IXI(CO): Progressing a scientific GRID project to an end-to-end solution

Thomas Hartkens, CTO

Overview

A brief history of “IXI”From the idea to a business plan Challenges in the first two years – GCP– Maintaining an audit trail and FDA 21 CFR part11– Quality Management System / ISO 9001:2000– Software validation

Conclusion

Why using Grid in Automated Medical Image Analysis?Huge volume of image data–hospitals typically produce several tera bytes per year–results of automated image analysis can be few times larger

Computationally demanding algorithms- sophisticated image analysis of one single image can take several hours (or even days)

Multiple processing steps (Workflows)- one solution consists often out of many single applications

Collaboration of different insitutions- is often required in clinical trials or research studies

Image database

Grid Demonstrator:A Dynamic Brain Atlas (2001-2002)

registration create atlas

AtlasPatient scan

transformation

Computational expensive !

DB query

Opening of the National e-Science Centre (NeSC), April 2002

Grid-enabled image registration and segmentation for medical research:

– to assess scalability of Dynamic Brain Atlas – to extend to data from outside the brain– to build an application interface

3 year project funded by e-science core programme

& GSK, Philips Medical Systems, Dunhill Charitable Trust

IXI components

IXI PortalGT3 Index Service

IXIWorkflow service

IXI insertion Service

IXI Core Service

ComputeResources

Service Provider #1

IXI Core Service

ComputeResources

Service Provider #2

MedicalImage

Database

Available Services Aggregations of MICL SDEs

Workflow submission

Invocations &Notifications

Result management

GridFTP

IXI components

IXI PortalGT3 Index Service

IXIWorkflow service

IXI insertion Service

IXI Core Service

ComputeResources

Service Provider #1

IXI Core Service

ComputeResources

Service Provider #2

MedicalImage

Database

Available Services Aggregations of MICL SDEs

Workflow submission

Invocations &Notifications

Result management

GridFTP

Algorithms wrapped as grid services for medical image analysis, e.g.•image segmentation•image registration

•non-rigid registration:•run-time on single CPU between

10 minutes and 24 hours

IXI components

IXI PortalGT3 Index Service

IXIWorkflow service

IXI insertion Service

IXI Core Service

ComputeResources

Service Provider #1

IXI Core Service

ComputeResources

Service Provider #2

MedicalImage

Database

Available Services Aggregations of MICL SDEs

Workflow submission

Invocations &Notifications

Result management

GridFTP

<IXIWorkflow>

<stage id=”0” serviceRef=”http://fmrib.ox.ac.uk/IXI/BETFactory”><global> <paramValue portID=”4”>0.6</paramValue> <paramValue portID=”5”>true</paramValue></global>

<tasks><task id=”0”> <paramValue portID=”0”> gsiftp://ixi.doc.ic.ac.uk/query/brain001.hdr </paramValue>

<paramValue portID=”1”> segmentedTarget.hdr </paramValue></task>

<task id=”1”> <paramValue portID=”0”> gsiftp://ixi.doc.ic.ac.uk/query/brain002.hdr </paramValue>

<paramValue portID=”1”> segmentedSrc.hdr </paramValue>

</task></tasks></stage>

<stage id=”1” serviceRef=”http://ixi.doc.ic.ac.uk/IXI/RigidRegFactory”><global> <!-- rreg parameters --> <paramValue portID=”5”>NMI</paramValue> <paramValue portID=”6”>100</paramValue></global>

<tasks><task id=”0”> <paramValue portID=”0”>${0.0.1}</paramValue> <paramValue portID=”1”>${0.1.1}</paramValue></task></tasks></stage></IXIWorkflow>

• Workflow engine• Workflow language

to combine image analysis services

•XML workflow file

IXI components

IXI PortalGT3 Index Service

IXIWorkflow service

IXI insertion Service

IXI Core Service

ComputeResources

Service Provider #1

IXI Core Service

ComputeResources

Service Provider #2

MedicalImage

Database

Available Services Aggregations of MICL SDEs

Workflow submission

Invocations &Notifications

Result management

GridFTP

• Web interface to launch workflows

• Grid applications to design workflows and to control the execution

IXI components

IXI PortalGT3 Index Service

IXIWorkflow service

IXI insertion Service

IXI Core Service

ComputeResources

Service Provider #1

IXI Core Service

ComputeResources

Service Provider #2

MedicalImage

Database

Available Services Aggregations of MICL SDEs

Workflow submission

Invocations &Notifications

Result management

GridFTP

• large data set of MRI brains• ~550 normal volunteers• age range 20-80 years• T1, duel echo (proton

density and T2 weighted) • acquired at 3 different sites• publicly available to

research community

Reference image Subject image

Rigid + non-rigid registration

Manual segmentation Computed boundary of calcaneus

Application: Automatic delineation of bones

calcaneus

Elastic Transformation

Apply transformation

Business idea

3 months later 6 months later 9 months later

Automated image analysis for the Drug Development ProcessMeasurement in Rheumatoid Arthritis: eg. grade of bone erosion

Baseline

Start of treatment using drug candidate

From the idea to a business plan ...

