Mulshine JL, Avila R, Yankelevitz D, Baer TM, San Jose Estépar R, Ambrose LF, Aldige CR. Lung Cancer Workshop XI. Journal of Thoracic OncologyJournal of Thoracic Oncology. 2015;10 :762-767.Abstract
The Prevent Cancer Foundation Lung Cancer Workshop XI: Tobacco-Induced Disease: Advances in Policy, Early Detection and Management was held in New York, NY on May 16 and 17, 2014. The two goals of the Workshop were to define strategies to drive innovation in precompetitive quantitative research on the use of imaging to assess new therapies for management of early lung cancer and to discuss a process to implement a national program to provide high quality computed tomography imaging for lung cancer and other tobacco-induced disease. With the central importance of computed tomography imaging for both early detection and volumetric lung cancer assessment, strategic issues around the development of imaging and ensuring its quality are critical to ensure continued progress against this most lethal cancer.
RATIONALE:COPD is associated with a worse overall survival in NSCLC. Lung emphysema is one component of COPD. We hypothesized that emphysema of the tumor region may result in larger tumors and a poorer overall survival.METHODS:We evaluated 304 cases of NSCLC from a prospectively enrolled cohort. The lung was divided into equal volumetric thirds (upper, middle, or lower region). Emphysema was defined as percentage of low attenuation areas less than -950 Hounsfield units (%LAA-950) and measured for each region. Whole-lung %LAA-950 was defined as the emphysema score of the entire lung parenchyma while regional %LAA-950 was the score within that particular region (upper, middle, or lower). The emphysema score of the region in which the tumor occurred was defined as the tumor %LAA-950. Tumor diameter was measured while blinded to characteristics of the lung parenchyma. A proportional hazards model was used to control for multiple factors associated with survival.RESULTS:Increasing tumor %LAA-950 was associated with larger tumors (P=0.024). Survival, stratified by stage, was significantly worse in those with tumor %LAA-950 greater than or equal to the 50th percentile vs. less than the 50th percentile (P=0.046). Whole-lung %LAA-950 and regional %LAA-950 (e.g. regional emphysema without tumor occurring in the region) were not significantly associated with survival. There were no differences in presenting symptoms or locations of mediastinal or distant metastasis by emphysema score. Increasing tumor %LAA-950 was associated with an increased risk of death (HRadj 1.36 [1.09, 1.68], P=0.006) after adjustment for age, sex, smoking status, histology, stage, performance status, chemotherapy, radiation, and surgery. Sensitivity analyses revealed no significant difference in the effect size or test of significance for each of the following conditions: 1) exclusion of cases with central tumor location, 2) exclusion of cases where surgery was performed, 3) exclusion of cases where radiation therapy was performed, 4) exclusion of cases where epidermal growth factor receptor tyrosine kinase inhibitors were administered, and 5) inclusion of only stage IV disease.CONCLUSIONS:Increasing emphysema of the region in which a NSCLC tumor occurs is associated with increasing tumor size and worse overall survival.
BACKGROUND:Cardiovascular diseases are frequent and a major cause of death in patients with chronic obstructive pulmonary disease (COPD). In the general population, various fat depots including abdominal visceral adipose tissue (VAT), subcutaneous adipose tissue (SAT), and liver fat have been linked to increased risk of cardiovascular diseases. We hypothesize that these adipose tissue compartments are associated with myocardial infarction (MI) in patients with COPD.METHODS:We collected measures of VAT and SAT areas and liver attenuation on the computed tomography scan of the chest from 1267 patients with COPD. MI was a self-reported physician-diagnosed outcome. The association between fat depots and self-reported history of MI was assessed by logistic regression analysis in which the patients within the 2 lowest tertiles of VAT and SAT areas were the reference group.RESULTS:Eighty three patients (6.6%) reported a history of MI at the time of enrollment. Compared to patients who did not have an MI episode, those who had a prior MI had a higher VAT area (mean ± SD, 303.4 ± 208.5 vs. 226.8 ± 172.6 cm(2); P=0.002) with no differences in SAT area and liver fat. After adjustment for age, gender, obesity, pack years of smoking, hypertension, high cholesterol, and diabetes, patients within the upper tertile (vs. those in the lower tertiles) of VAT area had increased odds of MI (odds ratio [OR] 1.86, 95% confidence interval [CI] 1.02 - 3.41).CONCLUSION:Increased abdominal visceral fat is independently associated with a history of MI in individuals with COPD.
