st andrews, may 2013 · 2019-04-09 · clinical laboratory genomics & transcriptomics cell...
TRANSCRIPT
St Andrews, May 2013 The roadmap continues
• Welcome • Fire alarms • Undergraduate examinations • Workgroups
Implementation of systems medicine across Europe
► Stakeholders meetings – big picture, systems biology to medicine
► Workshops – large, flexible
► Achievement to date
► Challenge – tractable clinical questions
Implementation of systems medicine
► Stakeholders meetings – big picture, systems biology to medicine
► Workshops – large, flexible
► Achievement to date
► Challenge – tractable clinical questions
“Systems biology...is about putting together rather than taking apart, integration rather than reduction. It requires that we develop ways of thinking about integration that are as rigorous as our reductionist programmes, but different....It means changing our philosophy, in the full sense of the term”. Denis Noble
Systems what? ► Biology – big model, dynamical,
comprehensive datasets, explanation and prediction, integrative
► Medicine – towards 4P: prevention,
predictive, participatory: incomplete datasets, imperfect quality, tractable problems, models and analysis
The purpose of the St Andrews meeting ► Inform the roadmap document – the European
standard, future goals, future funding, close working with the Commission, benefit to all
► Everyone to contribute – small numbers, people
with relevant insights into problems, rather than just systems expertise
► Diagnosis, taxonomy, treatment, discovery,
participation, prediction, economics, education, personalisation, prevention and public health
8
• “ The patient has a voice “ – Pim de Boer
• “ A new paradigm for cancer treatment “ –
Francis Lévi
• Focussed outputs – iterative modelling – Drieke Vandamme
CASyM is funded by the European Union; 7th Framework Programme under the Health Coorporation Theme and Grant Agreement # 305033
A new paradigm for cancer treatment Francis Lévi
Chronotherapy Unit, Department of Medical Oncology Paul Brousse hospital, Villejuif (France)
UMRS 776 Rythmes Biologiques et Cancers
But how efficiently can we use these data?
Metabolomics Proteomics Imaging Clinical laboratory
Genomics & Transcriptomics
Cell Biology & Molecular Biology
Technology Platforms
Pathology & Biomarkers
MS-data Images Biochemical data
Metabolomics data
Gene array dataSequencing data101
102
103
100
FACS dataTissue
microarrays
What can Systems Biology do for Medicine? We can produce more data on patients than ever before
Walter Kolch
Roadmap for Systems Medicine
2 years
5 years
10 years
Clinical needs
SysBio
Systems Medicine Paradigm
shift
Clinical practice
&RTD
• Rhythmic biology The mammalian Circadian Timing System
• Circadian disruption (or induction) on cancer Biomarkers
• Cancer chronotherapeutics Shifting treatment paradigm
• Conclusions & perspectives
Rest-activity rhythm
Molecular clocks in
peripheral organs
• Cell cycle & DNA repair • Metabolism • Drug detoxification • Angiogenesis
Circadian biomarkers
Lévi et al. Annu Rev Pharm Toxicol 2010
Body Temperature
rhythms
Cortisol, melatonin rhythms
Day/night Chronic jet lag
Disease processes
Treatment effects
Meal timing
Clock gene mutations
The Circadian Timing System
Drugs →
Drugs →
Lévi et al. Annu Rev Pharm Toxicol 2010 Bjarnason et al. Am. J Pathology 2001
hBmal1
0.2
0.4
0.6
0.8
1
0.0 08 12 16 20 00 04
hPer1 hBmal1
Clock gene transcription rhythms in human oral mucosa
Time (clock hours) CCG
Clock-Controlled genes
- Drug metabolism and detoxification Cyp3a, Ces1-3, UGT1A1, GST-π, Upa, Dpyd,… -Drug transport Abcb1a/b, Abcc2, Abcg2,… - Drug targets TS, Top1, Top2,… -Cell cycle, apoptosis, repair Wee1, P21, P53, c-Myc, Bcl-2, Bax, Mdm2, cyclin D, Tip60,…
The Molecular Clock System
In vitro circadian biology & pharmacology
Cell culture Circadian synchronisation
•50% FCS or • Dexamethasone
Samples every 4 h for 48-72 h
12 1 2
7 6 5 4 8
9 10
11
3
12 1 2
7 6 5 4 8
9 10
11
3
12 1 2
7 6 5 4 8
9 10
11
3
12 1 2
7 6 5 4 8
9 10
11
3
12 1 2
7 6 5 4 8
9 10
11
3
12 1 2
7 6 5 4 8
9 10
11
3
12 1 2
7 6 5 4 8
9 10
11
3
12 1 2
7 6 5 4 8
9 10
11
3
12 1 2
7 6 5 4 8
9 10
11
3
12 1 2
7 6 5 4 8
9 10
11
3
12 1 2
7 6 5 4 8
9 10
11
3
12 1 2
7 6 5 4 8
9 10
11
3
12 1 2
7 6 5 4 8
9 10
11
3
12 1 2
7 6 5 4 8
9 10
11
3
12 1 2
7 6 5 4 8
9 10
11
3
12 1 2
7 6 5 4 8
9 10
11
3 12 1 2
7 6 5 4 8
9 10
11
3
12 1 2
7 6 5 4 8
9 10
11
3
12 1 2
7 6 5 4 8
9 10
11
3
12 1 2
7 6 5 4 8
9 10
11
3
12 1 2
7 6 5 4 8
9 10
11
3
12 1 2
7 6 5 4 8
9 10
11
3
12 1 2
7 6 5 4 8
9 10
11
3
12 1 2
7 6 5 4 8
9 10
11
3
12 1 2
7 6 5 4 8
9 10
11
3
12 1 2
7 6 5 4 8
9 10
11
3
2 h
• Rhythmic biology The mammalian Circadian Timing System
• Circadian disruption (or induction) on cancer Biomarkers
• Cancer chronotherapeutics Shifting treatment paradigm
• Conclusions & perspectives
Rest-activity circadian biomarker before chemotherapy
Rest-activity monitoring Computation of I<O
I<O prediction of overall survival in 436 patients with mCRC
Circadian disruption: I<O less than 97.5%
I<O = 100%
I<O = 77.6%
Lévi et al. Submitted
Circadian disruption on chemotherapy
Circadian disruption on chemotherapy in mice 12 anticancer drugs according to dose and circadian timing
R24 = 0,48
Before irinotecan
PS = 0 After irinotecan
R24 = -0,04
PS = 3 Asthenia grade 3 Anorexia grade 3
(38) (39)
Circadian disruption
Innominato et al. Int J Cancer 2012
Rest-activity circadian biomarker during chemotherapy
• Rhythmic biology The mammalian Circadian Timing System
• Circadian disruption (or induction) on cancer Biomarkers
• Cancer chronotherapeutics Shifting treatment paradigm through CTS integration
into drug scheduling and delivery
• Conclusions & perspectives
Chronotolerance vs Chronoefficacy
Ortiz-Tudela et al. Handbook of Exp Pharm 2013
L-Alanosine
Vinorelbine
Pirarubucin
Oxaliplatin
Gemcitabine
Interleukin-2 Doxorubucin
Irinotecan Cytarabine
Docetaxel
Seliciclib
Interferon-β 5-fluoro-2'-deoxyuridine
0 12 24
0
12
24
5-Fluorouracil
Circadian timing of best tolerance (ZT hours)
Circ
adia
n tim
ing
of b
est e
ffica
cy (Z
T,ho
urs)
Combination chronotherapeutics
Fold increase in life span (vs untreated controls)
Ortiz –Tudela et al. Handbook of Exp Pharm 2013
-20
0
20
40
60
80
100
120
4 pm 12 pm 8 am 4 pm
5-FU profil
[5-F
U]
(% o
f max
con
cent
ratio
n)
Time (h)
10 pm 10 am
04 am
5-FU
Optimal fixed drug delivery profile
Lévi, Altinok, Goldbeter In: Cancer Systems Biology 2011
Host?