Prof. David Hawkes

Prof. Jo Hajnal

Prof. Derek Hill

Prof. Daniel Rueckert

Founders of IXICO:

Ixico Presentation

Business plan

The Market

The industry

Product & Unique Selling Preposition

Sustainable advantage

The team

Intellectual Property

Finance (forecast, funding requirements)

Exit strategy

Ixico Presentation

A crisis in drug discovery & development

Imaging can help…

“Imaging is a key technology for assessing, accelerating the development of, and guiding the use of new therapeutic options”George Mills, FDA

“It is estimated that between

$10m and $30m could be saved

per drug program through the use

of advanced imaging technologies

which could guide go/no go

decisions.”

Business Insights Journal, May 2006

Ixico Presentation

The Market

The customers are the pharmaceutical and biotech companies

What does an “imaging biomarker” product look like?

Ixico Presentation

Imaging supplier

Image Analysis in clinical trials

Results for databaseupload

Data transfermetadata Image

scoringand analysis

Procedures

Study set-up, regulatory charter,Site management(training, SOPs…)

Ixico Presentation

Potential revenue growth

Potential Market compared to projected sales

Total Market£161.9m

IXICO£??m

CNS & Oncology£124.6m

0

20

40

60

80

100

120

140

160

180

2006 2007 2008 2009 2010

Years

£m

Ixico Presentation

Image analysis suppliers

Dominated by small number of companies that specialise in traditional “radiological reading”

Fastest growth is in more sophisticated methods

– Regulator push for methods that are less subjective

– Industry need for more precise measures for better, faster, cheaper decision making

Ixico Presentation

Product

•Advice on image acquisition parameters•Automated image analysis service•Quality control of analysis results•Quality Management System•Electronic audit trail •Site Management •Data logistics •Imaging charter for regulators (FDA)

Ixico Presentation

Product

•Advice on image acquisition parameters•Automated image analysis service•Quality control of analysis results•Quality Management System•Electronic audit trail •Site Management •Data logistics •Imaging charter for regulators (FDA)

Ixico Presentation

USP

Image acquisition Image analysis+

Due diligence conducted by the Capital Fund identified unique combination of:

Technology Know-how Quality system+ +

The team

Dr. Thomas Hartkens

Dr. Kate McLeish

James Cameron

Richard Brooman

Prof. Derek Hill

Ian Alexander

IXICO's non executives•Peter Morgan – Chairman– Executive career with IBM and experience on several company boards– Formerly Director General of the Institute of Directors in London.

•Prof. Sir Michael Brady–Track record of building successful entrepreneurial companies using academic technology (most recently Mirada, acquired by CTI)

•Prof. Sir Colin Dollery–Clinical pharmacologist and leading authority on Clinical Trials

–Senior consultant in GlaxoSmithKline (GSK): adviser to Dr Yamada the Chairman of Research and Development and member of the committees that review all protocols for human research, on the Development Investment Board and on the Global Safety Board

•Peter Ellis–Executive Director of People in Health and previously senior partner in Ernst & Young's Global Consulting life sciences practice.

Challenges in the first two years

Good Clinical Practise (GCP)

Audit Trail Electronic audit trail compliant with FDA 21 CFR part

11

Quality Management SystemISO 9001:2000 certification

Software Validatione.g. V-model

28

Audit trail produced by Workflow System

Reference + Image data

29

Task submission

IWD

1 Coarse Registr.2 Bias Correction3 QC interface

30

Task processing

IWD

1 Coarse Registr.2 Bias Correction3 QC interface

31

Automatic task

Image analysisapplication

IWD

1 Coarse Registr. Date:11.12.2006 13:45 Result:Transformation Server:234.232.43.22 Bias Correction3 QC interface

Results & Audit trail

information

32

Task processing

IWD

1 Coarse Registr. Date:11.12.2006 13:45 Result:Transformation Server:234.232.43.22 Bias Correction3 QC interface

33

Task processing

IWD

1 Coarse Registr. Date:11.12.2006 13:45 Result:Transformation Server:234.232.43.22 Bias Correction Date:13.12.2006 3:59

Result:Image Server:234.256.43.83 QC interface

34

Manual task

Custom-made interface

IWD

1 Coarse Registr. Date:11.12.2006 13:45 Result:Transformation Server:234.232.43.22 Bias Correction Date:13.12.2006 3:59

Result:Image Server:234.256.43.83 QC interface

Date:15.12.2006 9:45 Result:Comment

Person:Kate McLeish

Kate McLeish

Results & Audit trail

information &Digital Signature

35

IXICO's Electronic Audit Trail

Result images

Electronic Audit TrailElectronic Audit TrailElectronic Audit Trail IWD 1 Coarse Registr. Date:11.12.2006 13:45 Result:Transformation Server:234.232.43.2

