CT Imaging Phenotypes in COPD

Raúl San José Estépar, Ph.D.

Laboratory of Mathematics in Imaging

Applied Chest Imaging Laboratory

Surgical Planning Laboratory

Brigham and Women’s Hospital

Introduction Emphysema Airways Airway Power

CT Imaging Phenotypes in COPD

Lung Cancer Workshop VII

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:

Introduction

Introduction Emphysema Airways Airway Power

CT Imaging Phenotypes in COPD

Lung Cancer Workshop VII

COPD: a growing disease

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

24 million people affected by COPD in US

Introduction

Introduction Emphysema Airways Airway Power

CT Imaging Phenotypes in COPD

Lung Cancer Workshop VII

Disease in Images

Airway Diseases

Emphysema Diseases

Introduction

Introduction Emphysema Airways Airway Power

CT Imaging Phenotypes in COPD

Lung Cancer Workshop VII

Quantitative CT

• CT is the modality of choice for quantitative lung imaging– Good contrast between tissue classes: air,

connective tissue, blood• Partial Volume Effect

– Physical metric: Density • Subject to artifacts and measurement conditions

– High resolution • No high enough for the disease site

Introduction

Introduction Emphysema Airways Airway Power

CT Imaging Phenotypes in COPD

Lung Cancer Workshop VII

What can we get from CT?

CT

HRCT

MSCT

Airway Phenotypes

Emphysema Phenotypes

Density

Size

Deformation

Edge Detection

Registration

Effective Linear Attenuation Coefficient

Morphology & Shape

Dynamic(INSP EXP)

Introduction

Gas trappingParenchyma interdependence

Introduction Emphysema Airways Airway Power

CT Imaging Phenotypes in COPD

Lung Cancer Workshop VII

CT-based biomarkers: Accuracy vs Precision

• How do we want to measure?– Accurate: the right” answer no bias– Precise: errors are as small as possible

– What is the main difference?

Accurate, not precise Precise, but not accurate

Introduction

Introduction Emphysema Airways Airway Power

CT Imaging Phenotypes in COPD

Lung Cancer Workshop VII

Wall thickness

• Wall thickness measurements are a clear example where accuracy has overplayed precision

Introduction

Introduction Emphysema Airways Airway Power

CT Imaging Phenotypes in COPD

Lung Cancer Workshop VII

Emphysema phenotypes

Effective Linear Attenuation Coefficient

Morphology & Shape

Density

Size

Histogram-based analysis

Cluster-based analysisShape-based analysis

Texture-based analysis

Introduction Emphysema Airways Airway Power

CT Imaging Phenotypes in COPD

Lung Cancer Workshop VII

Histogram-based measurements

• Low Attenuation Areas % (LAA%)– Conceptually more appealing– Histopathologic correlates

• 15th Percentile (Per15th)– More normally distributed– More sensitive to early changes

Emphysema

Introduction Emphysema Airways Airway Power

CT Imaging Phenotypes in COPD

Lung Cancer Workshop VII

Issues

• Lung density is influenced by– BMI– Noise– CT protocol

• Inter-center (or inter scanner) variability in CT measures of emphysema

• Volume dependence of emphysema measures

Emphysema

Introduction Emphysema Airways Airway Power

CT Imaging Phenotypes in COPD

Lung Cancer Workshop VII

Cluster-based analysis (power law)

Mishima, PNSA 1999

• Power law for the distribution of air pocket sizes.• Related to the fractal dimension of the alveolar

surface.• Sensitivity to early-stage disease

Emphysema

Introduction Emphysema Airways Airway Power

CT Imaging Phenotypes in COPD

Lung Cancer Workshop VII

Shape-based analysis

Keller, Reeves, Yankelevitz et al, Proc SPIE, 2009

• Descriptor of diaphragm curvature

• Correlated with DLCO% and VA

• Enhance information provided by histogram-based metrics.

Emphysema

Introduction Emphysema Airways Airway Power

CT Imaging Phenotypes in COPD

Lung Cancer Workshop VII

Texture-based analysis

• Exploit pixel relations: higher order order statistics and other image features.

• Require training stage.• Long processing time.• It has the potential of being less sensitive to scanner

variability.