BACKGROUND AND PURPOSE:Right Ventricular to Left Ventricular (RV/LV) diameter ratio has been shown to be a prognostic biomarker for patients suffering from acute Pulmonary Embolism (PE). While Computed Tomography Pulmonary Angiography (CTPA) images used to confirm a clinical suspicion of PE do include information of the heart, a numerical RV/LV diameter ratio is not universally reported, likely because of lack in training, inter-reader variability in the measurements, and additional effort by the radiologist. This study designs and validates a completely automated Computer Aided Detection (CAD) system to compute the axial RV/LV diameter ratio from CTPA images so that the RV/LV diameter ratio can be a more objective metric that is consistently reported in patients for whom CTPA diagnoses PE.MATERIALS AND METHODS:The CAD system was designed specifically for RV/LV measurements. The system was tested in 198 consecutive CTPA patients with acute PE. Its accuracy was evaluated using reference standard RV/LV radiologist measurements and its prognostic value was established for 30-day PE-specific mortality and a composite outcome of 30-day PE-specific mortality or the need for intensive therapies. The study was Institutional Review Board (IRB) approved and HIPAA compliant.RESULTS:The CAD system analyzed correctly 92.4% (183/198) of CTPA studies. The mean difference between automated and manually computed axial RV/LV ratios was 0.03±0.22. The correlation between the RV/LV diameter ratio obtained by the CAD system and that obtained by the radiologist was high (r=0.81). Compared to the radiologist, the CAD system equally achieved high accuracy for the composite outcome, with areas under the receiver operating characteristic curves of 0.75 vs. 0.78. Similar results were found for 30-days PE-specific mortality, with areas under the curve of 0.72 vs. 0.75.CONCLUSIONS:An automated CAD system for determining the CT derived RV/LV diameter ratio in patients with acute PE has high accuracy when compared to manual measurements and similar prognostic significance for two clinical outcomes.
This paper proposes an inference method well-suited to large sets of medical images. The method is based upon a framework where distinctive 3D scale-invariant features are indexed efficiently to identify approximate nearest-neighbor (NN) feature matches in O(log N) computational complexity in the number of images N. It thus scales well to large data sets, in contrast to methods based on pair-wise image registration or feature matching requiring O(N) complexity. Our theoretical contribution is a density estimator based on a generative model that generalizes kernel density estimation and K-nearest neighbor (KNN) methods. The estimator can be used for on-the-fly queries, without requiring explicit parametric models or an off-line training phase. The method is validated on a large multi-site data set of 95,000,000 features extracted from 19,000 lung CT scans. Subject-level classification identifies all images of the same subjects across the entire data set despite deformation due to breathing state, including unintentional duplicate scans. State-of-the-art performance is achieved in predicting chronic pulmonary obstructive disorder (COPD) severity across the 5-category GOLD clinical rating, with an accuracy of 89% if both exact and one-off predictions are considered correct.
Abstract. We present a generative probabilistic approach to discovery of disease subtypes determined by the genetic variants. In many diseases, multiple types of pathology may present simultaneously in a patient, making quantification of the disease challenging. Our method seeks com- mon co-occurring image and genetic patterns in a population as a way to model these two different data types jointly. We assume that each patient is a mixture of multiple disease subtypes and use the joint gen- erative model of image and genetic markers to identify disease subtypes guided by known genetic influences. Our model is based on a variant of the so-called topic models that uncover the latent structure in a collection of data. We derive an efficient variational inference algorithm to extract patterns of co-occurrence and to quantify the presence of heterogeneous disease processes in each patient. We evaluate the method on simulated data and illustrate its use in the context of Chronic Obstructive Pul- monary Disease (COPD) to characterize the relationship between image and genetic signatures of COPD subtypes in a large patient cohort.
