Publications by Year: 2014

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is characterized by expiratory flow limitation, causing air trapping and lung hyperinflation. Hyperinflation leads to reduced exercise tolerance and poor quality of life in COPD patients. Total lung capacity (TLC) is an indicator of hyperinflation particularly in subjects with moderate-to-severe airflow obstruction. The aim of our study was to identify genetic variants associated with TLC in COPD. METHODS: We performed genome-wide association studies (GWASs) in white subjects from three cohorts: the COPDGene Study; the Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE); and GenKOLS (Bergen, Norway). All subjects were current or ex-smokers with at least moderate airflow obstruction, defined by a ratio of forced expiratory volume in 1 second to forced vital capacity (FEV1/FVC)

BACKGROUND: The risk factors for acute episodes of respiratory disease in current and former smokers who do not have COPD are unknown. METHODS: Eight thousand two hundred forty-six non-Hispanic white and black current and former smokers in the Genetic Epidemiology of COPD (COPDGene) cohort had longitudinal follow-up (LFU) every 6 months to determine acute respiratory episodes requiring antibiotics or systemic corticosteroids, an ED visit, or hospitalization. Negative binomial regression was used to determine the factors associated with acute respiratory episodes. A Cox proportional hazards model was used to determine adjusted hazard ratios (HRs) for time to first episode and an acute episode of respiratory disease risk score. RESULTS: At enrollment, 4,442 subjects did not have COPD, 658 had mild COPD, and 3,146 had moderate or worse COPD. Nine thousand three hundred three acute episodes of respiratory disease and 2,707 hospitalizations were reported in LFU (3,044 acute episodes of respiratory disease and 827 hospitalizations in those without COPD). Major predictors included acute episodes of respiratory disease in year prior to enrollment (HR, 1.20; 95% CI, 1.15-1.24 per exacerbation), airflow obstruction (HR, 0.94; 95% CI, 0.91-0.96 per 10% change in % predicted FEV1), and poor health-related quality of life (HR, 1.07; 95% CI, 1.06-1.08 for each 4-unit increase in St. George’s Respiratory Questionnaire score). Risks were similar for those with and without COPD. CONCLUSIONS: Although acute episode of respiratory disease rates are higher in subjects with COPD, risk factors are similar, and at a population level, there are more episodes in smokers without COPD.

RATIONALE AND OBJECTIVES: Pulmonary edema and pulmonary hypertension are postsurgical complications of pneumonectomy that may represent the remaining pulmonary vasculature’s inability to accommodate the entirety of the cardiac output. Quantification of the aggregate pulmonary vascular cross-sectional area (CSA) has been used to study the development of pulmonary vascular disease in smokers. In this study, we applied this technique to demonstrate the potential utility of pulmonary vascular quantification in surgical risk assessment. Our hypothesis was that those subjects with the lowest aggregate vascular CSA in the nonoperative lung would be most likely to have elevated pulmonary vascular pressures in the postoperative period. MATERIALS AND METHODS: A total of 61 subjects with postoperative hemodynamics and adequate imaging were identified from 159 patients undergoing pneumonectomies for mesothelioma. The total CSA of blood vessels perpendicular to the plane of computed tomographic (CT) scan slices was computed for blood vessels

RATIONALE: Emphysema is a heritable trait that occurs in smokers with and without chronic obstructive pulmonary disease. Emphysema occurs in distinct pathologic patterns, but the genetic determinants of these patterns are unknown. OBJECTIVES: To identify genetic loci associated with distinct patterns of emphysema in smokers and investigate the regulatory function of these loci. METHODS: Quantitative measures of distinct emphysema patterns were generated from computed tomography scans from smokers in the COPDGene Study using the local histogram emphysema quantification method. Genome-wide association studies (GWAS) were performed in 9,614 subjects for five emphysema patterns, and the results were referenced against enhancer and DNase I hypersensitive regions from ENCODE and Roadmap Epigenomics cell lines. MEASUREMENTS AND MAIN RESULTS: Genome-wide significant associations were identified for seven loci. Two are novel associations (top single-nucleotide polymorphism rs379123 in MYO1D and rs9590614 in VMA8) located within genes that function in cell-cell signaling and cell migration, and five are in loci previously associated with chronic obstructive pulmonary disease susceptibility (HHIP, IREB2/CHRNA3, CYP2A6/ADCK, TGFB2, and MMP12). Five of these seven loci lay within enhancer or DNase I hypersensitivity regions in lung fibroblasts or small airway epithelial cells, respectively. Enhancer enrichment analysis for top GWAS associations (single-nucleotide polymorphisms associated at P 5 × 10(-6)) identified multiple cell lines with significant enhancer enrichment among top GWAS loci, including lung fibroblasts. CONCLUSIONS: This study demonstrates for the first time genetic associations with distinct patterns of pulmonary emphysema quantified by computed tomography scan. Enhancer regions are significantly enriched among these GWAS results, with pulmonary fibroblasts among the cell types showing the strongest enrichment.

