CancerGrid: developing open standards for clinical cancer
informatics
James Brenton1, Carlos Caldas1, Jim Davies2, Steve Harris2 and Peter Maccallum1
1
Hutchison/MRC Research Centre, University of Cambridge, Hills Road, Cambridge CB2 2XZ
Oxford University Computing Laboratory, Wolfson Building, Parks Road, Oxford OX1 3QD
2
Abstract
CancerGrid is a consortium developing open standards for clinical cancer informatics based on data
and metadata representation, distributed service-oriented architectures, and collaborative working in
virtual organisations with exceptional confidentiality constraints. In this paper we outline the unique
challenges that clinical trials and translational research pose to the e-Science community, and
investigate how existing technologies can best be deployed to support research with a significant
clinical component. We discuss the broader picture of national and international programmes for
cancer research, and evaluate the usability of the current generation of software tools in support of
these programmes.
1. Introduction and background.
The development of new cancer therapies is a
long and hard process with low success rates
and timescales measured in the decades. This
might improve through molecular approaches to
cancer research, but the fundamental links
between the operation of cancer at the
molecular level and its manifestation in the
patient population will only be determined when
molecular effects are observed simultaneously
with the clinical effects they generate.
Unfortunately clinical trials with tissue-based
molecular research components are not well
supported by existing information systems.
The CancerGrid consortium [1] has been
formed to take advantage of recent
developments in Semantic Web technology,
Grids, Service-Oriented Architectures (SOA),
and Computer Supported Collaborative
Working (CSCW). It will pursue the strategic
goal of integrating clinical and research
informatics infrastructures.
To date CancerGrid has secured funding
from the MRC for a three year technology
development phase, from the EPSRC for
international collaboration and from Microsoft
Research to study advanced Web services
applications. It is interacting with the national
programme for research and clinical trials
management represented by the National
Cancer Research Institute (NCRI) and its
international equivalents including the US
National Cancer Institute’s Centre for
Bioinformatics (NCICB) to ensure development
will provide re-usable software toolkits and
knowledge for the cancer research community.
2. New developments in cancer
research practice demand a novel
information architecture.
Legislative changes such as the European
Commission
Clinical
Trials
Directive
2001/20/EC and the US Food and Drug
Administration’s 21CFR Part 11 have put
significant new pressures on clinical trials
coordinators, in particular more stringent
requirements on IT systems validation and on
the frequency and promptness of contact with
clinicians following serious adverse events. UK
clinical trials units need an easy to validate set
of components with inbuilt support for human
to human interaction to support rapid trial
deployment.
Cancer researchers in the UK are committed
to translational research, bridging the gap
between laboratory research and clinic.
However difficulties abound; individual datasets
and sample collections are too small to produce
statistically significant results so need to be
pooled while unification can only be reliably
achieved for simple measures; access to data
gives rise to problems with anonymisation and
re-identification of patients; and there are no
standards for the collection, labelling and
annotation of tissue sample sets. Translational
researchers need flexible, well-structured data
models and terminologies which enable data
sharing while supporting the development of
novel techniques.
Recent successes in Cancer therapy such as
Tamoxifen and Herceptin in breast cancer and
Gleevec in leukaemia owe their success to an
understanding of individual tumours at the
molecular level; each of these compounds is
only effective in individuals whose cancer cells
express particular proteins. This suggests that
future improvements in survival rates will be
dependent on increased matching of treatments
to personal genetic makeup. To fully develop
this approach, larger numbers of increasingly
targeted trials will be required. National cancer
programmes need tools to support, monitor and
direct the global knowledge base these trials
will represent.
3. A prototype model-centred
architecture for breast cancer trials.
3.1 CancerGrid design priniciples.
Current practice in clinical trials is based on a
patchwork of paper based systems and custom
IT solutions for individual services. The
CancerGrid project is moving its exemplar trials
to an SOA-based document workflow system,
with the goal of providing a Grid of generic
services which can be configured to provide
support for multiple trials.
The past ten years have shown the great
potential of custom web-delivered n-tier
systems to solve individual service needs.
However, this approach is expensive when each
trial needs a custom solution, and to date has
shown only limited success in long-term
interoperability of the resulting solutions.
We are taking the positive aspects of webbased delivery mechanisms, but adding the
design
philosophy
of
Model-Driven
Architecture (MDA), the Semantic Web, and
Grids.