RATIONALE:Chronic obstructive pulmonary disease (COPD) is defined by the presence of airflow limitation on spirometry, yet COPD subjects can have marked differences in CT imaging. These differences may be driven by genetic factors. We hypothesized that a genome-wide association study of quantitative imaging would identify loci not previously identified in analyses of COPD or spirometry. In addition, we sought to determine whether previously described genome-wide significant COPD and spirometric loci were associated with emphysema or airway phenotypes.OBJECTIVE:To identify genetic determinants of quantitative imaging phenotypes.METHODS:We performed a genome-wide association study on two quantitative emphysema and two quantitative airway imaging phenotypes in the COPDGene (non-Hispanic white and African-American), ECLIPSE, NETT, and GenKOLS studies; and on % gas trapping in COPDGene. We also examined specific loci reported as genome-wide significant for spirometric phenotypes related to airflow limitation or COPD.RESULTS:The total sample size across all cohorts was 12,031, of which 9,338 were from COPDGene. We identified five loci associated with emphysema-related phenotypes, one with airway-related phenotypes, and two with gas trapping. These loci included previously reported associations, including the HHIP, 15q25, and AGER loci, as well as novel associations near SERPINA10 and DLC1. All previously reported COPD and a significant number of spirometric GWAS loci were at least nominally (P < 0.05) associated with either emphysema or airway phenotypes.CONCLUSIONS:Genome-wide analysis may identify novel risk factors for quantitative imaging characteristics in COPD, and also identify imaging features associated with previously identified lung function loci. .
BACKGROUND:Chronic obstructive pulmonary disease causes significant morbidity and concomitant pulmonary vascular disease and cardiac dysfunction are associated with poor prognosis. Computed tomography-detected relative pulmonary artery (PA) enlargement defined as a PA to ascending aorta diameter ratio >1 (PA:A>1) is a marker for pulmonary hypertension and predicts chronic obstructive pulmonary disease exacerbations. However, little is known about the relationship between the PA:A ratio, pulmonary blood volume, and cardiac function.METHODS AND RESULTS:A single-center prospective cohort study of patients with chronic obstructive pulmonary disease was conducted. Clinical characteristics and computed tomography metrics, including the PA:A and pulmonary blood vessel volume, were measured. Ventricular functions, volumes, and dimensions were measured by cine cardiac MRI with 3-dimensional analysis. Linear regression examined the relationships between clinical characteristics, computed tomography and cardiac MRI metrics, and 6-minute walk distance. Twenty-four patients were evaluated and those with PA:A>1 had higher right ventricular (RV) end-diastolic and end-systolic volume indices accompanied by lower RV ejection fraction (52±7% versus 60±9%; P=0.04). The PA:A correlated inversely with total intraparenchymal pulmonary blood vessel volume and the volume of distal vessels with a cross-sectional area of <5 mm(2). Lower forced expiratory volume, PA:A>1, and hyperinflation correlated with reduced RV ejection fraction. Both PA diameter and reduced RV ejection fraction were independently associated with reduced 6-minute walk distance.CONCLUSIONS:The loss of blood volume in distal pulmonary vessels is associated with PA enlargement on computed tomography. Cardiac MRI detects early RV dysfunction and remodeling in nonsevere chronic obstructive pulmonary disease patients with a PA:A>1. Both RV dysfunction and PA enlargement are independently associated with reduced walk distance.CLINICAL TRIAL REGISTRATION:URL: http://www.clinicaltrials.gov. Unique identifier: NCT00608764.
