The need for standardisation from a clinical...

The need for standardisation

from a clinical perspective

Norbert Graf

University of the Saarland

Pediatric Oncology and Hematology

66421 Homburg / Germany

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


Declan Butler: Nature: 453:840-842, 2008

� Human Genome Project and bioinformatics

� Expression vectors for novel protein target

production

� Computer-aided drug design

Drivers of molecular therapeutics


� Robotic high-throughput screening

� Combinatorial chemistry

� Platform approach to drug discovery

� Huge increase in number of molecular targets

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


seamless integration of� In vitro data

� Clinical data

� Imaging data

� Public databases

� Computational mathematical methods and techniques are necessary

Need for Standardisation

�Researchers

�Academic

�Clinical

� Industrial


� Industrial

�Communication

� Integration

�Exchange

Need for Standardisation

� Infrastructure / Communication

�Data

� Interfaces

�Tools


�Tools

�Models

�Computational methodologies

Objective: Fighting Diseases

IT Research

Basic Clinical


Basic Research

Legal / EthicalResearch

ClinicalResearch

Translational Research

bench

Molecular level

feed

back

Scientistbasic-science breakthroughs


bedside

feed

back

Physician

Cellular level

clinical level

clinical applications

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


�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.

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


� those of previous EC frameworks

� national funding schemes

� together with industry

� healthcare providers

� international organisations

� thereby ensuring that the impacts will be realised

Standardisation

�Data�Molecular biology

� Heterogeneity of tumour material

� Tumour stem cells

� Signatures versus pathways


� Signatures versus pathways

� Cross platform analysis

� Imaging studies� Segmentation of tumours

�Clinical data� Prospective clinical trials

� Cross trial queries

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


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

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 ?


have ?

�how do we make different sorts of data

combinable ?

Barry Smith

Data entryInform submitter

Recycle Tumorbox

Tissue storage DNA blood/kidney DNA tumor RNA tumor

Cell cultureCell cultureSeraSera

PathologyPathology

Biobanking


LOH:1p, 1q

11p15 / p13, 11q16q22q

Real time PCR

Microarray

ß-Catenin Exon 3PCR / Sequence

(WT1)(DHPLC/Sequencing)

Associated screens,requests from

scientific community

Gene Arrays (Nephroblastoma)


Clustering of genes selected for intermediate vs. high risk histology

Clustering of genes selected for relapsed versus non-relapsed tumors

The Emergent Integrated Circuit of the Cell


Douglas Hanahan, Robert A. Weinberg: The Hallmarks of Cancer. Review. Cell, Vol. 100, 57–70, January 7, 2000

Acquired capabilities of cancer


Douglas Hanahan, Robert A. Weinberg: The Hallmarks of Cancer. Review. Cell, Vol. 100, 57–70, January 7, 2000

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


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

Clinical Trial Question

Diagnosis Surgery

Chemo-therapy

Histology

90% + x% survival

postop. radio -/


Histology Metastasis Stage

10% - x% relapses/death

postop. radio -/chemotherapy

and/or

retinoic acidHigh risk ?

Multi centre genomic trials

�Many centres are able to process genomic

data on-site

�Different platforms are used

�Question:


�Question:� Reproducibility

� Generality of genomics measurements

MCMP scenario


C. Desmedt, F. Buffa, personal communication;

ACGT D12.6, 2008

Imaging


T1 T1 + contrast T2 T2 flair

Tumour shape and size ?

Clinical data


Clinical trials

95

5050

60

70

80

90

100

Germany USA


15

0

10

20

30

40

50

Children AYA Adults

Couzin J: Survival in young adults with Cancer… Science 317:1160-1162, 2007

Paediatric Oncology

Ove

rall

surv

ival


Ove

rall

surv

ival

Clinical Trials in EuropeK

eim

B:

Tie

d u

p in

red

tap

e, E

uro

pea

n t

rial

s sh

ut

do

wn

. Nat

ure

Med

icin

e 13

:110

, 200

7


Kei

m B

: T

ied

up

in r

ed t

ape,

Eu

rop

ean

tri

als

shu

t d

ow

n. N

atu

re M

edic

ine

13:1

10, 2

007

The Tower of Babel


Pieter Brueghel the Elder (1563)

Standardisation

�Classifications

� ICD, …

�Terminologies

�SNOMED CT, …


�SNOMED CT, …

�Ontologies

�Gene ontology, …

� Semantic Web

�Natural language processing (NLP)

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


� 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.

Gene Ontology


http://bioportal.bioontology.org/


ACGT Master Ontology


ObTiMARepository

Trial Outline Builder


Trial Outline Builder

Patient Data Management System

CRF CreatorTrial Builder

patient specific view

graphical schema

general view

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.


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.

Value conflicts

conflict

Individual

interest

Collective

interests


conflict

between

Privacy Access

Balance?

�Genetic data always personal data?

�Can pseudonymous genetic data be regarded

as anonymous data for a controller, who

Data protection regarding human genetic research


as anonymous data for a controller, who

doesn‘t have the link?

�How to define additional knowledge, by

which a person can be identified?

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)


reference templates)

� Condition for anonymization of genetic data: De facto

anonymous data = anonymous data

� Relevant factor: effort for identification

Security architecture

� Defined the ACGT security architecture in line with the existing legal and data protection


existing legal and data protection framework.

� Interplay of IT services as well as processes and policies.

CAT Workbench

� Make a “data protection” configuration once… run it

several times…


Custodix, Belgium

Standardisation

� Interfaces

�tools

�Models




�communication

�exchange

Multilevel data integration and analysis


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


� 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

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


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

Preconditions

�Trust in In Silico Modells

� Part of a clinicogenomic trial

� Validation by reality

� be aware that a clinician treats patients

Computer


In Silico Experiment

Reality

comparisontu

ning

Computer

Human Being

Preconditions

In Silico Experiment comparisontuni

ng

Virtuality


Reality

comparisontuni

ng

Reality

Virtuality

Preconditions

Use in Clinical Trials


Reality

Use in Clinical Trialsa physician has to define,

what can be accepted as a minimal deviation

between in silico prediction

and reality

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


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

In Silico Oncology - RecipeSheet


Aran Lunzer et al., Meme Media Laboratory, Hokkaido University N-13, W-8 Sapporo, 060-8628 Japan

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


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

"If it were not for the

great variability among

individuals, medicine


individuals, medicine

might as well be a

science and not an art."

Sir William Osler, 1892

The need for standardisation from a clinical...

Documents

Transcript of The need for standardisation from a clinical...