Xu, TMI, 2006

Emphysema

Introduction Emphysema Airways Airway Power

CT Imaging Phenotypes in COPD

Lung Cancer Workshop VII

Airway Phenotypes

Airways

Effective Linear Attenuation Coefficient

Morphology & Shape

Density

Size

Peak Wall Attenuation

Airway sizeTree morphology

Airway Power

Introduction Emphysema Airways Airway Power

CT Imaging Phenotypes in COPD

Lung Cancer Workshop VII

Airway Size

• Small airways are the site of obstruction– Difficult to measure at current resolutions– Distal thickening is related to proximal

effects (Nakano,2005)• Airway size phenotypes

– Wall Thickness– Wall Area % (WA%)– Pi10: Extrapolated square root of wall area

of an ideal airway of 10 mm internal Perimeter.

Airways

Introduction Emphysema Airways Airway Power

CT Imaging Phenotypes in COPD

Lung Cancer Workshop VII

Wall thickness: THE airway phenotype?

- Some open-ended questions· Does inflammation and airway remodeling merely leads to airway

thickening?· What is the CT-intensity telling about the diseases?

- CT measures the linear attenuation coefficient of the underlying tissue structures. This can be used as a indirect measurement for density (no without many caveats)

- Hypothesis: · Airway wall compositions changes due to mural remodeling can be

detectable by CT X-ray attenuation· Changes in wall X-ray attenuation may correlate with degree of

expiratory airflow obstruction

Airways

Introduction Emphysema Airways Airway Power

CT Imaging Phenotypes in COPD

Lung Cancer Workshop VII

Preliminary Evidences

- Micro-CT of an hamartoma:

- Normal Airway: Histology vs CT

Alveolar parenchyma CartilageFibroblasts/

inflammatory cells

Alveolar parenchyma CartilageFibroblasts/

inflammatory cells

Airways

Introduction Emphysema Airways Airway Power

CT Imaging Phenotypes in COPD

Lung Cancer Workshop VII

Wall X-ray Attenuation

- Washko et al, JAP 2009.

- Increased Wall attenuation with disease progression.

- Wall attenuation shows higher correlation with FEV1% predicted (R= -0.47, P<0.0001) than wall thickness (R= -0.34, P<0.0001).

Gender and Airway Wall Attenuation

0100200300400500600700800900

Normal 1 2 3/4

GOLD Stage

CT

Den

sity

*

Males

Females

- In a multivariate analysis, percentage of emphysema and wall attenuation were significant predictors of FEV1% predicted (P<0.0001), but not wall thickness.

Airways

Introduction Emphysema Airways Airway Power

CT Imaging Phenotypes in COPD

Lung Cancer Workshop VII

Mass Conversation Principle

- Development of a new phenotype that has as primary goal to be precise while capturing the main airway components: morphology and composition

- Scanner can be approximate as a linear system: mass has to be preserved.

CT (h(x))

mass mass

Airway Power

Introduction Emphysema Airways Airway Power

CT Imaging Phenotypes in COPD

Lung Cancer Workshop VII

Airway Power

Airway Power

T

Introduction Emphysema Airways Airway Power

CT Imaging Phenotypes in COPD

Lung Cancer Workshop VII

Simulation: Power vs Wall thickness

Airway Power

Introduction Emphysema Airways Airway Power

CT Imaging Phenotypes in COPD

Lung Cancer Workshop VII

Simulation: Power vs Wall Attenuation

Airway Power

Introduction Emphysema Airways Airway Power

CT Imaging Phenotypes in COPD

Lung Cancer Workshop VII

Simulation: Power vs Parenchyma Attenuation

Airway Power

Introduction Emphysema Airways Airway Power

CT Imaging Phenotypes in COPD

Lung Cancer Workshop VII

COPDGene Phantom

- Four scanners: Philips, GE, Siemens and GE (Low dose)

- Two reconstruction kernels

- Each tube is used as its own control

- A precise metric should be stable across brands and protocols

CTP666-1

CTP666-2

CTP666-6

CTP666-3CTP666-4

CTP666-5

Airway Power

Introduction Emphysema Airways Airway Power

CT Imaging Phenotypes in COPD

Lung Cancer Workshop VII

Relative error per scanner

Airway Power

Introduction Emphysema Airways Airway Power

CT Imaging Phenotypes in COPD

Lung Cancer Workshop VII

Relative error between lose dose and high dose

Airway Power

Introduction Emphysema Airways Airway Power

CT Imaging Phenotypes in COPD

Lung Cancer Workshop VII

Relative error for all possible combinations

Airway Power

Introduction Emphysema Airways Airway Power

CT Imaging Phenotypes in COPD

Lung Cancer Workshop VII

Conclusions

• CT is the primary imaging tool to characterize COPD– COPD phenotypes are still a moving target

• Shared quantitative challenges due to scanner variability– Reverse engineer scanner effects– Exploit signal invariant properties to define new

metrics