and
modelling studies (WP9, WP10 and WP11)
WP9: Objectives
• To study the role of “atypical” bacteria and viruses, including novel pathogens, in patients with community-acquired LRTI
• To assess risk factors for infection with (resistant) S. pneumoniae and H. influenzae in patients with community-acquired LRTI
• To develop clinical models to differentiate viral from bacterial infections and identify pneumonia
• To develop clinical models to identify patients at risk for adverse outcomes including severe and prolonged illness
WP9: Description of the WorkSetting
• Same cohort for all objectives of WP9 (and for the randomised clinical trial of WP10)
• About 6 large computerised primary care research networks across the EU– representative populations for the main regions in
Europe – affiliated with major hospitals.
• Protocols for inclusion of study subjects and data collection developed in other WP
• Inclusion criteria will be tailored to the definitions developed in WP8
WP9: Description of the WorkThree types of investigations
An aetiological study• A case-control study nested in the predefined cohorts of each national
network- cohorts of approximately 2,400 adults and elderly/network- nested random sample of 25% of the cohort (approximately
600/network)• Blood and urine sampling, nose-throat swabs for GRACE-TECH • Pulmonary measurementsA diagnostic cross-sectional study• Starting point: baseline of the aetiological study • Cases with suspected community-acquired LRTI (max of about 500
cases/network)• Blood and urine sampling, nose-throat swabs for GRACE-TECH• Pulmonary measurements A prognostic study • Starting point: baseline of the diagnostic study• Cases with confirmed community-acquired LRTI • Follow up prospectively during 3 months All studies: Web-based data collection
WP9: Expected Achievements
• A simple clinical algorithm that can help the primary care clinician to distinguish viral from bacterial infections, and acute bronchitis
• A simple clinical algorithm that can support the primary care clinician to detect community-acquired pneumonia.
• A simple algorithm that will enable the primary care clinician to discern patients with community-acquired LRTI at risk for complications from patients with self-limiting disease with low risk for poor outcome
• Provide data for economic modelling (WP11)
WP10: Objectives
• To assess the effectiveness of antibiotics among patients with community-acquired LRTI in order to understand which subgroups selectively benefit from antibiotic treatment
• To develop and assess a practice based intervention based on improvements of antibiotic prescribing behaviour in patients with community-acquired LRTI and explore the effect on antibiotic resistance
WP10: Description of the workTwo clinical trials
Antibiotic randomised placebo-controlled double-blind trial• Starting point: nested in the diagnostic study• Cases with community-acquired LRTI, not CAP (max of about 500
cases/network)• Intervention: antibiotic or placebo; patients stratified by three age
groups• Bed-side patient testing• Blood and urine sampling, nose-throat swabs for GRACE-TECH• Pulmonary measurements • Web-based data collection. • Outcomes: deterioration of illness; symptom severity and duration, … Outreach RCT of optimal package of care• 30 practices/network of “not low” AB prescribers• randomly chosen in each of the 6 networks (i.e. 180 practices)• Intervention: academic detailing/outreach and controls• Outcomes: AB prescribing, hospitalisation, length of illness, …
WP10: Expected Achievements
• Identification of subgroups of patients with community-acquired LRTI who benefit from antibiotic treatment
• A practice based validated intervention for improving antibiotic prescribing in patients with community-acquired LRTI
WP11: Objectives
• To model the macroeconomic impact of antibiotic resistance and policies to contain it
• To model the cost-effectiveness of the management strategies developed in the observational studies
• To conduct economic evaluations in parallel with the intervention studies
• To conduct economic evaluations of molecular diagnostics
WP11: Description of the Work • Macro-economic modelling of impact of resistance and policies to
contain it: Model: Computable General Equilibrium UK approach, extended to other European countriesPolicy options: derived mainly from exploration of WP8
• Estimating costs and health outcomes associated with resistant and
susceptible disease:Methods: – comparisons between subjects infected with AB resistant or susceptible
bacteria, with appropriate statistical modelling– Event History Models
Resource use data: questionnaires in WP9 and WP10; existing routine data systems
• Economic evaluation alongside intervention studies: First 18 months: develop protocols for primary (reduction in antibiotic prescribing) and other outcome parameters Remainder: economic evaluation
• Economic evaluation of molecular diagnostics
WP11: Expected Achievements
• A model for the macroeconomic impact of antibiotic resistance and policies to contain resistance
• Cost-effectiveness of the management strategies developed in the observational and intervention studies
• Economic evaluation of molecular diagnostics
