COPDGene® : Genetic Epidemiology of

COPD

NA-MIC: All Hand MeetingRaúl San José & James Ross

BWH

Overview COPDGene Data Analysis Future Directions

COPD: Chronic Obstructive Pulmonary Disease

Definition: “Airflow limitation that is not fully reversible. The airflow limitation is usually progressive and associated with an abnormal inflammatory response of the lung to noxious particles or gases.”

Causes:

Overview

Overview COPDGene Data Analysis Future Directions

COPD: a growing disease

Projected to be the third-leading cause of death by 2020

24 million people affected by COPD in US

Overview

Overview COPDGene Data Analysis Future Directions

COPD: The Diseases

What is the underlying process?

Slowly progressive irreversible destruction of the lung tissue

Emphysema: air sacs that exchange gases

Airway disease (Chronic Bronchitis): airways that conduct these gases

End Result: Progressive shortness of breathCoughSputum production

Overview

Overview COPDGene Data Analysis Future Directions

Disease in Images

Airway Diseases

Emphysema Diseases

Overview

Overview COPDGene Data Analysis Future Directions

COPDGene

Only 20% of smokers develop COPD

COPDGene

Genetic factors

Multi-center study funded by the National Heart, Lung and Blood Institute (NHLBI).

Co-PIs: Drs. James Crapo, Edwin Silverman.

21 clinical sites

3 Image analysis centers:

• Denver

• Iowa

• BWH

Overview COPDGene Data Analysis Future Directions

COPDGene: Hypothesis

1) Precise phenotypic characterization of COPD subjects using computed tomography, as well as clinical and physiological measures, will provide data that will enable the broad COPD syndrome to be segregated into clinically significant subtypes.

2) Genome-wide association studies will identify genetic determinants for COPD susceptibility that will provide insight into clinically relevant COPD subtypes.

3) Distinct genetic determinants influence the development of emphysema and airway disease.

COPDGene

Overview COPDGene Data Analysis Future Directions

COPDGene: Goals

• Collect a large population of COPD subjects and smokers without COPD: 10,000

• Two racial/ethnic groups: Non-Hispanic whites and Non-Hispanic African Americans

• Extensive Characterization (Chest CT scans)– Inspiratory, Expiratory– High resolution CT (0.7mm isotropic with 50% overlap)– 2 reconstructions kernels (smooth and sharp)

• Use genome-wide association analysis to find inherited causes of COPD and COPD subtypes

COPDGene

Overview COPDGene Data Analysis Future Directions

COPDGene: Study Design

COPDGene

Figure 7. Genome Wide Association of COPD: Study Design

Phase 1

Phase 2

Phase 3

Genome Wide Screen

Case/Control Cohorts

Non-Hispanic Whiten=3000/3000

African Americann=1500/1500

Boston Early Onset COPD Family Study

n=160 families,1100 individuals

~6000 SNP Candidates

50 regions (flanking SNPs)

Fast track panel*

Case/ControlNon-Hispanic White

n=1000/1000

Case/ControlNon-Hispanic White

n=1000/1000

Case/ControlAfrican American

n=500/500

Case/ControlAfrican American

n=500/500

Phase 4

Case/ControlNon-Hispanic White

n=1000/1000

Case/ControlAfrican American

n=500/500

Candidate Gene Analysis

~6000 SNP Candidates

50 regions (flanking SNPs)

~3-5 Gene Candidates ~3-5 Gene Candidates

International COPD Genetics

Networkn=1150 probands

+ 1950 sibs

Confirmation of SNP Signals

Region Mapping

GOLD 1 Cohort

Non-Hispanic Whiten=1000

African Americann=500

Overview COPDGene Data Analysis Future Directions

COPDGene: Current status

COPDGene

• Since Sept 2007 over 6500 subjects have been recruited.

• First 2500 have been fully analyzed.

Overview COPDGene Data Analysis Future Directions

Challenges

• Data management– Storage: 40,000 scans, 20 TB expected to archive full

cohort– Quality control: Initial and processing– Querying and retrieval

• Image analysis: inspiration and expiration– Lung area and lobes– Airway segmentation– Robust: outlier detection– Minimal user input

• High-throughput analysis– Batch analysis– Grid deployment

Data Analysis

Overview COPDGene Data Analysis Future Directions

Analysis Centers

• National Jewish (Denver): Drs. Lynch and Schroeder– Q&A– Emphysema and Airway analysis using VIDA– Primary archiving center– Result integration

• BWH (Boston): Dr. Washko– High-throughput emphysema analysis– New phenotypes– Data replication

• University of Iowa: Dr. Hoffman– COPDGene Phantom Analysis (Q&A)– VIDA customization

Data Analysis

Overview COPDGene Data Analysis Future Directions

BWH Pipeline

• Lung Imaging Platform– ITK-based filters for lung extraction, lobe

segmentation and parenchymal texture analysis– Emphysema quantification– Air trapping quantification– Tracheal air correction– VTK-based filters for airway measurements– Command Line Tools

• Grid Wizard Enterprise for pipeline deployment

• Iterative Lobe segmentation in Slicer 3

Data Analysis

Overview COPDGene Data Analysis Future Directions

BWH Pipeline

• Filters– itkLungConventions– itkExtractLungLabelMapImageFilter– itkPartialLungLabelMapImageFilter– itkMergeLungLabelMapsImageFilter– itkAutoThresholdAirwaySegmentatio

nImageFilter– itkWholeLungVesselAndAirwaySegm

entationImageFilter– itkSplitLeftAndRightLungsImageFilte

r– itkLabelLungRegionsImageFilter– itkAirwayGraphTraits– itkImageToAirwayGraphFilter– itkImageToAirwayGraphFunctor– itkMinCostPathAirwaySegmentationI

mageToGraphFilter

Data Analysis

• Tools– ConvertDicom– GeneratePartialLungLabelMap– GenerateEmphysemaMeasures– QualityControl– ExtractLungLabelMap– MergeLungLabelMaps– GenerateHUStatistics– SegmentationAssistant– GenerateMedianFilteredImage– SplitLeftAndRightLungs– LabelLungRegions– GenerateAirwayPhantom

Overview COPDGene Data Analysis Future Directions

BWH Pipeline

Data Analysis

Overview COPDGene Data Analysis Future Directions

Data Quality: Dashboard

Data Analysis

Overview COPDGene Data Analysis Future Directions

Future Directions

Future Directions

• Airway Analysis– User-driven path extraction– Fully automatic approach based on Scale-space

particles

• Development of new airway phenotypes– Role of airway density in disease– New approaches for emphysema

• Multi scanner brand correction• Automatic pipeline supervision and reporting• Insp.-Exp. registration for lobar ventilation

assessment