In the MDA approach, systems are defined
in terms of their data and process models, at a
level
independent
of
the
underlying
implementation technology. Mappings onto
specific technologies are then produced, with
the help of automated tools wherever possible.
In the Semantic Web approach, data models
can be built from the composition and
transformation of XML schemas, and formal
models expressed in OWL can be used to
specify components and processes. Building a
clinical trial using composition of structured
data elements which can be used from capture
through to analysis also allows improvements
both in the quality of data collected and in its
eventual re-use.
The Grid approach encourages systems to be
built as configurable generic services, with
specialised resources such as persistence
mechanisms virtualised. Grid research is
particularly concerned with authentication and
authorisation, important in the trials area where
users and services have different requirements
and rights for data entry and analysis.
3.2 The prototype system.
We have built a prototype system to
demonstrate our approach, based on the current
breast cancer therapy clinical trials tAnGo [2]
and neo-tAnGo [3] for which the official
documentation is already prepared and paperbased data capture is in progress. As the
CancerGrid project progresses, it will be
validated against the real data capture in these
trials.
Figure 1 shows the processes which have
been implemented for tAnGo in the prototype, a
subset of the set-up and data entry phases of the
trial. The full system will enhance this with
laboratory data capture and storage and analysis
mechanisms.
A generic clinical trials protocol model, a
common data element repository and a
vocabulary service have been created in Protégé
using its XML back-end plug-in. An instance
of this model, encoding the key elements of the
tAnGo clinical trial protocol and its patient
registration and randomisation criteria has been
entered. The Protégé XML file can now be
transformed using XSLT to extract an XML
representation of the clinical trial protocol.
This document has been further transformed
to generate trial metadata, an HTML web page
describing tAnGo in detail. This demonstrates
how the electronic trials protocol document
could be used to drive clinical trials registration
and discovery systems.
The description of the registration and
randomisation case report form has also been
transformed into two XML schemas, one the
data model for data entry, and another the rules
for patient eligibility in the trial. The data
collection protocols accompanying the common
data elements have been extracted to create
HTML instructions for the completion of the
case report form.
Using both Adobe PDF forms and Microsoft
InfoPath, the schema has been realised as a
data-entry form suitable for completion by a
clinician. The InfoPath example makes use of
Web services to provide live access to a
database of randomising hospital consultants as
the form is completed. A second .NET based
Web service has been created that receives
XML documents from the completed forms
together with XML schemas and XPATH
statements derived from the protocol model.
The service tests for validity, eligibility and
subsequent processing requirements and
Figure 1: The current CancerGrid prototype, showing the workflow driven by the trials
protocol (modelled in Protégé), transformed into data and metadata for trials processes
(using XSLT), which are then operated using XML-based document workflows and
Web services (here using Microsoft Infopath as the user interface).
demonstrates how parts of the data capture
pathway for trials can be based on configurable
services. The validated entry is then ready for
the next stage in the trials workflow,
randomisation. In the complete system the
randomisation will be a separate Web service.
While the XML and Web service prototype
for tAnGo demonstrates the principles of
document and service creation, we have in
parallel provided a Zope/Plone [4, 5] based
CSCW solution for the neo-tAnGo trial’s
existing static Word and PDF documents. This
required the development of a custom four-level
Zope security model, with (1) administrators,
(2) trial coordinators responsible for portal
content, (3) clinical and research nurse members
needing access to documents without
modification privileges and (4) anonymous
visitors who might include patients and the
general public. In the final system many of
these
documents
will
be
generated
automatically from the protocol on demand,
because minor changes in the protocol can still
result in a significant effort by trial coordinators
to update all affected content.
4. Architecture in context; the
evolving landscape of clinical trials
management.
4.1 Clinical vocabularies and ontologies
require investment and service provision at
an international level.
Once the software infrastructure is in place to
support trials management, the provision of
high-quality curated data elements will be a
determining factor in the success of the project.
Collaboration with UK and international cancer
organisations is required to increase the pool of
available managed data resources and
terminologies.
CancerGrid is working with the NCICB, and
plans to reuse the existing caDSR product to
host standard data elements in a Web service
environment, along with other components of
the caBIG architecture [6].
This type of data element sharing requires a
framework which imposes a common metamodel, so that a standard toolset can be used to
incorporate the elements into software systems.