Cell cycle, 22 h Variability, 5% Circadian entrainment
Tumor?
Cell cycle, 18 h Variability, 15% No circadian entrainment
Oncologist Patient Consultation
Care Unit Programmation Pharmacy
Coordination
Personnalized medical care plan Prescription, verification
Home
Home Care
Chronotherapy Unit, Hôpital Paul Brousse, Villejuif 1990-2013: ~ 3 000 patients
Research & Development Family
doctor
Education • health care personnels • patients
Giacchetti et al. J Clin Oncol 2006; Ann Oncol 2012 Innominato et al. Chronobiology Int 2011 Int J Cancer 2012; Cancer 2013
Conventional chemotherapy
Chronotherapy
564 patients first line treatment for metastatic colorectal cancer 36 centers, 10 countries
Time (months)0 12 24 36 48 60 72 84 96 108 120
Pro
po
rtio
n a
live
0,0
0,1
0,2
0,3
0,4
0,5
0,6
0,7
0,8
0,9
1,0 None (G0)Mild (G1-2)Severe (G3-4)
Time (months)0 12 24 36 48 60 72 84 96 108 120
Pro
po
rtio
n a
live
0,0
0,1
0,2
0,3
0,4
0,5
0,6
0,7
0,8
0,9
1,0 None (G0)Mild (G1-2)Severe (G3-4)
FOLFOX2
p < 0.0001
chronoFLO4
p = 0.36
Neutropenia Neutropenia
Time (months)0 12 24 36 48 60 72 84 96 108 120
Pro
po
rtio
n a
live
0,0
0,1
0,2
0,3
0,4
0,5
0,6
0,7
0,8
0,9
1,0 None (G0)Mild (G1-2)Severe (G3-4)
chronoFLO4
p = 0.36
Neutropenia
Innominato et al. Chronobiology Int 2011
FOLFOX2 chronoFLO4
CTS toxicity
No CTS toxicity
p = 0.136
CTS toxicity
No CTS toxicity
p < 0.0001
Circadian Timing System Toxicity : BWt loss & asthenia Innominato et al. Cancer 2013
Tolerability Coordinated peripheral clocks
Predictable optimal timing
Drug detoxification
Circadian physiology Rest-activity Body temperature Hormones & cytokines Feeding pattern
Tumor inhibition
Anticancer drug
Toxicity
Disruption
Poor coordination
Tumor progression
Poor detoxification
Unpredictable optimal timing Lévi et al.
Annu Rev Pharm Toxicol 2010
CTS integration for treatment optimization
21
Systems cancer chronotherapeutics
Ballesta et al. PLOS Comput Biol 2011 Ortiz –Tudela et al. Handbook of Exp Pharm 2013
Rest-activity rhythm Cancer processes
Treatment effects Temperature rhythm
Multidrug chronotherapy effects on circadian biomarkers
Cancer Chronotherapy Pilot 40 patients: BWt, symptoms, rest-activity rhythm
Actigraph Data
Home Gateway
Tele-health System (SARA)
Tele-health Data
GPRS or IP Network
Remote Service Provider
Tele-health Service (SARA) Hydra
Middlew
are
Medical Web App
Contact Centre
Social Response
Medical Response
Technical Provider
Chronochemotherapy at home in 2 patients with metastatic colorectal cancer receiving Irinotecan, Oxaliplatin, 5Fluorouracil, Leucovorin (chronoIFLO4)
Daily teletransmission of rest-activity patterns during multidrug chronotherapy at home
97.8%
Patient 1 Patient 2
96.8%
98.9%
99.1%
98.7%
99.2%
I<O I<O
Toward a shift in paradigm of cancer treatments
►Conventional chemotherapy principle: The more the toxicity, the better the efficacy
►Chronotherapeutics principle: The better the tolerability, the better the efficacy (personalized model-based drug delivery)
CASyM is funded by the European Union; 7th Framework Programme under the Health Cooperation Theme and Grant Agreement # 305033
The patient has a voice
dr. Pim de Boer
Lung Foundation Netherlands / Longfonds
Leiden University Medical Center
Patient empowerment
► “Nothing about us without us” (B. de Szemere. Hungary, from 1848 to 1860. R. Bentley, London. 1860. p173; J.I. Charlton.
Nothing about us without us. Disability oppression and empowerment. University of California
Press, Berkeley CA. 1998; many patient organisations now)
► “My right knee”. (D.M. Berwick. Improving patient care. My right knee. Ann Intern Med 2005, 142: 121-125)
1. No needless death; 2. No needless pain; 3. No provision of helplessness; 4. Not keeping
waiting; 5. No waste of resources => need for contract MD-patient to improve quality of HC.
► “Don’t look at me but SEE me. Don’t listen to me but HEAR me”
(L. Engelen. The patient as partner. Scouting expedition by the UMC St Radboud. BSvL, Houten
NL. 2012)
Patients are not disease subjects only need for holistic views;
often patients tell more behind their words.
