CT-based Phenotype for Airway Remodeling in COPD

CT-based Phenotype for Airway Remodeling in COPD based on Airway Wall Density Power
Grant support: NIH/NHLBI 1K25HL104085-01
Raul San Jose Estepar

Dr. Raúl San José Estépar

Co-Director, Applied Chest Imaging Laboratory
Lead Investigator, Brigham and Women's Hospital
Associate Professor of Radiology, Harvard Medical School
Raúl is co-director of the Applied Chest Imaging Laboratory, lead scientist at Brigham and Women's Hospital and Associate Professor of Radiology at Harvard Medical School. 
 
1249 Boylston St, Room 216
Boston, MA, 02215
p: 617 525-6227
Hunninghake GM, Hatabu H, Okajima Y, Gao W, Dupuis J, Latourelle JC, Nishino M, Araki T, Zazueta OE, Kurugol S, Ross JC, San José Estépar R, Murphy E, Steele MP, Loyd JE, Schwarz MI, Fingerlin TE, Rosas IO, Washko GR, O'Connor GT, Schwartz DA. MUC5B promoter polymorphism and interstitial lung abnormalities. N Engl J Med 2013;368(23):2192-200.Abstract
BACKGROUND: A common promoter polymorphism (rs35705950) in MUC5B, the gene encoding mucin 5B, is associated with idiopathic pulmonary fibrosis. It is not known whether this polymorphism is associated with interstitial lung disease in the general population. METHODS: We performed a blinded assessment of interstitial lung abnormalities detected in 2633 participants in the Framingham Heart Study by means of volumetric chest computed tomography (CT). We evaluated the relationship between the abnormalities and the genotype at the rs35705950 locus. RESULTS: Of the 2633 chest CT scans that were evaluated, interstitial lung abnormalities were present in 177 (7%). Participants with such abnormalities were more likely to have shortness of breath and chronic cough and reduced measures of total lung and diffusion capacity, as compared with participants without such abnormalities. After adjustment for covariates, for each copy of the minor rs35705950 allele, the odds of interstitial lung abnormalities were 2.8 times greater (95% confidence interval [CI], 2.0 to 3.9; P<0.001), and the odds of definite CT evidence of pulmonary fibrosis were 6.3 times greater (95% CI, 3.1 to 12.7; P<0.001). Although the evidence of an association between the MUC5B genotype and interstitial lung abnormalities was greater among participants who were older than 50 years of age, a history of cigarette smoking did not appear to influence the association. CONCLUSIONS: The MUC5B promoter polymorphism was found to be associated with interstitial lung disease in the general population. Although this association was more apparent in older persons, it did not appear to be influenced by cigarette smoking. (Funded by the National Institutes of Health and others; ClinicalTrials.gov number, NCT00005121.).
Rudyanto RD, Muñoz-Barrutia A, Diaz AA, Ross J, Washko GR, Ortiz-de-Solorzano C, Estepar RSJ. MODELING AIRWAY PROBABILITY. Proc IEEE Int Symp Biomed Imaging 2013;Abstract
We present a probability model for lung airways in computed tomography (CT) images. Lung airways are tubular structures that display specific features, such as low intensity and proximity to vessels and bronchial walls. From these features, the posterior probability for the airway feature space was computed using a Bayesian model based on 20 CT images from subjects with different degrees of Chronic Obstructive Pulmonary Disease (COPD). The likelihood probability was modeled using both a Gaussian distribution and a nonparametric kernel density estimation method. After exhaustive feature selection, good specificity and sensitivity were achieved in a cross-validation study for both the Gaussian (0.83, 0.87) and the nonparametric method (0.79, 0.89). The model generalizes well when trained using images from a late stage COPD group. This probability model may facilitate airway extraction and quantitative assessment of lung diseases, which is useful in many clinical and research settings.