2 Bias Correction Date:13.12.2006 3:59

Result:Image

Server:234.256.43.83 QC interface

Date:15.12.2006 9:45 Result:Comment

Person:Kate McLeish

Kate McLeish

21 CFR Part 11Electronic records; electronic signatures

Designed to provide FDA assurance that electronic records / signatures are– Trustworthy– Reliable

Equivalent to paper records and handwritten signatures

Applies to all FDA regulated industries

21 CFR part 11

Requirements

Electronic recordsControls aimed at security and integrity of recordsWhat information needs to be included with a signed electronic record How the signature must be linked to the record

Electronic signaturesUnique to an identified individualComponents of an electronic signature (in general, 2)Security and integrity of ID codes and passwords

Software validation

IXICO's Workflow System

IXICO's Electronic Paper Trail

Automatic Task

IWD

1 Coarse Registr.2 Bias Correction3 QC interface

IWD

1 Coarse Registr. Date:11.12.2006 13:45 Result:Transformation Server:234.232.43.22 Bias Correction3 QC interface

IWD

1 Coarse Registr. Date:11.12.2006 13:45 Result:Transformation Server:234.232.43.22 Bias Correction Date:13.12.2006 3:59

Result:Image Server:234.256.43.83 QC interface

IWD

1 Coarse Registr. Date:11.12.2006 13:45 Result:Transformation Server:234.232.43.22 Bias Correction Date:13.12.2006 3:59

Result:Image Server:234.256.43.83 QC interface

Date:15.12.2006 9:45 Result:Comment

Person:Kate McLeish

Kate McLeish

IWD

1 Coarse Registr. Date:11.12.2006 13:45 Result:Transformation Server:234.232.43.22 Bias Correction Date:13.12.2006 3:59

Result:Image Server:234.256.43.83 QC interface

Date:15.12.2006 9:45 Result:Comment

Person:Kate McLeish

Kate McLeish

Derek Hill

Manual Task

Automatic Task

ReportAnalysis has shown that XY% of all cases ....

ISO 9001:2000 based QMS

ISO 9001:2000

Does NOT say anything about the quality of the product.

BUT guarantees a constant product quality or an improvement of quality over time.

“Idea” of QMS

1.Write down what you are doing.2.Follow what you have written down.3.Improve documentation in a

“controlled” way.

Preserve and improve knowledge base

ISO 9001:2000 certification

Does NOT certify a product Butcertifies that the company works according to the ISO 9001:2000 standard

ISO 9001:2000 based QMS4. Quality Management System4. Quality Management System

5. Management responsibilities5. Management responsibilities

6. Resource management6. Resource management

7. Product realization7. Product realization

8. Measurement, analysis and improvement8. Measurement, analysis and improvement

Written procedures System deployment procedure

Written procedures System deployment procedure

Contract Agreement

Contract Amendment

Contract Processing Overview

Site Management

Site Training

Protocol Optimization

Adverse Findings

Data Transfer

Data Admission

Data Export

Data Delivery

Software Design

Workflow System Deployment

Workflow design

Software Transfer

Control of documents

Control of records

Internal audit

Issue tracking

Control of Nonconformity, Corrective and Preventive Action

Customer Feedback

Document Review

Document Version Control

Training

Recruitment

Purchasing

Risk Assessment

IP Transfer

Document control

Document server

Documents and records

Internal or external audit

ISO 9001:2000

IXICO's QMS

1.

2.

Management responsibility

To define measurable objectives

Involvement of people: creates an environment where people become fully involved in achieving the organization's objectives

Leadership: is needed to provide unity of purpose and direction

Review

Product realization

Customer-related processes–Determination / review of product requirements –Customer communication

Design and development–Definition of inputs and outputs of design–Planning–Verification and Validation

PurchasingProduction and service provisionControl of service provision; Validation of service Identification and traceability of product

FDA: Software validation

R eview

v erification

V alidation

Needs &Intended

Uses

Require-ments

Design InputProcess

Stage 1 Design Output

Final Design Output

Initial Design Stage

... Nth DesignStage

Production

TestArticles

Possible Interim Reviews

Diagram by Alford Taylor, Director, Devision of Electrical and Software Engineering, CDRH / FDA

Software design procedure: V-model

Traceability Matrix

End-to-end solution

Conclusion

•Innovations in the technology might not be “selling point”

•Research implementation <-> production system

•Electronic company cannot be implemented as a business without quality standards.

•Exciting journey

Thank you!