► Reflection interviews (mirror interviews)
See yourself being treated in a hospital. How are you treated, how did you feel, were you being
listened to and attended for when you asked the doctors or nurses, etc. HuMedSci
Consultancy
Patient involvement: definition
Patient participation or involvement in research:
taking part in any of the processes of formulation,
passage and implementation of research
Why is patient involvement needed?
► Normative argument:
(Multimorbid) patients are affected by their own treatments
► Instrumental argument:
* more relevance of the research
* better quality of the research
* better results and chances for societal implementation
► Legitimacy:
Democratic decision making in research, its policy & budgetting
“Patients are experts in living with and treatment of their own disease(s)”
Patient empowerment HuMedSci Consultancy
Theoretical framework Problem identification
Problem definition
Approach- methodology
Execution of research Interpretation & evaluation
com
mu
nic
atio
n
Adaptation
Knowledge transfer
Implementation Research
“Patient” as co-producer/leader Society science
health care
politics
public
individuals groups
communities
operational
strategic
Based on: D Wilcox, 1994; D Winstanley, 1995; C Hart, 1997; G Chanan, 1999; Franklin & Sloper, 2005
HuMedSci Consultancy
industry
Patient as partner: co-decider
consultant-advisor information carrier
subject in study decoration
Examples of best practices – 1: research
http://www.lindalliance.org/
http://www.ubiopred.eu http://www.patientsacademy.eu
ECAB protocol review process Our experienced treatment advocates, expert patients and community advisors read and review trial protocols and informed patient consent forms from the patients’ perspective…
Examples of best practices – 2: health care
http://www.involve.org.uk
COPD standard of care
patient version (NL)
Practical approaches: examples
How to run a patient organisation,
how to involve patients in research, which tools
are needed (a grid supplied), communication,...
See EPF: http://www.eu-patient.eu
How to evaluate documents or protocols,
tools to participate in councils or advisory
boards, training on the use,...
See e.g.: http://www.pgosupport.nl
Appraisal criteria include domains:
relevance; QoL; QoC; ethics-safety; information-communication
G Teunissen et al. J Participat Med 2013, 5: e16
Practical approaches: what did we learn?
IMI U-BIOPRED & PROactive projects; Longfonds PAB:
+ patients being listened to for needs and wishes
+ project adaptation relevant to patients/participants
+ patient partnership = being taken seriously, no tokenism
-- expectations: lack of clarity on role charter & protocol
-- involvement: communication; function within/outside project
-- travel for meetings: disease; work; no or small budget in project
-- language barrier: esp. for non-English speaking patients
-- visibility: patients and researchers unknown to each other
-- knowledge: specific tasks need specific knowledge training
Systems medicine and patients as a partner
- THE patient doesn‘t exist – stratification is needed
but inform patient community first on need for stratification
- Patients expect a holostic view MDs (should) learn to provide this
systems medicine will add to this view
- Needs and wishes of patients: e.g. early diagnostics, psychosocial
and multi-morbidity aspects, polypharmacy, and prevention
- Involvement of patients as partner from the beginning
- Safety and privacy issues: databanks, personal data, third party use
- Ethical issues: all data used? burden of testing? consent for what?
- Communication and dissemination: feedback, informing, etc.
Consequences of patient as a partner
- Time and effort involved in process: invest now routine later
- Inventory of needs-wishes of (groups of) patients
- More time for interaction MD - (chronic) patient needed (> 3 min.)
- Explore new ways of interaction (digital; shared decision making;
all inclusive; style language; age; info finding; involve relatives etc.)
- Involve all stakeholders to gain support (include prim. care; pts;
health governments, healthcare insurers)
- Adapted curricula for students (para- and medical) regarding
engagement
- We continuously learn from each other
Thanks to:
VU University – Athena Institute:
Janneke Elberse
Jacqueline Broerse
Longfonds:
Patient advisory board
Truus Teunissen
Dorothee Laan
PROactive:
Patient Input Platform
Ethics Board
Thierry Troosters (KU Leuven)
U-BIOPRED:
Patient Input Platform
Ethics Board
Safety Monitoring Board
Peter Sterk (AMC Amsterdam)
Dr. W.I. de Boer E: [email protected]
HuMedSci Consultancy
CASyM is funded by the European Union;
7th Framework Programme under the Health Coorporation
Theme and Grant Agreement # 305033
Round table methodology Stakeholder conference St.Andrews
What outputs do we need?
► Current state of the art ► Clinical needs ► Opportunities for Systems Medicine ► Prioritized actions in short, middle and long term (2,5 and 10 years)
How will we get them ? ► Brainstorm: State of the art (45min)
► Identification of priority issues (45min) • Every participant writes down 2 priority issues on a post-it • all priority issues are put on a time-line • From these priority issues 2 are selected by the group
► Definition of actions /strategy (45min)
► Wrap-up and detailing of at least 1 priority action (45min) (aim, duration, SWOT analysis, expertise needed,…)
► After the coffee break RT leaders present the results, time for discussion
Who? ► 1 round table leader, expert in the field leads discussions manages the group synthesis of proposals ► 1 note-taker document the discussion will assist the round table leader ► 1 facilitator Keep time ensure the method is respected
What are the big questions in non-cancer lung disease (particularly chronic obstructive lung disease) and how might Systems Medicine address them?
RT N° 1
IMPA
CT
LOW
M
IDD
LE
SHORT TERM MID TERM LONG TERM
HIG
H
1-2 years 2-4 years > 4 years
What are the big questions in non-cancer lung disease (particularly chronic obstructive lung disease) and how might Systems Medicine address them?
RT N° 1
PRIORITY ISSUES
ACTIONS
EXPECTED RESULTS
What are the big questions in non-cancer lung disease (particularly chronic obstructive lung disease) and how might Systems Medicine address them?
RT N° 1
STRENGTHS WEAKNESSES
OPPORTUNITIES THREATS
CASyM is funded by the European Union; 7th Framework Programme under the Health Coorporation Theme and Grant Agreement # 305033
Questions?
CASyM – a brief overview Marc Kirschner on behalf of the CASyM Consortium
What is CASyM?
CASyM Coordinating Action Systems Medicine - Implementation of Systems Medicine across Europe Launched by the EC under the FP7 programme Preparing for the future research and innovation activities in systems medicine. Coordination Dr. Marc Kirschner, Project Management Jülich (PtJ), Forschungszentrum Jülich GmbH, Germany Duration 4 years - 1 November 2012 – 30 October 2016
What is CASyM?
