Genetic Epidemiology of COPD

In this competitive renewal, the major goal is to extend the COPDGene Study by performing five-year longitudinal follow-up visits with chest CT scans on all available COPDGene subjects.  To identify rare variants influencing COPD susceptibility, exome chip genotyping will be performed in all subjects, followed by whole genome sequencing in selected subjects and targeted replication sequencing.  The physiological, imaging, clinical, and genetic data will be used to develop a new classification system for COPD.  Dr. Silverman and Dr. James Crapo are the PIs of the Genetic Epidemiology of COPD. 

Raúl San José Estépar

Dr. Raúl San José Estépar

Associate Professor of Radiology in Harvard Medical School
Lead Investigator at Brigham and Women's Hospital
Raúl is Associate Professor of Radiology at Harvard Medical School and a Research Associate at Brigham and Women's Hospital. He is the co-director of the Applied Chest Imaging Laboratory (ACIL).
1249 Boylston St, Room 216
Boston, MA, 02215
p: 617 525-6227
Ross JC, Kindlmann GL, Okajima Y, Hatabu H, Díaz AA, Silverman EK, Washko GR, Dy J, San José Estépar R. Pulmonary lobe segmentation based on ridge surface sampling and shape model fitting. Med Phys. 2013;40 (12) :121903.Abstract

PURPOSE: Performing lobe-based quantitative analysis of the lung in computed tomography (CT) scans can assist in efforts to better characterize complex diseases such as chronic obstructive pulmonary disease (COPD). While airways and vessels can help to indicate the location of lobe boundaries, segmentations of these structures are not always available, so methods to define the lobes in the absence of these structures are desirable. METHODS: The authors present a fully automatic lung lobe segmentation algorithm that is effective in volumetric inspiratory and expiratory computed tomography (CT) datasets. The authors rely on ridge surface image features indicating fissure locations and a novel approach to modeling shape variation in the surfaces defining the lobe boundaries. The authors employ a particle system that efficiently samples ridge surfaces in the image domain and provides a set of candidate fissure locations based on the Hessian matrix. Following this, lobe boundary shape models generated from principal component analysis (PCA) are fit to the particles data to discriminate between fissure and nonfissure candidates. The resulting set of particle points are used to fit thin plate spline (TPS) interpolating surfaces to form the final boundaries between the lung lobes. RESULTS: The authors tested algorithm performance on 50 inspiratory and 50 expiratory CT scans taken from the COPDGene study. Results indicate that the authors' algorithm performs comparably to pulmonologist-generated lung lobe segmentations and can produce good results in cases with accessory fissures, incomplete fissures, advanced emphysema, and low dose acquisition protocols. Dice scores indicate that only 29 out of 500 (5.85%) lobes showed Dice scores lower than 0.9. Two different approaches for evaluating lobe boundary surface discrepancies were applied and indicate that algorithm boundary identification is most accurate in the vicinity of fissures detectable on CT. CONCLUSIONS: The proposed algorithm is effective for lung lobe segmentation in absence of auxiliary structures such as vessels and airways. The most challenging cases are those with mostly incomplete, absent, or near-absent fissures and in cases with poorly revealed fissures due to high image noise. However, the authors observe good performance even in the majority of these cases.

Zulueta-Coarasa T, Kurugol S, Ross JC, Washko GG, San José Estépar R. Emphysema classification based on embedded probabilistic PCA. Conf Proc IEEE Eng Med Biol Soc. 2013;2013 :3969-72.Abstract

In this article we investigate the suitability of a manifold learning technique to classify different types of emphysema based on embedded Probabilistic PCA (PPCA). Our approach finds the most discriminant linear space for each emphysema pattern against the remaining patterns where lung CT image patches can be embedded. In this embedded space, we train a PPCA model for each pattern. The main novelty of our technique is that it is possible to compute the class membership posterior probability for each emphysema pattern rather than a hard assignment as it is typically done by other approaches. We tested our algorithm with six emphysema patterns using a data set of 1337 CT training patches. Using a 10-fold cross validation experiment, an average recall rate of 69% is achieved when the posterior probability is greater than 75%. A quantitative comparison with a texture-based approach based on Local Binary Patterns and with an approach based on local intensity distributions shows that our method is competitive. The analysis of full lungs using our approach shows a good visual agreement with the underlying emphysema types and a smooth spatial relation.

San José Estépar R, Kinney GL, Black-Shinn JL, Bowler RP, Kindlmann GL, Ross JC, Kikinis R, Han MLK, Come CE, Diaz AA, et al. 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.