The need for standardisation from a clinical...
Transcript of The need for standardisation from a clinical...
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The need for standardisation
from a clinical perspective
Norbert Graf
University of the Saarland
Pediatric Oncology and Hematology
66421 Homburg / Germany
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GPS: Genomic Prescribing System
Copyright: Norbert Graf
Ratain MJ: Personalized Medicine: Building the GPS to Take Us There. CLINICAL PHARMACOLOGY & THERAPEUT ICS 81:321-322, 2007
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Copyright: Norbert Graf
Declan Butler: Nature: 453:840-842, 2008
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Copyright: Norbert Graf
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� Human Genome Project and bioinformatics
� Expression vectors for novel protein target
production
� Computer-aided drug design
Drivers of molecular therapeutics
Copyright: Norbert Graf
� Robotic high-throughput screening
� Combinatorial chemistry
� Platform approach to drug discovery
� Huge increase in number of molecular targets
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Systems-biology-driven concepts in biomedicine
� Characterization of the underlying disease biology and treatment� Physiological modelling
� Pharmacokinetic modelling
� Powerful integrative platforms are required for seamless integration of
Copyright: Norbert Graf
seamless integration of� In vitro data
� Clinical data
� Imaging data
� Public databases
� Computational mathematical methods and techniques are necessary
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Need for Standardisation
�Researchers
�Academic
�Clinical
� Industrial
Copyright: Norbert Graf
� Industrial
�Communication
� Integration
�Exchange
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Need for Standardisation
� Infrastructure / Communication
�Data
� Interfaces
�Tools
Copyright: Norbert Graf
�Tools
�Models
�Computational methodologies
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Objective: Fighting Diseases
IT Research
Basic Clinical
Copyright: Norbert Graf
Basic Research
Legal / EthicalResearch
ClinicalResearch
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Translational Research
bench
Molecular level
feed
back
Scientistbasic-science breakthroughs
Copyright: Norbert Graf
bedside
feed
back
Physician
Cellular level
clinical level
clinical applications
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The 'Infinity Initiative'
�aims to bring together leading researchers
and important industry players
�to create networks among them and
�to support for early standardisation of the
Copyright: Norbert Graf
�to support for early standardisation of the
necessary interfaces
� in order to guarantee easy and appropriate technical
solutions for rapid further development in this field.
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VPH NoE
�The VPH NoE will connect the diverse VPH projects � including not only those funded as part of the VPH initiative but also � those of previous EC frameworks
Copyright: Norbert Graf
� those of previous EC frameworks
� national funding schemes
� together with industry
� healthcare providers
� international organisations
� thereby ensuring that the impacts will be realised
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Standardisation
�Data�Molecular biology
� Heterogeneity of tumour material
� Tumour stem cells
� Signatures versus pathways
Copyright: Norbert Graf
� Signatures versus pathways
� Cross platform analysis
� Imaging studies� Segmentation of tumours
�Clinical data� Prospective clinical trials
� Cross trial queries
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Seamless integration of data
VVirtual OOrganizations
Semantic Services Grid Infrastructure
Data Service Analytical Services
Research
Center
A
CTdata
Tool 1
Tool 2Protein
Database
DataServicesTool 1
Research
Center
B
Microarray Database
Copyright: Norbert Graf
Grid Portal
Infrastructure
(VO Mang., Metadata, Registry, Publishing, Query, Invocation,
Security, etc.)
Analytical Services
Services
Analytical Services
Tool 1
Tool 2
Grid Data ServicePublic data
& tools
Tool NTool 1
Tool 2
ImagingDatabase
Microarray Database
Research
Center
N
DataServices
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Accumulation of huge amounts of data
�How do we know what data we have ?
�How do I know what data you have ?
�How do we know what data we don’t
have ?
Copyright: Norbert Graf
have ?
�how do we make different sorts of data
combinable ?