CASyM is tasked with formulating a European wide
implementation strategy (road map) for Systems Medicine
► The road map is driven by clinical needs: It aims to identify areas
where a systems approach will address clinical questions and solve
clinical problems.
Inclusive – a concept, not a club ► Fostering partnerships, integration, open network and concerted
actions.
22 PARTNERS & 11 COUNTRIES: GERMANY UNITED KINGDOM FRANCE SWEDEN LUXEMBOURG NETHERLANDS SLOVENIA IRELAND ICELAND ISRAEL ITALY
Expertise represented in CASyM
Public funding bodies and ministries
Clinical Centers,
Hospitals, Schools of Medicine
SysMed Institutes and
Research Cluster
Universities and Systems
Biology Centers
Industry and SMEs
Objectives of CASyM
Clinical needs
Engagement of all relevant stakeholders
(open network)
Interaction with key
national and European initiatives.
Systems Medicine road development
Work packages of CASyM
WP1 - Conceptual framework for the Systems Medicine road map: Stakeholders, target areas, structure, integration
WP2 - Education & multidisciplinary training: Training concepts, workshops, summer schools, CPD courses
WP3 - Technologigal and methodological basis: Clinical relevant questions
WP4 - Strengthening innovation activities: Fostering “win-win” academia-industry relationships
WP5 - Integration of national efforts: Implementation of relevant funding schemes
WP6 - Dissemination: Central website, publications, publicity, sustainability
WP7 - Management: Administrative management
The vision of CASyM
Harnessing the advances in biology, computational biology and Systems Biology for the benefit of the patient.
Science can produce more patients data than ever before
Metabolomics Proteomics Imaging Clinical laboratory
Genomics & Transcriptomics
Cell Biology & Molecular Biology
Technology Platforms
Pathology & Biomarkers
MS-data Images Biochemical data
Metabolomics data
Gene array data Sequencing data 101
102
103
100
FACS data Tissue
microarrays
But how efficiently can these data be used?
Metabolomics Proteomics Imaging Clinical laboratory
Genomics & Transcriptomics
Cell Biology & Molecular Biology
Technology Platforms
Pathology & Biomarkers
MS-data Images Biochemical data
Metabolomics data
Gene array dataSequencing data101
102
103
100
FACS dataTissue
microarrays
Systems Biology Approaches can provide the Heads-Up-Display that allows the clinician to navigate patients’ data for making optimal decisions about diagnosis and therapy.
Clinical samples
Mutation data
Pathway mapping
RASSF1A
APOPTOSIS
Mitogens Growth factors
Receptor receptor
Ras
RAFPP
P
P
MEKP
ERKPP
MST2
LATS1
PROLIFERATION
p53p73
Patients’ samples
Pathway literature
Clinical literature
Evidence & data
Clinical data
Over
all su
rviva
l
Survival in months
Dukes’ B (N=34)
Dukes’ A (N=24)
RKIP weak/negative
Dukes’ C (N=55)
0.5
P values:A vs. B: 0.70B vs. C: 0.03A vs. C: 0.08
Dukes’ Stage Survival Time Standard Error 95% Confidence IntervalA Mean: 59 months 7 46 - 72
Median: 72 months 14 44 - 100 B Mean: 70 months 7 56 - 84
Median: not applicableC Mean: 49 months 7 36 - 62
Median: 36 months 10 17 - 55
Signalling networks
Plasma membrane EGFR Frizzled
WntEGF
β-cat
β−cat/APC*/Axin*/GSK3β
β-cat*/APC*/Axin*/GSK3β APC*/Axin*
/GSK3β
Dshi Dsha
2
β-cat/TCF
TCF
Axin a
Slug
E-cadLPDM
SOS/Grb2
RasRas-GTP
Raf-1Raf-1*
MEKMEKpp
ERKERKppRKIPp RKIP
Snail
E-cad
c
c
GSK3β
2
SnailSlug
PKCδ
GSK3β
2
4
4
Slug
E-cad
RKIP
Axin
ERK pathway
Gene regulation
∅
∅
TranscriptionStoichiometric conversionTranscriptional repressionInhibitionFacilitationEnzymatic catalysis
DegradationConstitutive protein synthesis
Line connection
APC/Axin/GSK3β
GSK3β
Axin
∅
APC/Axin
APC
β−cat/APC a
β−cat*
∅
Wnt pathway
EMT (metastasis)
x1 x2
x3
x4
x5
x7
x8
x9
x10x11
x12
x13
x14
x15
x16
x18
x19x20
x21x22
x23x24
x25x26 x27
x28
x29
x30x31
x27
x5
x17
x13
x5
∅
∅ ∅
RKIP
GSK3β*x6
v1
v2
v3
v4v5 v6
v7v8
v9
v10
v11
v12
v13
v14
v15
v16
v17
v28
v29v30
v31
v32
v33v34
v35
v37
v36
∅
∅
v19v20
v21 v22
v23
v24v25
v26
v27
v38
v39
v40v41
v42
v43v44
v45v46
v47v18 ∅
Notation
∅
Omic profiles
Multidimensional inputs
Computational models Patient
stratification
Therapy response
P=0.0002
Survival in months
Overa
ll sur
vival
0.5
5 year survival: 82%
5 year survival: 48%
Prognosis
Validation
Virtual patients
Personalised diagnostics
Improved diagnostics & therapies
Personalised therapies &
A vision for Systems Medicine
How will CASyM contribute to this vision? ► CASyM will develop a road map for the implementation of
Systems Medicine
2 years
5 years
10 years
Clinical needs
What will CASyM achieve? Stakeholders
Clinicians, Patients Biomedcial researchers
Health care organisations Industry
Technology base -omics data
Data management Computational modelling
Molecular pathology
Beneficiaries Participatory medicine Stakeholder meetings Workshops Conferences
Technology needs Advanced data analysis Deep data mining Data integration
Application of Systems Medicine Where will be the biggest impact?
What are the best applications? How can we fully exploit the potential?
Prevention and early intervention
Training Postgenome generation
Complexity of diseases Use of novel technologies
Clinical needs Better diagnostics Better treatments Better clinical trials Faster drug approvals Cheaper healthcare
New generation of clinician-scientists Interdisciplinary training programmes Integration between basic research and clinical practice
Innovation Systems approaches in industry
Best practice
Exploitation Success stories Enhancing European competitiveness
What will CASyM achieve?