BACKGROUND:Computed tomographic (CT) airway lumen narrowing is associated with lower lung function. Although volumetric CT measures of airways (wall volume [WV] and lumen volume [LV]) compared to cross sectional measures can more accurately reflect bronchial morphology, data of their use in never smokers is scarce. We hypothesize that native tracheobronchial tree morphology as assessed by volumetric CT metrics play a significant role in determining lung function in normal subjects. We aimed to assess the relationships between airway size, the projected branching generation number (BGN) to reach airways of <2mm lumen diameter -the site for airflow obstruction in smokers- and measures of lung function including forced expiratory volume in 1 second (FEV1) and forced expiratory flow between 25% and 75% of vital capacity (FEF 25-75).METHODS:We assessed WV and LV of segmental and subsegmental airways from six bronchial paths as well as lung volume on CT scans from 106 never smokers. We calculated the lumen area ratio of the subsegmental to segmental airways and estimated the projected BGN to reach a <2mm-lumen-diameter airway assuming a dichotomized tracheobronchial tree model. Regression analysis was used to assess the relationships between airway size, BGN, FEF 25-75, and FEV1.RESULTS:We found that in models adjusted for demographics, LV and WV of segmental and subsegmental airways were directly related to FEV1 (P <0.05 for all the models). In adjusted models for age, sex, race, LV and lung volume or height, the projected BGN was directly associated with FEF 25-75 and FEV1 (P=0.001) where subjects with lower FEV1 had fewer calculated branch generations between the subsegmental bronchus and small airways. There was no association between airway lumen area ratio and lung volume.CONCLUSION:We conclude that in never smokers, those with smaller central airways had lower airflow and those with lower airflow had less parallel airway pathways independent of lung size. These findings suggest that variability in the structure of the tracheobronchial tree may influence the risk of developing clinically relevant smoking related airway obstruction.
Genetic risk loci have been identified for a wide range of diseases through genome-wide association studies (GWAS), but the relevant functional mechanisms have been identified for only a small proportion of these GWAS-identified loci. By integrating results from the largest current GWAS of chronic obstructive disease (COPD) with expression quantitative trait locus (eQTL) analysis in whole blood and sputum from 121 subjects with COPD from the ECLIPSE Study, this analysis identifies loci that are simultaneously associated with COPD and the expression of nearby genes (COPD eQTLs). After integrative analysis, 19 COPD eQTLs were identified, including all four previously identified genome-wide significant loci near HHIP, FAM13A, and the 15q25 and 19q13 loci. For each COPD eQTL, fine mapping and colocalization analysis to identify causal shared eQTL and GWAS variants identified a subset of sites with moderate-to-strong evidence of harboring at least one shared variant responsible for both the eQTL and GWAS signals. Transcription factor binding site (TFBS) analysis confirms that multiple COPD eQTL lead SNPs disrupt TFBS, and enhancer enrichment analysis for loci with the strongest colocalization signals showed enrichment for blood-related cell types (CD3 and CD4+ T cells, lymphoblastoid cell lines). In summary, integrative eQTL and GWAS analysis confirms that genetic control of gene expression plays a key role in the genetic architecture of COPD and identifies specific blood-related cell types as likely participants in the functional pathway from GWAS-associated variant to disease phenotype.
RATIONALE: Chronic lung diseases are associated with cardiovascular disease. How these associations evolve from young adulthood forward is unknown. Understanding the preclinical history of these associations could inform prevention strategies for common heart-lung conditions. OBJECTIVES: To use the Coronary Artery Risk Development in Young Adults (CARDIA) study to explore the development of heart-lung interactions. METHODS: We analyzed cardiac structural and functional measurements determined by echocardiography at Year 25 of CARDIA and measures of pulmonary function over 20 years in 3,000 participants. MEASUREMENTS AND MAIN RESULTS: Decline in FVC from peak was associated with larger left ventricular mass (β = 6.05 g per SD of FVC decline; P < 0.0001) and greater cardiac output (β = 0.109 L/min per SD of FVC decline; P = 0.001). Decline in FEV1/FVC ratio was associated with smaller left atrial internal dimension (β = -0.038 cm per SD FEV1/FVC decline; P < 0.0001) and lower cardiac output (β = -0.070 L/min per SD of FEV1/FVC decline; P = 0.03). Decline in FVC was associated with diastolic dysfunction (odds ratio, 3.39; 95% confidence interval, 1.37-8.36; P = 0.006). CONCLUSIONS: Patterns of loss of lung health are associated with specific cardiovascular phenotypes in middle age. Decline in FEV1/FVC ratio is associated with underfilling of the left heart and low cardiac output. Decline in FVC with preserved FEV1/FVC ratio is associated with left ventricular hypertrophy and diastolic dysfunction. Cardiopulmonary interactions apparent with common complex heart and lung diseases evolve concurrently from early adulthood forward.