OBJECTIVES: We postulated that ventilation-perfusion (V/Q) relationships within the lung might influence where lung cancer occurs. To address this hypothesis we evaluated the location of lung adenocarcinoma, by both tumor lobe and superior-inferior regional distribution, and associated variables such as emphysema. MATERIALS AND METHODS: One hundred fifty-nine cases of invasive adenocarcinoma and adenocarcinoma with lepidic features were visually evaluated to identify lobar or regional tumor location. Regions were determined by automated division of the lungs into three equal volumes: (upper region, middle region, or lower region). Automated densitometry was used to measure radiographic emphysema.

BACKGROUND: Preserved Ratio Impaired Spirometry (PRISm), defined as a reduced FEV1 in the setting of a preserved FEV1/FVC ratio, is highly prevalent and is associated with increased respiratory symptoms, systemic inflammation, and mortality. Studies investigating quantitative chest tomographic features, genetic associations, and subtypes in PRISm subjects have not been reported.

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.

Guiding diffusion tract-based anatomy by functional magnetic resonance imaging (fMRI), we aim to investigate the relationship between structural connectivity and functional activity in the human brain. To this purpose, we introduced a novel groupwise fMRI-guided tractographic approach, that was applied on a population ranging between prodromic and moderate stages of Alzheimer’s disease (AD). The study comprised of 15 subjects affected by amnestic mild cognitive impairment (aMCI), 14 diagnosed with AD and 14 elderly healthy adults who were used as controls. By creating representative (ensemble) functionally guided tracts within each group of participants, our methodology highlighted the white matter fiber connections involved in verbal fluency functions for a specific population, and hypothesized on brain compensation mechanisms that potentially counteract or reduce cognitive impairment symptoms in prodromic AD. Our hope is that this fMRI-guided tractographic approach could have potential impact in various clinical studies, while investigating white/gray matter connectivity, in both health and disease.

Hypoxemia is a major complication of chronic obstructive pulmonary disease (COPD) that correlates with disease prognosis. Identifying genetic variants associated with oxygenation may provide clues for deciphering the heterogeneity in prognosis among patients with COPD. However, previous genetic studies have been restricted to investigating COPD candidate genes for association with hypoxemia. To report results from the first genome-wide association study (GWAS) of resting oxygen saturation (as measured by pulse oximetry [Spo2]) in subjects with COPD, we performed a GWAS of Spo2 in two large, well characterized COPD populations: COPDGene, including both the non-Hispanic white (NHW) and African American (AA) groups, and Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE). We identified several suggestive loci (P 1 × 10(-5)) associated with Spo2 in COPDGene in the NHW (n = 2810) and ECLIPSE (n = 1758) groups, and two loci on chromosomes 14 and 15 in the AA group (n = 820) from COPDGene achieving a level of genome-wide significance (P 5 × 10(-8)). The chromosome 14 single-nucleotide polymorphism, rs6576132, located in an intergenic region, was nominally replicated (P 0.05) in the NHW group from COPDGene. The chromosome 15 single-nucleotide polymorphisms were rare in subjects of European ancestry, so the results could not be replicated. The chromosome 15 region contains several genes, including TICRR and KIF7, and is proximal to RHCG (Rh family C glyocoprotein gene). We have identified two loci associated with resting oxygen saturation in AA subjects with COPD, and several suggestive regions in subjects of European descent with COPD. Our study highlights the importance of investigating the genetics of complex traits in different racial groups.

A large number of pigmented skin lesions (PSLs) are a strong predictor of malignant melanoma. Many dermatologists advocate total body photography for high-risk patients because detecting new-appearing, disappearing, and changing PSL is important for early detection of the disease. However, manual inspection and matching of PSL is a subjective, tedious, and error-prone task. A computer program for tracking the corresponding PSL will greatly improve the matching process. In this paper, we describe the construction of the first human back template (atlas), which is used to facilitate spatial normalization of the PSL during the matching process. Four pairs of anatomically meaningful landmarks (neck, shoulder, armpit, and hip points) are used as reference points on the back image. Using the landmarks, a grid with longitudes and latitudes is constructed and overlaid on each subject-specific back image. To perform spatial normalization, the grid is registered into the back template, a unit-square rectilinear grid. To demonstrate the benefits of using the back template, we apply several state-of-the-art point-matching algorithms on 56 pairs of real dermatological images and show that utilizing spatially normalized coordinates improves the PSL matching accuracies.