Stakeholders Clinicians, Patients
Biomedcial researchers Health care organisations
Industry
Technology base -omics data
Data management Computational modelling
Molecular pathology
Beneficiaries Participatory medicine Stakeholder meetings Workshops Conferences
Technology needs Advanced data analysis Deep data mining Data integration
Application of Systems Medicine Where will be the biggest impact?
What are the best applications? How can we fully exploit the potential?
Prevention and early intervention
Training Postgenome generation
Complexity of diseases Use of novel technologies
Clinical needs Better diagnostics Better treatments Better clinical trials Faster drug approvals Cheaper healthcare
New generation of clinician-scientists Interdisciplinary training programmes Integration between basic research and clinical practice
Innovation Systems approaches in industry
Best practice
Exploitation Success stories Enhancing European competitiveness
ROADMAP
Networking and disseminating the CASyM concept and its achieved results
Integration of national efforts in Systems Medicine
StakeholdersClinicians, Patients
Biomedcial researchersHealth care organisations
Industry
Technology base-omics data
Data managementComputational modelling
Molecular pathology
BeneficiariesParticipatory medicineStakeholder meetingsWorkshops Conferences
Technology needsAdvanced data analysisDeep data miningData integration
Application of Systems MedicineWhere will be the biggest impact?
What are the best applications?How can we fully exploit the potential?
Prevention and early intervention
Training Postgenome generation
Complexity of diseasesUse of novel technologies
Clinical needsBetter diagnosticsBetter treatmentsBetter clinical trialsFaster drug approvalsCheaper healthcare
New generation of clinician-scientistsInterdisciplinary training programmesIntegration between basic research and clinical practice
InnovationSystems approaches in industry
Best practice
ExploitationSuccess storiesEnhancing European competitiveness
ROADMAP
What will CASyM achieve?
What is CASyM?
The big picture: Relevance to P4 medicine, health
and wealth
Inclusive – a concept, not a
club: Partnerships, open network and concerted actions
Representative: Political, public,
Academic, healthcare,
Industry/SMEs
Real life examples - Science, drug
discovery, patho-physiology,
patient´s benefit and public health Translational:
Across disciplines
Adaptable: Addresses real problems and
evolves over time.
Awareness - Education and
training
Join CASyM and work with us on the future of healthcare & medicine!
www.casym.eu
Organization and support
The CASyM Steering Committee David Harrison (speaker) – The University Court of the University of St. Andrews, United Kingdom Damjana Rozman (deputy speaker) –University of Ljubljana, Faculty of Medicine, Slovenia Mikael Benson (deputy speaker) –The Center for Individualized Medication Linköping University Hospital, Sweden Charles Auffray – European Institute for Systems Biology & Medicine/HLA & Médecine, France Rob Diemel – The Netherlands Organisation for Health Research and Development Walter Kolch – University College Dublin, Ireland Frank Laplace – Federal Ministry of Education and Research, Germany Francis Lévi – Institut National de la Sante et de la Recherche Medicale, France Johannes Schuchhardt – MicroDiscovery GmbH, Germany Olaf Wolkenhauer – University of Rostock, Germany
Coordination Marc Kirschner – Forschungszentrum Jülich, Project Management Jülich (PtJ), Gemany
CASyM is funded by the European Union; 7th Framework Programme under the Health Coorporation Theme and Grant Agreement # 305033
Round table1 - What are the big questions in non-cancer lung disease (particularly chronic obstructive lung disease) and how might Systems Medicine address them? Leader: Alfredo Cesario
State of the Art (1: background concepts)
► COPD AND Systems Medicine / Systems Biology (and vice-versa) medline (pubmed) search 12th May: no “big questions” answered…
However, some concepts well accepted: Integration of an ever-increasing variety and quantity of biological, clinical, epidemiological,
environmental, functional, genetic, genomic, pathological, physiological (and imaging?) data through systems approaches is the cornerstone for the personalized treatment (P4 / SM) of individuals.
Auffray C, et al. Systems medicine: the future of medical genomics and healthcare, Genome Med 2009 Bousquet et al. Systems medicine and integrated care to combat chronic noncommunicable Disease, Genome Med 2011 Auffray C, et al. Systems biology and personalized medicine - the future is now. Biotechnol J 2012 Hood L, et al. Revolutionizing medicine in the 21st century through systems approaches. Biotechnol J 2012 Chen R et al. Personal omics profiling reveals dynamic molecular and medical phenotypes. Cell 2012 Smarr L: Quantifying your body: a how-to guide from a systems biology perspective. Biotechnol J 2012
Focus on the development of panels of indicators for disease control as part of decision- support systems for the monitoring of prominent complex diseases, such as Chronic Obstructive Pulmonary disease, by patients and their physicians (P4 in practice)
Agusti A, et al. The COPD control panel: towards personalised medicine in COPD. Thorax 2012
State of the Art (2: ongoing research activities) Respiratory Diseases (COPD) SB/SM EU projects: U-Biopred (FP7, IMI, asthma focused fingerprint / handprint) Medall (FP7, Cooperation Health, Allergy) AirProm (FP7, Cooperation Health, Patient Specific Computational Modelling) Synergy COPD (FP7, ICT, SM Simulation Environment – COPD as use case) SysClad (FP7, Cooperation Health, Chronic Lung Allograft Dysfunction) Biobridge (FP6, Cooperation Health, systemic effects of COPD/HF/DMII – focus on nitroso/redox unbalance CVS, skeletal muscle wasting/dysfunction). “…the complexities of the interactions between susceptibility (i.e. genetic determinants) and life style factors (i.e. low physical activity, tobacco smoking, nutrition, etc...) put on display the insufficiencies of the classical hypothesis-based research approach to effectively explore the underlying mechanisms determining the clinical problem. It prompts the need for complementary novel strategies based on integrative translational research using Systems Biology methodologies aligning two well differentiated dimensions, biomedical and bioinformatics” (2006...)