Compliance with standards, such as ISO11179
adopted by NCICB, may be the solution. While
such standards-based modelling imposes
overheads, it will support UK cancer
researchers’ efforts to collaborate with
Australasia, the EU and North America.
4.2 Clinical trials management processes are
heterogenous and evolving.
The prototype system is directed at a small
subset of the eventual user community,
specifically trials coordinators and data entry
clinical research staff. Eventually the system
will
need
to
support
statisticians,
bioinformaticians, regulatory authorities and
commercial interests in a framework which
preserves the evolving ethical and legislative
constraints in the trials process.
The regulatory frameworks, operating
procedures and relationships between clinics,
accredited trials units and national trials services
are constantly evolving. The CancerGrid
architecture cannot target a single fixed
organisational model, but will instead build a
flexible role-based model into the system and its
deployment and configuration technology.
5. CancerGrid’s challenges to the
current generation of Semantic Web
technologies.
CancerGrid will test the latest developments in
MDA. Current commercial MDA tools provide
good support for code skeleton generation in
Java and C# but still require significant software
development expertise. Moving to an XML
centred system making use of XSLT reduces the
need for software components – many steps in
the model transformation process become
metadata-defined. Adopting ontologies rather
than schemas for models allows better designed
systems, with aspects of formal specification
built in; but the toolkits to support ontology
based development are not as mature as the
equivalent software design tools. Developments
in this area are required; formal specification
tools that non-logicians can use.
The CancerGrid architecture will require a
dependable persistence infrastructure. While
datasets remain small, XML document
repositories such as Xindice will be sufficient,
but as tissue based data is included relational
databases will be required. For these, an objectrelational mapping technology such as OJB
could be used; but we are also considering the
benefits of the OGSA-DAI approach, which
would allow databases to interact with the
system via XML intermediary formats. In either
case we will virtualise the persistence
mechanism; trials data will need to persist for
up to 50 years, so it is reasonable to expect
several migrations of the underlying technology
during that time, while the data models should
remain constant.
CancerGrid will test the current limits of
Web service and Grid security models. The
principle of moving healthcare records over
TCP/IP has been demonstrated in several
previous e-Science projects such as e-Diamond
[7]. However, the current WS-I Basic Profile
security model encounters some issues with
firewalls. Trusted communication between NHS
clinics, universities and trials units will require a
more advanced approach based on robust,
interoperable WS-Security implementations.
Authentication is also an issue. Users will need
to access multiple resources outside their own
institutions. Each trial could build a networked
authentication system based on a technology
such as LDAP, but management of that system
would quickly become a significant overhead. A
full solution for the UK-wide or international
collaboration
may
require
the
latest
developments in role-based inter-organizational
security, such as the Shibboleth system [8].
CancerGrid is building systems to support
human and automated workflows. We will make
use of the latest developments in areas such as
BPEL and Taverna/Freefluo. Bioinformatics
and statistical analysis is currently done using
command-line tools or custom applications. By
integrating analyses as Web service workflow
components, built on Grid/Web convergence
technologies such as GT4, we can make toolkits
available to users and also improve the
specification and reproducibility of the analysis
of this valuable data.
6. Conclusions
Current molecular approaches to cancer
research mean that we need to conduct more
trials on faster timescales. The data for those
trials should be collected in systems which
prepare them for re-use in merged large-scale
datasets.
An XML-based, MDA approach has been
demonstrated to adapt well to the trials data
capture process. We are extending this to a
Grid/SOA model of configurable services for
complex virtual organizations. We plan to
construct a Grid of services which can be
reconfigured to match the rules and
organizational structure of each clinical trial.
Existing e-Science and commercial software
development tools support parts of the process.
As Semantic Web and Grid technologies
develop, we hope be able to use them to deliver
a system where a legal, ethical and
organizational model can be translated directly
into the deployment and configuration rules for
a validated trials data management system.
7. References
[1] http://www.cancergrid.org
[2] http://www.cancerinformatics.org.uk
[3] http://ncicb.nci.nih.gov
[2] TANGO clinical trial ISRCTN 51146252
[3] Neo-tAnGo clinical trial ISRCTN 78234870
[4] http://www.zope.org
[5] http://www.plone.org
[6] Buetow, KH Science 308 821-824 (2005)
[7] http://www.ediamond.ox.ac.uk
[8] http://shibboleth.internet2.edu