Barry Smith
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Data entryInform submitter
Recycle Tumorbox
Tissue storage DNA blood/kidney DNA tumor RNA tumor
Cell cultureCell cultureSeraSera
PathologyPathology
Biobanking
Copyright: Norbert Graf
LOH:1p, 1q
11p15 / p13, 11q16q22q
Real time PCR
Microarray
ß-Catenin Exon 3PCR / Sequence
(WT1)(DHPLC/Sequencing)
Associated screens,requests from
scientific community
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Gene Arrays (Nephroblastoma)
Copyright: Norbert Graf
Clustering of genes selected for intermediate vs. high risk histology
Clustering of genes selected for relapsed versus non-relapsed tumors
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Copyright: Norbert Graf
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The Emergent Integrated Circuit of the Cell
Copyright: Norbert Graf
Douglas Hanahan, Robert A. Weinberg: The Hallmarks of Cancer. Review. Cell, Vol. 100, 57–70, January 7, 2000
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Acquired capabilities of cancer
Copyright: Norbert Graf
Douglas Hanahan, Robert A. Weinberg: The Hallmarks of Cancer. Review. Cell, Vol. 100, 57–70, January 7, 2000
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Retinoic acid dependent genes
regulation in
Wilms tumors with RA treated cells
high risk relapse MZ 128 WS 427
CCNA2 2,1 2,1 -1,8 -1,6
UBE2C 2,8 2,7 -1,8 -1,2
CKS2 2,8 2,3 -1,8
RARRES3 -2,1 -2,1 1,1 2,3
Copyright: Norbert Graf
RARRES3 -2,1 -2,1 1,1 2,3
RARRES1 -2,0 -1,7 3,4
C3AR1 -3,2 -2,4 -2,2
CCL2 -2,4 -2,5 1,4 2,1
CTGF -3,0 -3,7 1,1 1,6
ITM2B -2,0 -1,7 1,1 1,5
IGFBP3 -2,2 -1,6 2,1 1,2
AQP1 -3,0 -1,8 -2,7 -1,2
Genes assoc. with progression: opposite expression with ATRA
results from microarray analysis
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Clinical Trial Question
Diagnosis Surgery
Chemo-therapy
Histology
90% + x% survival
postop. radio -/
Copyright: Norbert Graf
Histology Metastasis Stage
10% - x% relapses/death
postop. radio -/chemotherapy
and/or
retinoic acidHigh risk ?
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Multi centre genomic trials
�Many centres are able to process genomic
data on-site
�Different platforms are used
�Question:
Copyright: Norbert Graf
�Question:� Reproducibility
� Generality of genomics measurements
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MCMP scenario
Copyright: Norbert Graf
C. Desmedt, F. Buffa, personal communication;
ACGT D12.6, 2008
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Imaging
Copyright: Norbert Graf
T1 T1 + contrast T2 T2 flair
Tumour shape and size ?
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Clinical data
Copyright: Norbert Graf
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Clinical trials
95
5050
60
70
80
90
100
Germany USA
Copyright: Norbert Graf
15
0
10
20
30
40
50
Children AYA Adults
Couzin J: Survival in young adults with Cancer… Science 317:1160-1162, 2007
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Paediatric Oncology
Ove
rall
surv
ival
Copyright: Norbert Graf
Ove
rall
surv
ival
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Clinical Trials in EuropeK
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Copyright: Norbert Graf
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The Tower of Babel
Copyright: Norbert Graf
Pieter Brueghel the Elder (1563)
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Standardisation
�Classifications
� ICD, …
�Terminologies
�SNOMED CT, …
Copyright: Norbert Graf
�SNOMED CT, …
�Ontologies
�Gene ontology, …
� Semantic Web
�Natural language processing (NLP)
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The Open Biomedical Ontologies
�The OBO Foundry is a collaborative
experiment
� involving developers of science-based ontologies
� who are establishing a set of principles for ontology
Copyright: Norbert Graf
� who are establishing a set of principles for ontology
development
� with the goal of creating a suite of orthogonal
interoperable reference ontologies in the biomedical
domain.
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Gene Ontology
Copyright: Norbert Graf
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http://bioportal.bioontology.org/
Copyright: Norbert Graf
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ACGT Master Ontology
Copyright: Norbert Graf
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Copyright: Norbert Graf
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ObTiMARepository
Trial Outline Builder
Copyright: Norbert Graf
Trial Outline Builder
Patient Data Management System
CRF CreatorTrial Builder
patient specific view
graphical schema
general view
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Copyright: Norbert Graf
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Copyright: Norbert Graf
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User Roles & Rights
� ObTiMA is a clinical trial management system accessed
by many users with heterogeneous responsibilities.
� A Role Based Access Control approach provides a
satisfactory solution in regulating the various tasks
performed by users.
Copyright: Norbert Graf
performed by users.
� Each user is assigned to one or more roles that
characterize their purpose and function in ObTiMA.
� Roles control user access to different parts of ObTiMA
according to the rights assigned to them.
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Value conflicts
conflict
Individual
interest
Collective
interests
Copyright: Norbert Graf
conflict
between
Privacy Access
Balance?
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�Genetic data always personal data?