Ross JC, Díaz AA, Okajima Y, Wassermann D, Washko GR, Dy J, San José Estépar R. AIRWAY LABELING USING A HIDDEN MARKOV TREE MODEL. Proc IEEE Int Symp Biomed Imaging 2014;2014:554-558.Abstract
We present a novel airway labeling algorithm based on a Hidden Markov Tree Model (HMTM). We obtain a collection of discrete points along the segmented airway tree using particles sampling [1] and establish topology using Kruskal's minimum spanning tree algorithm. Following this, our HMTM algorithm probabilistically assigns labels to each point. While alternative methods label airway branches out to the segmental level, we describe a general method and demonstrate its performance out to the subsubsegmental level (two generations further than previously published approaches). We present results on a collection of 25 computed tomography (CT) datasets taken from a Chronic Obstructive Pulmonary Disease (COPD) study.
San José Estépar R, Kinney GL, Black-Shinn JL, Bowler RP, Kindlmann GL, Ross JC, Kikinis R, Han MLK, Come CE, Diaz AA, Cho MH, Hersh CP, Schroeder JD, Reilly JJ, Lynch DA, Crapo JD, Wells MJ, Dransfield MT, Hokanson JE, Washko GR. Computed tomographic measures of pulmonary vascular morphology in smokers and their clinical implications. Am J Respir Crit Care Med 2013;188(2):231-9.Abstract
RATIONALE: Angiographic investigation suggests that pulmonary vascular remodeling in smokers is characterized by distal pruning of the blood vessels. OBJECTIVES: Using volumetric computed tomography scans of the chest we sought to quantitatively evaluate this process and assess its clinical associations. METHODS: Pulmonary vessels were automatically identified, segmented, and measured. Total blood vessel volume (TBV) and the aggregate vessel volume for vessels less than 5 mm(2) (BV5) were calculated for all lobes. The lobe-specific BV5 measures were normalized to the TBV of that lobe and the nonvascular tissue volume (BV5/T(issue)V) to calculate lobe-specific BV5/TBV and BV5/T(issue)V ratios. Densitometric measures of emphysema were obtained using a Hounsfield unit threshold of -950 (%LAA-950). Measures of chronic obstructive pulmonary disease severity included single breath measures of diffusing capacity of carbon monoxide, oxygen saturation, the 6-minute-walk distance, St George's Respiratory Questionnaire total score (SGRQ), and the body mass index, airflow obstruction, dyspnea, and exercise capacity (BODE) index. MEASUREMENTS AND MAIN RESULTS: The %LAA-950 was inversely related to all calculated vascular ratios. In multivariate models including age, sex, and %LAA-950, lobe-specific measurements of BV5/TBV were directly related to resting oxygen saturation and inversely associated with both the SGRQ and BODE scores. In similar multivariate adjustment lobe-specific BV5/T(issue)V ratios were inversely related to resting oxygen saturation, diffusing capacity of carbon monoxide, 6-minute-walk distance, and directly related to the SGRQ and BODE. CONCLUSIONS: Smoking-related chronic obstructive pulmonary disease is characterized by distal pruning of the small blood vessels (<5 mm(2)) and loss of tissue in excess of the vasculature. The magnitude of these changes predicts the clinical severity of disease.
Nava R, Escalante-Ramírez B, Cristóbal G, San José Estépar R. Extended Gabor approach applied to classification of emphysematous patterns in computed tomography. Med Biol Eng Comput 2014;52(4):393-403.Abstract
Chronic obstructive pulmonary disease (COPD) is a progressive and irreversible lung condition typically related to emphysema. It hinders air from passing through airpaths and causes that alveolar sacs lose their elastic quality. Findings of COPD may be manifested in a variety of computed tomography (CT) studies. Nevertheless, visual assessment of CT images is time-consuming and depends on trained observers. Hence, a reliable computer-aided diagnosis system would be useful to reduce time and inter-evaluator variability. In this paper, we propose a new emphysema classification framework based on complex Gabor filters and local binary patterns. This approach simultaneously encodes global characteristics and local information to describe emphysema morphology in CT images. Kernel Fisher analysis was used to reduce dimensionality and to find the most discriminant nonlinear boundaries among classes. Finally, classification was performed using the k-nearest neighbor classifier. The results have shown the effectiveness of our approach for quantifying lesions due to emphysema and that the combination of descriptors yields to a better classification performance.