OUTPUT: Biological knowledge through the simulation environment AND contributions in several bio-informatic dimensions: - multilevel data integration; - development of SBML standards ensuring interoperability among different ICT tools; - development of deterministic modelling of oxygen transport-central metabolism and mitochondrial ROS generation; - preparing tools for inference analysis and probabilistic modelling; - integration of simulation environment into a workable portal
State of the Art (3: biomedical dimensions) Challenges / Priorities COPD not an homogeneous disease heterogeneity lies at the pulmonary and extra-pulmonary level (systemic) and beyond (genetics, lifestyle,…) COPD complex phenotype is a summative entity (of phenotypic traits / comorbidities ?) with emerging
properties that cannot be attributed to each of the elements considered separately hence redefinition of (COPD) taxonomy (multidimensional) as THE challenge for a SB/SM modelling
exercise ? therefore validation of actionable interventions new-taxonomy driven through solid(ly) clinical benchmarks (severity / activity / impact)? Severity (degree of functional reserve): FEV1; IC/TLC; Arterial Oxygenation; exercise capacity Activity (doesn’t go in parallel with severity): rate of change of FEV1, continued smoking, frequency of exacerbations; persistence of systemic inflammation (circulating leukocytes; C-reactive protein; IL-6; fibrinogen and selected biomarkers (!); Impact (degree of perception) : COPD Assessment Test; mMRC
Implementation / Actions ( redefinition of taxonomy) Methodology (1): General Framework 1) From CASyM 1 (Lyon) – RT 3/9: The distribution and co-existence of chronic diseases is studied via
hypothesis-driven approaches based on existing disease ontologies, i.e. “classical phenotypes” (Coronary Heart Disease / HF, COPD, Diabetes).
COPD centered: COPD + related diseases via systems approaches Top down, ontology driven, classical diagnostic (eligibility) criteria Classical Phenotypes 2) From CASyM 1 (Lyon) – RT 3/9: Bottom up, via the modelling of novel “complex phenotypes” including co-
morbidities, risk factors, drug response and socio-economic determinants using hypothesis-free statistical models and data from patients.
Co-morbidity centered: applying SB/SM approaches to overlapping co-morbidities 1 & 2) Reshape (research ?) exercise to allow full deployment and (hopefully) validation of systems medicine
approaches. This includes, as well, addressing inequality and literacy (patients & operators) correlated with highly technological approaches. Health technology assessment further considered as a tool for accountability and sustainability matters.
Methodology (2): Recruitment From CASyM 1 (Lyon) – RT 3/9 New paradigms of recruitment of Systems Medicine based clinical trials and SMknowledge / understanding studies. 1) Existing Cohorts (SOPs? Data completeness and Quality?) discovery 2) New Cohorts (CT, Obs,…) specific interventions 1& 2) Investigation regarding the changing paradigms of recruitment (SM based) : - Patients / physicians - Industry / regulatory agencies Methodology (3): Data From CASyM 1 (Lyon) – RT 3/9 Which data ? What depth? standardization & harmonization – Exchange & Sharing Validation of standardisation / harmonisation strategies – Exchange & Sharing (Systems Medicine oriented) in the data handling.
Implementation / Actions ( recruitment & data)
CASyM is funded by the European Union; 7th Framework Programme under the Health Coorporation Theme and Grant Agreement # 305033
Round table 2: What are the big questions in infection and how might Systems Medicine address them? Leader: François Gueyffier
Conflicts of interest F. Gueyffier ► From 2001 to 2011, head of the Clinical Investigation Center in
Lyon, France (about 100 clinical research contracts with pharmaceutical industry)
► Since 2009, shareholder of NovaDiscovery (http://www.novadiscovery.com/)
► PI of clinical trials using blood pressure lowering drugs, in a rare disease or in arterial hypertension
► Head of a team including the coordinator of CRESIM project ► Member of the steering committee of the French EcoFect LabEx
(http://ecofect.universite-lyon.fr/)
Objective of St Andrews Round Tables
► To specifically investigate examples of real medical problems and to determine what questions are tractable using Systems Medicine approaches
► Focus of our RT : “What are the big questions in infection and how might Systems Medicine address them? “
Application of Systems Medicine ► Where will be the biggest impact?
− Frequent and severe diseases − With unmet medical needs − Or with special research expectations
− Understanding mysteries in pathophysiology of immune system more or less related to infection (cancer, CV diseases, auto-immunity)
► What are the best applications? − Easy-to-use & efficient, with feasible implementation
► How can we fully exploit the potential?
► Prevention and early intervention − Eradication of infectious agent : out of scope of e:Med − Understanding the key factors for infectious diseases control, implementing
preventive efficient measures
Reasons to choose big questions topics ► High prevalence ► High lethality / disability rates ► Room for optimization of treatment ► Big research challenges ► Deciphering the potential of zoonoses, which
represent 60% of the emerging diseases at the world wide scale (Jones et al. 2008).
► Interactions with other diseases − Cancer − Cardiovascular diseases − Auto-immune diseases
6 diseases cause 90% of infectious deaths ► Infectious diseases are now the world's biggest killer
of children and young adults (half of premature deaths)
► More than 13 million deaths a year - one in two deaths in developing countries
6 diseases cause 90% of infectious deaths ► Pneumonia
− Kills more children than any other infectious disease − 10 to 40 000 deaths in an average influenza season in US
► Tuberculosis − Kills 1.5 million people per year, 1st in ado and adults − Nearly 1/3 of the world population has latent TB infection; causes 1/3 or
HIV related deaths. ► Diarrhoeal diseases (cholera, dysentery, typhoid, rotavirus, etc.)
− Two million lives a year among children under five ► Malaria
− Incidence of 275 million per year − Kills over one million people a year
► Measles − Most contagious disease, about 900 000 deaths a year
► HIV/AIDS − 33 million people living with HIV
Malaria ► Globally, an estimated 3.3 billion people were at risk of malaria in
2011, with populations living in sub-Saharan Africa having the highest risk of malaria infection. Approximately half of countries with ongoing malaria transmission are on track to meet the World Health Assembly target to achieve a 75% reduction in malaria case incidence rates by 2015, compared to levels in 2000.
► Number of malaria cases − 219 million estimated malaria cases in 2010 (range: 154–289 million).
► Number of malaria deaths − 660 000 estimated malaria deaths in 2010 (range: 490 000–836 000).
► Elimination − 10 of the 99 countries with ongoing malaria transmission are classified as being
in malaria elimination phase.
Tuberculosis ► One of the leading causes of death by infection
worldwide ► Efficient treatments but prolonged and multi-drugs ► Challenges :
− Shortening of the treatment − Defining the best drugs associations on bacterial multiplication and
resistance occurrence
AIDS ► … ► New expectations from patients to make the disease
more acceptable in daily life − Mastering virus transmission − Focus on prevention, adapted to individual behaviors − Pre-contamination Treatment
Septic shock ► 15 to 19 million cases of sepsis occur worldwide each
year. In the USA, about 750,000 cases of severe sepsis represent an estimated mortality of 200,000 per year.
► The annual cost of hospital care for patients with severe sepsis in the USA has been estimated at 16.7 billion dollars.