�Can pseudonymous genetic data be regarded
as anonymous data for a controller, who
Data protection regarding human genetic research
Copyright: Norbert Graf
as anonymous data for a controller, who
doesn‘t have the link?
�How to define additional knowledge, by
which a person can be identified?
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Genetic data = personal data?
� Genetic data is potentially personal data, as the
identification of the data subject is always possible if
the controller has additional knowledge (for example
reference templates)
Copyright: Norbert Graf
reference templates)
� Condition for anonymization of genetic data: De facto
anonymous data = anonymous data
� Relevant factor: effort for identification
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Security architecture
� Defined the ACGT security architecture in line with the existing legal and data protection
Copyright: Norbert Graf
existing legal and data protection framework.
� Interplay of IT services as well as processes and policies.
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CAT Workbench
� Make a “data protection” configuration once… run it
several times…
Copyright: Norbert Graf
Custodix, Belgium
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Standardisation
� Interfaces
�tools
�Models
�Computational methodologies
Copyright: Norbert Graf
�Computational methodologies
�communication
�exchange
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Multilevel data integration and analysis
Copyright: Norbert Graf
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Bottom-up approach
� All known parts (genes, proteins) of a system are assembled and connected into a formal structure until a model of the system is attained
� Models across cellular systems� Alliance for Cellular Signaling
� http://www.signaling-gateway.org/
� Cell systems Initiative
Copyright: Norbert Graf
� Cell systems Initiative
� http://www.cellsystems.org/
� E-cell Project
� http://www.e-cell.org/ecell/
� Institute for Systems Biology
� http://www.systemsbiology.org/
� Molecular Sciences Institute
� http://www.molsci.org/
� Reconfiguration after detection of a new component or connection of the whole model is necessary
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Top-down approach
� Begins with clinical observation and knowledge
about the behaviour of a system as a whole
� Modelling process continues with the identification
of subsystems required to reproduce the disease
process
Copyright: Norbert Graf
process
� The process continues in an iterative fashion by
adding greater details to each subsystem
� Each subsystem is constrained by the overall
behaviour of the entire system
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Preconditions
�Trust in In Silico Modells
� Part of a clinicogenomic trial
� Validation by reality
� be aware that a clinician treats patients
Computer
Copyright: Norbert Graf
In Silico Experiment
Reality
comparisontu
ning
Computer
Human Being
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Preconditions
In Silico Experiment comparisontuni
ng
Virtuality
Copyright: Norbert Graf
Reality
comparisontuni
ng
Reality
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Virtuality
Preconditions
Use in Clinical Trials
Copyright: Norbert Graf
Reality
Use in Clinical Trialsa physician has to define,
what can be accepted as a minimal deviation
between in silico prediction
and reality
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New patient with nephroblastoma
CLINICAL DATA
Age, Sex, Weight, …
Syndromes
IMAGING DATA
CT or MRI (DICOM)
Tumour volumeTumour shapeTumour composition
(cystic, necrotic, solid,hemorrhagic regions,…)
MOLECULAR DATA
Pattern of autoantibodiesto tumour antigens
TREATMENT SCHEDULE
Pharmacokinetic data
Oncosimulator
Data collection
Copyright: Norbert Graf
PREDICTION OF RESPONSE TO PREOPERATIVE CHEMOTHERAPY
Would CT be beneficial?NO
YES
Check prediction and if reasonable
proceed to surgery
CHECK PREDICTION AND IF REASONABLE APPLY CT SCHEMERecord actual treatment, histology,
outcome, …
DO THE SIMULATION AND THE REALITY AGREE?
YES
NO ���� an adaptation is necessary
Oncosimulator
ok
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In Silico Oncology - RecipeSheet
Copyright: Norbert Graf
Aran Lunzer et al., Meme Media Laboratory, Hokkaido University N-13, W-8 Sapporo, 060-8628 Japan
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How far to go with standardisation?
Paylor: … „These findings can
be considered a proof of
principle that standardization
may indeed result in findings
that are more restricted to a
Copyright: Norbert Graf
Richter SH et al.: Environmental standardization: cure or cause of poor reproducibility in animal experiments? Nature Methods 6:257-261, 2009
Paylor R: Questioning standardization in science, Nature Methods 6:253-254, 2009
that are more restricted to a
particular laboratory and not
a generalized observation.“
Heterogenous conditions lead to more reproducible behavioral results
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"If it were not for the
great variability among
individuals, medicine
Copyright: Norbert Graf
individuals, medicine
might as well be a
science and not an art."
Sir William Osler, 1892
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Copyright: Norbert Graf