Kurugol S, Washko GR, Estepar RSJ. RANKING AND CLASSIFICATION OF MONOTONIC EMPHYSEMA PATTERNS WITH A MULTI-CLASS HIERARCHICAL APPROACH. Proc IEEE Int Symp Biomed Imaging 2014;2014:1031-1034.Abstract
Emphysema has distinct and well-defined visually apparent CT patterns called centrilobular and panlobular emphysema. Existing studies concentrated on the classification of these patterns but they have not looked at the complete evolution of this disease as the destruction of lung parenchyma progresses from normal lung tissue to mild, moderate, and severe disease with complete effacement of the lung architecture. In this paper, we discretize this continuous process into five classes of increasing disease severity and construct a training set of 1161 CT patches. We exploit three solutions to this monotonic multi-class classification problem: a global rankSVM for ranking, hierarchical SVM for classification and a combination of these two, which we call a hierarchical rankSVM. Results showed that both hierarchical approaches were computationally efficient. The classification accuracies were slightly better for hierarchical SVM. However, in addition to classification, ranking approaches also provided a ranking of patterns, which can be utilized as a continuous disease progression score. In terms of the classification accuracy and ratio of pair-wise constraints satisfied, hierarchical rankSVM outperformed the global rankSVM.
Diaz AA, Zhou L, Young TP, McDonald M-L, Harmouche R, Ross JC, Estepar RSJ, Wouters EFM, Coxson HO, MacNee W, Rennard S, Maltais F, Kinney GL, Hokanson JE, Washko GR. Chest CT measures of muscle and adipose tissue in COPD: gender-based differences in content and in relationships with blood biomarkers. Acad Radiol 2014;21(10):1255-61.Abstract
RATIONALE AND OBJECTIVES: Computed tomography (CT) of the chest can be used to assess pectoralis muscle area (PMA) and subcutaneous adipose tissue (SAT) area. Adipose tissue content is associated with inflammatory mediators in chronic obstructive pulmonary disease (COPD) subjects. Based on gender differences in body composition, we aimed to assess the hypothesis that in subjects with COPD, the relationships between PMA, SAT, and blood biomarkers of inflammation differ by gender. MATERIALS AND METHODS: We compared chest CT measures of PMA and SAT on a single slice at aortic arch and supraesternal notch levels from 73 subjects (28 women) with COPD between genders. The relationships of PMA and SAT area to biomarkers were assessed using within-gender regression models. RESULTS: Women had a lesser PMA and a greater SAT area than men (difference range for PMA, 13.3-22.8 cm²; for SAT, 11.8-12.4 cm²; P < .05 for all comparisons) at both anatomic levels. These differences in PMA and SAT remained significant after adjustment for age and body mass index. Within-gender regression models adjusted for age showed that SAT was directly associated with C-reactive protein (for aortic arch level, P = .04) and fibrinogen (for both anatomic locations, P = .003) only in women, whereas PMA was not associated with any biomarkers in either gender. CONCLUSIONS: It appears that in subjects with COPD, there are gender-based differences in the relationships between subcutaneous adipose tissue and inflammatory biomarkers.
Wassermann D, Ross J, Washko G, Wells WM, San Jose-Estepar R. Deformable Registration of Feature-Endowed Point Sets Based on Tensor Fields. Proc IEEE Comput Soc Conf Comput Vis Pattern Recognit 2014;2014:2729-2735.Abstract
The main contribution of this work is a framework to register anatomical structures characterized as a point set where each point has an associated symmetric matrix. These matrices can represent problem-dependent characteristics of the registered structure. For example, in airways, matrices can represent the orientation and thickness of the structure. Our framework relies on a dense tensor field representation which we implement sparsely as a kernel mixture of tensor fields. We equip the space of tensor fields with a norm that serves as a similarity measure. To calculate the optimal transformation between two structures we minimize this measure using an analytical gradient for the similarity measure and the deformation field, which we restrict to be a diffeomorphism. We illustrate the value of our tensor field model by comparing our results with scalar and vector field based models. Finally, we evaluate our registration algorithm on synthetic data sets and validate our approach on manually annotated airway trees.