► Complex interplay between regulation systems, leading to explosive behaviors − Stimulated by pathogen and its derivatives as endotoxins − Hyper-response pro-inflammation, violent and visible − Vasodilation, ischemia and organ failure − Hyper response anti-inflammation, less visible but responsible of late
deaths, e.g. secondary hospital acquired infections
Various types of stakeholders ► Patients ► Clinicians ► Researchers ► Pharmaceutical and medical device industry ► Regulators ► Health care payers ► Research payers ► …
RT2: What are the big questions in infection and how might Systems Medicine address them?
IMPA
CT
SHORT TERM MID TERM LONG TERM
1-2 years 2-4 years > 4 years
Molecular microbiolog\ (genomics) >diagnose (genome) by MS signatures &species >diagnose by genome > species plus drug resistance (epidemiology built in for public health)
Sepsis&critical care phenotype
Antibiotic resistance
Better patients phenotyping >prior to disease >real time in market >changes plus ring alarm bells >post analysis to (analytics) to improve algorithms.
Nosokomial infections > susceptibility plus infestation
Clinical endpoints are unclear > how do we measure cure oin e.g. TB (relapse\reinfection being a problem)?
Patient data >electronic health records
Humanized animal models
How do we challenge current regimens? (model development raises questions)
New antibiotics > needs new bacterial focused compound libraries
Infection and chronic health
Pandemic outbreaks > early warning systems (e.g. WHO; when there is an outbreak, is the proper scientific structure established?) Computational systems
chemistry >Antibiotic discovery
Symbiosis \ Dysbiosis > what is health!
Envisaged priorities ► Tackling anti-infective resistance ► Pathogen agents
− Rapid and deep diagnosis / antibiotic resistance – molecular microbiology (genomics)
► Patients − Better patient phenotyping – Analytics / Bioinformatics − Early diagnosis – Infestation – susceptibility to infection – nosocomial infections (ST/MT) − Infection diagnostic / Sepsis phenotyping / real time patients health record − Identification of clinical endpoints – How do we measure cure / relapse − Infection chronic disease access
► Treatments − New antibiotics / computational systems / more bacteria-focused − Humanized animal models − How to challenge accepted therapeutic regimens
► Pandemic outbreaks – Alert systems ► Infection & chronic health : Immunity and inflammation – CV, Kc and
auto-immunity
Priority 1 : Tackling anti-infective resistance Actions
− Networking of databases, policies of databases exchanges across countries − Guidelines to support shared clinical data bases − Exploit high throughput molecular diagnostic, genomic type… − Integration of omics and clinical relevant data… Use of European clinical data
infrastructures − Data handling of huge amount of data; physically centralized data base (shared
need with other diseases domains; thousand genomes – infection…) − Gut microbes taxonomy − Complex interactions between microbiomal environment and the drugs safety
and efficacy − Innovative computational / data handling approaches − Visualization of data – rapid access to relevant results − Develop an infection control system − New drugs / molecular engineering / reverse engineering / small molecular
library
Priority 1 : Tackling anti-infective resistance
Expected results − Bedside rapid screening tool which could guide therapy within 24 hours… − New drug targets… less redundant therapy – appropriate redundancy − Use of the environment… ecological regimens (e.g. fecal transplants…) − Making diagnosis approach more closely related to the therapeutic
choices – − Theranostics – predictive biomarkers to stratify patients
RT2: What are the big questions in infection and how might Systems Medicine address them?
STRENGTHS WEAKNESSES
OPPORTUNITIES THREATS
− Rapid\early gains (if successful can go far beyond actual status quo, has potential for great impact, diagnostic fingerprinting\epidemiology already established)
− Instant public understanding − Reduce inappropriate prescribing
Data challenge Lowering mortality
Health system inertia
Problem specification
Missing standards
Systems complexity (clinical system\clinical practice and complexity of whole biological systems)
Money (attractive for SMEs)
Priority 1 : Tackling anti-infective resistance
► Strengths − Rapid early gains − Public understanding − Worldwide global issue
► Weaknesses − Health system inertia − System complexity; requires systems biology / medicine approaches
► Opportunities − Patients engagements − Likely mortality gains, but also social organization gains − Vast market, opportunities for SMEs
► Threats − Data challenges − Problem specification − Missing standards − Validation issues
Priority 2 : Infection & chronic health : Immunity and inflammation – CV, Kc and auto-immunity
► Actions − Defining the patient phenotype − Problem specifications… − Inflammasome − Which models ?
− Understanding the expression level regulation of immune system… − Antibodies specification…
► Expected results
This priority issue was regarded as too complex. Chronic health cannot be explained without better patient phenotyping.
Clinical questions to be addressed
► Clinical trials (short term)- systems biology approaches could guide clinical trial design shortening times and costs
► Re-definition of clinical phenotypes based on molecular and dynamic parameters
► Discovery of effective biomarkers of multiple nature for disease progression (clinically useful: risk, prognosis, diagnosis); several biomarkers are often needed to make appropriate medical decisions.
► Combinatorial therapy for reducing toxicity (mid-term?); this approach would be useful to find out a combination and lower doses of effective drugs; in particular in the case of co-morbidity, in the frequent cases where more than one disease is affecting the patient
► Improvement of drug development, optimized drug efficacy and delivery, drug safety (via the of study drug-metabolizing enzymes pathways), timing and dosage of therapy
► It is important also to address the healthy individual (long term?)
CASyM is funded by the European Union; 7th Framework Programme under the Health Coorporation Theme and Grant Agreement # 305033
FP7 RECOIN project : Studying the Mechanisms of Enhanced Pathogenesis in Polymicrobial Respiratory Co-Infection Objective: Illness caused by respiratory infection with Influenza viruses represents a vast healthcare and economic burden in the modern world. It is well established that respiratory viral infections are often complicated by secondary bacterial infections, however co-infection often causes a much more severe disease than either microorganism would individually. The mechanisms behind this synergy are not fully understood, however adhesion; the first step in bacterial colonisation, has been shown to be enhanced in virus-infected cells. We hypothesise that early events following Influenza infection of lung epithelium promote bacterial adhesion by regulating primary receptor trafficking and may offer new targets for anti-bacterial intervention. The aims of this project are to dynamically characterise the adhesion of individual bacteria to airway epithelial cells with high-temporal and spatial resolution and to study the effects of Influenza A co-infection on this phenomenon. We will develop new protocols to track bacteria in three dimensions in order to study individual adhesion events and will calculate diffusion modes during and after bacterial contact with the host cells. These studies will provide novel insights into the processes underlying bacterial adhesion and will explore the mechanism of viral-bacterial synergy to discover new targets for the prevention and treatment of serious respiratory infections.
