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EDA in Pharmacogenomics

WithSAS JMP and Windows WF

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Contents

IntroductionHapmap, JMP and Windows WFHapmap JMP Windows WF ApplicationNext StepsConclusionsQuestions

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Introduction

Dosing ModelsModel ComparisonModelling EDAStatistical Workflow of a

Pharmacogenomic StudyWarfarinSubgroup Analysis

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Clinical Dosing Model

Demographic

Pharma

Clinical

From The International Warfarin Pharmacogenetics Consortium. N Engl J Med 2009;360(8):753-764

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Pharmacogenetic Dosing Model

Demographic

Genetic

Pharma

Clinical

From The International Warfarin Pharmacogenetics Consortium. N Engl J Med 2009;360(8):753-764

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Model Comparison

From The International Warfarin Pharmacogenetics Consortium. N Engl J Med 2009;360(8):753-764

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Model Comparison Workflow

Impute

Split

Split

ModelTest Average10 x

ModelTest Average10 x

ModelTest Average10 x

Compare

Select

Validate

X x

A B

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Statistical Workflow of a Pharmacogenomic Study 1

From Turner SD, Crawford DC, Ritchie MD. Expert Rev Clin Pharmacol 2009;2(5):559-570

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Modelling EDA

Modelling / Comparisons: Routine Process • WF compatible

EDA : Investigative Process• Smaller (routine) processes

Model Extension• Modelling + EDA• WF possibility ?

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Warfarin

From Wadelius M, Pirmohamed M. Pharmacogenomics J 2006;7(2):99-111.

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Warfarin 2

From Wadelius M, Pirmohamed M. Pharmacogenomics J 2006;7(2):99-111.

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Statistical Workflow of a Pharmacogenomic Study 2

From Turner SD, Crawford DC, Ritchie MD. Expert Rev Clin Pharmacol 2009;2(5):559-570

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Subgroup Analysis

Presumable more unknown factors are involved that are distributed differently in different populations, e.g. dietary habits.

Given this state of knowledge the question remains whether to use one universal dosing algorithm or to use different dosing algorithms for different subpopulations.

This subgroup analysis could be extended to other model factors• clinical (diseases / disease states)• pharma (high responder / low responder)

Test Test Test Test Test

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Hapmap, JMP and WWF

HapmapJMPHapmap JMP WorkflowWindows WFWindows WF ActivitiesActivities inside a State

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Hapmap

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Hapmap 2

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JMP

JMP AutomationJMP ScriptJMP Workflow Builder

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JMP 2

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Hapmap JMP Workflow

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Windows WF

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Windows WF Activities

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Activities inside a State

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Start JMP Script in Activity

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Hapmap JMP WWF Application

User Input for State EventsUser Input for JMP ScriptJMP ReportVKORC1 Marker rs9923231JMP Script Results

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Hapmap JMP WWF Application 2

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User Input for State Events

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User Input for JMP Script

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JMP Report

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VKORC1 Marker rs9923231

refhom-count

het-count

otherhom-count

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Results Restriction using Chi-Square Test

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JMP Script Results

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Next Steps

Different Model factorsDifferent Modelling TechniquesTaverna WorkflowWarfarin HistoryWWF Custom ActivityTrackingPersistenceError HandlingWorkflow Re-use / Validation

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Different Model Factors

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VKORC1 Marker rs9923231

Clin1Clin2Clin3

Pharm1Pharm2Pharm3

Ethnic

Pharma

Clinical

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Different Modelling Techniques

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Detecting and Controlling for Population Stratification

From Turner SD, Crawford DC, Ritchie MD. Expert Rev Clin Pharmacol 2009;2(5):559-570

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Taverna Workflow

Open SourceBeanshell ScriptsRshell Scripts(On – off) Data Flow“UI” Command Line App

From http:\\taverna.sourceforge.net

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Warfarin History

Anti-clotting Agent high responders low responders

Rodenticide resistance

Rare Familial Diseases coagulation factor deficiencies

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Compare Genes of Species or Families

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WWF Custom Activity

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Tracking

State 1State 2State 3State 4…

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Tracking2

From Chappell D, The Workflow Way. Microsoft. 2009; 1-27.

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Persistence

From Chappell D, The Workflow Way. Microsoft. 2009; 1-27.

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Persistence 2

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Error Handling

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Workflow Re-use / Validation

From http:\\taverna.sourceforge.net

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Workflow Validation 2

Validate

Stop Workflow

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Error Handling 2

FTP Unzip

Reconnect

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Hapmap JMP WWF Application3

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Conclusions

It is possible to combine a data fetch and JMP scripts in a Windows workflow.

The graphical designer is attractive but not a Lego-like activity.

With more elaborate modelling or EDA workflows, the Tracking, Persistence and Error handling features probably make it worth considering.

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Questions

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