Castaldi PJ, San José Estépar R, Mendoza CS, Hersh CP, Laird N, Crapo JD, Lynch DA, Silverman EK, Washko GR. Distinct quantitative computed tomography emphysema patterns are associated with physiology and function in smokers. Am J Respir Crit Care Med 2013;188(9):1083-90.Abstract
RATIONALE: Emphysema occurs in distinct pathologic patterns, but little is known about the epidemiologic associations of these patterns. Standard quantitative measures of emphysema from computed tomography (CT) do not distinguish between distinct patterns of parenchymal destruction. OBJECTIVES: To study the epidemiologic associations of distinct emphysema patterns with measures of lung-related physiology, function, and health care use in smokers. METHODS: Using a local histogram-based assessment of lung density, we quantified distinct patterns of low attenuation in 9,313 smokers in the COPDGene Study. To determine if such patterns provide novel insights into chronic obstructive pulmonary disease epidemiology, we tested for their association with measures of physiology, function, and health care use. MEASUREMENTS AND MAIN RESULTS: Compared with percentage of low-attenuation area less than -950 Hounsfield units (%LAA-950), local histogram-based measures of distinct CT low-attenuation patterns are more predictive of measures of lung function, dyspnea, quality of life, and health care use. These patterns are strongly associated with a wide array of measures of respiratory physiology and function, and most of these associations remain highly significant (P < 0.005) after adjusting for %LAA-950. In smokers without evidence of chronic obstructive pulmonary disease, the mild centrilobular disease pattern is associated with lower FEV1 and worse functional status (P < 0.005). CONCLUSIONS: Measures of distinct CT emphysema patterns provide novel information about the relationship between emphysema and key measures of physiology, physical function, and health care use. Measures of mild emphysema in smokers with preserved lung function can be extracted from CT scans and are significantly associated with functional measures.
Kim Y-I, Schroeder J, Lynch D, Newell J, Make B, Friedlander A, San José Estépar R, Hanania NA, Washko G, Murphy JR, Wilson C, Hokanson JE, Zach J, Butterfield K, Bowler RP, Bowler RP. Gender differences of airway dimensions in anatomically matched sites on CT in smokers. COPD 2011;8(4):285-92.Abstract
RATIONALE AND OBJECTIVES: There are limited data on, and controversies regarding gender differences in the airway dimensions of smokers. Multi-detector CT (MDCT) images were analyzed to examine whether gender could explain differences in airway dimensions of anatomically matched airways in smokers. MATERIALS AND METHODS: We used VIDA imaging software to analyze MDCT scans from 2047 smokers (M:F, 1021:1026) from the COPDGene® cohort. The airway dimensions were analyzed from segmental to subsubsegmental bronchi. We compared the differences of luminal area, inner diameter, wall thickness, wall area percentage (WA%) for each airway between men and women, and multiple linear regression including covariates (age, gender, body sizes, and other relevant confounding factors) was used to determine the predictors of each airway dimensions. RESULTS: Lumen area, internal diameter and wall thickness were smaller for women than men in all measured airway (18.4 vs 22.5 mm(2) for segmental bronchial lumen area, 10.4 vs 12.5 mm(2) for subsegmental bronchi, 6.5 vs 7.7 mm(2) for subsubsegmental bronchi, respectively p < 0.001). However, women had greater WA% in subsegmental and subsubsegmental bronchi. In multivariate regression, gender remained one of the most significant predictors of WA%, lumen area, inner diameter and wall thickness. CONCLUSION: Women smokers have higher WA%, but lower luminal area, internal diameter and airway thickness in anatomically matched airways as measured by CT scan than do male smokers. This difference may explain, in part, gender differences in the prevalence of COPD and airflow limitation.

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