FP7 INTRICATE project : Infectious triggers of chronic autoimmunity
Objective: This proposal builds on existing expertise and collaborations of a multidisciplinary Consortium of basic scientists and clinical investigators each of whom has made a substantial individual contribution to understanding the links between infection and autoimmunity. The aim of the INTRICATE Consortium is to prosecute a programme of Translational Research that deliniates the role of infection in the induction and perpetuation of severe systemic autoimmune disease with the ultimate object of identifying new therapeutic strategies based on knowledge of pathogenesis. Our strategy will systematically analyse the complex and diverse processes involved in a ?model? human disease: - Anti-neutrophil cytoplasmic antibody (ANCA) associated systemic vasculitis (AASV). AASV is ideally suited because it is known to be caused by autoantibodies of defined specificity and second because it is strongly linked to infection to infection. INTRICATE will use mouse models to answer the specific question whether infection with clinically relevant bacteria induces autoimmune disease in transgenic mice that express the human autoantigen. The use of novel high-throughput antigen array technology in well-characterized patient cohorts and analysis of microbial and host specific mechanisms combined with genome wide association study (GWAS) will determine whether dysbiosis or infection with specific microorganisms triggers the induction or re-activation of AASV. Unraveling the pathogenic processes that are responsible for this chronic autoimmune disease and the knowledge gained will lead to the development of novel preventive and therapeutic strategies.
Round table 3: What are the big questions in public health (obesity and exercise) and how might Systems Medicine address them? Leader: Natal van Riel
State of the art ► Public health is population based, not individualized ► Increase of public awareness in many areas, but
limited impact ► Lacking in primary prevention, focus on secondary
and tertiary prevention ► A deficit perspective ► Reductionist approach
physical activity, diet, smoking, alcohol, drugs, sexual health, violence and injury, mental health, air pollution (outdoor and indoor)
Apply a systems approach in public health
RT3: What are the big questions in public health (obesity and exercise) and how might Systems Medicine address them?
Primary prevention: the goal is to protect healthy people from developing a disease Secondary prevention: goal is to halt or slow the progress of disease in its earliest stages Tertiary prevention: goals include preventing further physical deterioration and maximizing quality of life
Priority issues Participatory Prevention in Public Health 1. Prevention
► Focus on primary prevention ► Target all levels in policy ‘rainbow’ (from individual to
socio-economic, cultural and environmental context) ► Education and health literacy
2. Citizen participation ► Empowerment of patient and public
3. Systems oriented methods ► Longitudinal data, modelling ► How to measure effectiveness?, Health Technology Assessment
4. Assets perspective ► Healthy ageing, health equality ► Integrative approach of health factors and comorbidities
5. Context ► Political will ► Ethical questions
RT3: What are the big questions in public health (obesity and exercise) and how might Systems Medicine address them?
IMPA
CT
LOW
M
IDD
LE
SHORT TERM MID TERM LONG TERM
HIG
H
1-2 years 2-4 years > 4 years
validation of the approach
RT3: What are the big questions in non-cancer lung disease (particularly chronic obstructive lung disease) and how might Systems Medicine address them?
Conceptualization of a systems approach in -Public Health -in primary prevention
Participatory actions to identify pilot projects
Pilot project Community level
Participatory model at community level
Building assets Change paradigm from reductionist to asset benefits
Health Change Behaviour change
Tools methodology
Systems medicine Personalized approach to public health in a cohort model
RT3: What are the big questions in public health (obesity and exercise) and how might Systems Medicine address them?
PRIORITY ISSUES
ACTIONS
EXPECTED RESULTS
► Participatory Prevention in Public Health ► Targeting all levels in policy rainbow and primary, secondary and tertiary prevention
► Develop collaborations and obtain funding to conceptualize a systems approach for
PH, and new methods and tools ► Pilot project ► Implementation of policy in different countries and EU
► A framework for Systems Medicine based PH ► Change paradigm for PH ► Socio-economic and health benefits for society and individual citizen
RT3: What are the big questions in non-cancer lung disease (particularly chronic obstructive lung disease) and how might Systems Medicine address them?
STRENGTHS WEAKNESSES
OPPORTUNITIES THREATS
Participatory Comprehensive – not reductionist Based on established theory Multidisciplinary Benefit for the individual
Low fit with systems biology Ethical issues unclear
Novelty Socio-economic impact Change in public health practice Health impact Horizon 2020
Complexity of public health issues Data availability Costs Lack of engagement of stakeholders
Round table 4: What are the big questions in drug development and how might Systems Medicine address them? Leader: Alex McDonald
Paul et al
Phase II/III Attrition Key to R&D Productivity
However: Phase II/III attrition appears to be increasing • novel targets • new diseases/populations • higher safety hurdles • risk/benefit • cost effectiveness
Inflammation
Kidney Lung
Coagulation
Heart and Circulation
Developmental Treatments
INPUTS Individual Patient
Characteristics:
Vital signs
Comorbidities
Genetics
A“Virtual Clinician” applies interventions (fluids, etc.)
Lymphatics
Immunetrics builds models that make quantitative, clinically applicable predictions.
OUTPUTS Mortality
Treatment effect
Organ function time courses
Biomarker time courses
State of the Art in Sepsis and Critical Care
IMPA
CT
LOW
M
IDD
LE
SHORT TERM MID TERM LONG TERM
HIG
H
1-2 years 2-4 years > 4 years
RT4: What are the big questions in Drug Development and how might Systems Medicine address them?
Dose, regimen and timing Population (stratification, prognosis and prediction)
RT4: What are the big questions in drug development and how might Systems Medicine address them?
PRIORITY ISSUES
ACTIONS
EXPECTED RESULTS
Population (stratification, prognosis and prediction)
Dose, regimen and timing
Action 2: Develop exemplar systems dynamic models that are both descriptive and predictive, models that are open to new inputs, able to encompass experimental and clinical heterogeneity, using data from other/different sources.
Results 1: Summary of systematic review
Action 1: Systematic Review of systems dynamic models in above areas
Results 2: One or more exemplar models to showcase the systems medicine approach
Action: Disease prioritisation – respiratory and oncology
RT4: What are the big questions in drug development and how might Systems Medicine address them?
STRENGTHS WEAKNESSES
OPPORTUNITIES THREATS
The SWOT analysis will be presented in the follwing meeting report.