WP12: Objectives
• To contribute information aimed at increasing awareness among the public and policy makers of the importance, economic impact and threat of antimicrobial resistance
• To develop education and training support to disseminate awareness and knowledge relevant to antibiotic resistance and its control
• To develop educational packages including web-based resources and workshops to inform postgraduate lifelong learning needs of prescribing professionals
WP12: Description of the Work
• Participating scientific societies: ERS and ESCMID (organising committee)
• Target audience: hospital practitioners, primary care clinicians, community pharmacists, Public Health practitioners, and laboratory researchers
• Instruments: – Teaching courses and workshops at changing
location– Educational web site: Virtual Learning Centre (VLC)
consisting of a web based learning and assessment package
WP12: Expected Achievements
• Increasing awareness among the public and policy makers of the threat of antimicrobial resistance
• Dissemination of knowledge relevant to antibiotic resistance and its control
• Educational (web-based) postgraduate learning packages
Joint Programme of Activities (first 18 months)
• Establishment of the platforms • Development and sharing of common research and
molecular diagnostic tools and methods (WP3-7)• Development of questionnaires and databases for
reagents, strains, patient specimens and data (WP2-7)• Observational studies on current management of
community-acquired LRTI in European primary care (WP8)
• Selection of the primary care networks for WP9 and WP10
• Development and integration of data collection for economic models (WP11)
Joint Programme of Activities (18 months to 5 years)
• Development and application of molecular technologies (WP3, WP5-7)
• Studies on genetic risk factors (WP4)• Observational (WP9) and intervention (WP10) studies• Integrating the data to develop innovative management
strategies• Development and promotion of evidence-based
recommendations for an optimal treatment of community-acquired LRTI through cost-effective strategies
• Application of economic models into microbial and human research (WP11)
Joint Programme of Activities(full duration)
• Spreading the excellence• Development of computer programmes
and educational tools for continued training
• Enhancing and strengthening the network activities through looking for new partners and finding funding sources
• Collaboration with other (EU-funded) research programmes
Potential Applications of GRACE (I)
• Novel rapid genome based diagnostic tests for the detection of pathogens implicated in community-acquired LRTI
• A European repository of research tools, strains, and patient specimens linked to a database including microbial and patient information, for genomic diagnostics
• Pneumococcal genes important for virulence and for antibiotic resistance development
• Optimal pneumococcal treatment and prevention strategy linked to severity of community-acquired LRTI
• Human susceptibility genes affecting severe community-acquired LRTI• Potential human target pathways for new immunomodulatory
approaches• Potential genetic risk profiles for various presentations and outcomes of
community-acquired LRTI in several European populations• Evidence-based definitions of the major community-acquired LRTI
Potential Applications of GRACE (II)
• Clinical models to differentiate viral from bacterial infections and identify pneumonia.
• Clinical models to identify patients at risk for adverse outcomes including severe and prolonged illness
• More focused management of patients with community-acquired LRTI, through new genomic tools, thereby resulting in better resource utilisation
• Clinical outcome measures for evaluating interventions• Feasible, acceptable and cost-effective practise based intervention in
reducing inappropriate antibiotic use in patients with community-acquired LRTI
• A model for the macroeconomic impact of antibiotic resistance and policies to contain resistance
• A model for economic evaluations of molecular diagnostics• Educational packages to inform postgraduate lifelong learning needs of
prescribing professionals
Long-term Impact of GRACE
• Establish the principle and practice of linking basic science with clinical care for community-acquired LRTI
• Enhance the competitiveness of European translational research
• Link science with education and provide a focus for spreading of excellent practice throughout Europe
• Cement future international research collaborations linking international experts in primary and secondary care research in community-acquired LRTI
• Contribute to EC policy developments• Strengthen European excellence and achieve a
leadership on community-acquired LRTI
Conclusion
• GRACE will serve as model of how different but relevant disciplines in health care can be integrated and combined and of how the full cycle of translating basic science innovation into clinical care can be achieved efficiently and seamlessly.
• GRACE will develop into a “European Lower Respiratory Tract Infection Research Centre” to investigate and improve the bed-side management of community-acquired LRTI.