BACKGROUND: Chronic obstructive pulmonary disease causes significant morbidity and concomitant pulmonary vascular disease and cardiac dysfunction are associated with poor prognosis. Computed tomography-detected relative pulmonary artery (PA) enlargement defined as a PA to ascending aorta diameter ratio >1 (PA:A>1) is a marker for pulmonary hypertension and predicts chronic obstructive pulmonary disease exacerbations. However, little is known about the relationship between the PA:A ratio, pulmonary blood volume, and cardiac function. METHODS AND RESULTS: A single-center prospective cohort study of patients with chronic obstructive pulmonary disease was conducted. Clinical characteristics and computed tomography metrics, including the PA:A and pulmonary blood vessel volume, were measured. Ventricular functions, volumes, and dimensions were measured by cine cardiac MRI with 3-dimensional analysis. Linear regression examined the relationships between clinical characteristics, computed tomography and cardiac MRI metrics, and 6-minute walk distance. Twenty-four patients were evaluated and those with PA:A>1 had higher right ventricular (RV) end-diastolic and end-systolic volume indices accompanied by lower RV ejection fraction (52±7% versus 60±9%; P=0.04). The PA:A correlated inversely with total intraparenchymal pulmonary blood vessel volume and the volume of distal vessels with a cross-sectional area of <5 mm(2). Lower forced expiratory volume, PA:A>1, and hyperinflation correlated with reduced RV ejection fraction. Both PA diameter and reduced RV ejection fraction were independently associated with reduced 6-minute walk distance. CONCLUSIONS: The loss of blood volume in distal pulmonary vessels is associated with PA enlargement on computed tomography. Cardiac MRI detects early RV dysfunction and remodeling in nonsevere chronic obstructive pulmonary disease patients with a PA:A>1. Both RV dysfunction and PA enlargement are independently associated with reduced walk distance. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00608764.
Ross JC, Diaz AA, Okajima Y, Wassermann D, Washko GR, Dy J, San Jose Estépar R. Airway labeling using a Hidden Markov Tree Model, in Biomedical Imaging (ISBI), 2014 IEEE 11th International Symposium onBiomedical Imaging (ISBI), 2014 IEEE 11th International Symposium on. ; 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  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.
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.
Interventions in the body increase markedly in difficulty when the instrument body and distal tip cannot be seen from an outside vantage point. Thus most endoscopic applications, including cystoscopy, neuroendoscopy, bronchoscopy, upper GI endoscopy, and colonoscopy, require long training periods to attain proficiency, and even experts may find themselves disoriented during a procedure. As well, retroperitoneal laparoscopy, where the distal tip of the laparoscope is not seen directly from the pneumoperitoneal space, faces similar challenges. In the following, we will discuss “endoscopy” with the understanding that the techniques may also be applied to laparoscopy.
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.
Rationale and Objectives: Asthma is associated with chronic airflow obstruction (CAO). Our goal was to assess the association of computed tomographic (CT) measures of airway wall volume (WV) and lumen volume (LV) with the forced expiratory volume in one second (FEV1) and CAO in smokers with childhood-onset asthma (CA). Methods: We analyzed clinical, lung function, and volumetric CT airway volumes data from 7,266 smokers including 590 with CA. Small WV and small LV of segmental airways were defined as measures 1 SD below the mean. We assessed the association between small WV, small LV, FEV1 and CAO (post-bronchodilator FEV1/forced vital capacity ratio <0.7) using linear and logistic models. Measurements and Main Results: CA subjects had smaller WV and LV than those without CA (mean ± SD, 371.3 ± 92.5mm3 vs. 388.7 ± 94.0mm3, P<0.0001; 230.8 ± 76.9 mm3 vs. 257.4 ± 80.9mm3, P<0.0001). Among CA subjects, those with the smallest WV and LV had the lowest FEV1 and greatest odds of CAO. A similar tendency was seen in those without CA. When comparing these 2 groups, small WV and small LV were more strongly associated with FEV1 (for WV, β [95%CI] -331ml [-488 - -174] vs. -244ml [-294 - -194]; for LV, -534ml [-669 - -398] vs. -435ml [-485 - -386] and CAO (Odds ratio 2.10 (1.27-3.46) vs. 2.02 [1.72-2.36]; 4.32 [2.64-7.08] vs. 3.55 [3.00-4.19], respectively) among CA subjects in multivariate models. Conclusion: In smokers with CA smaller airways are associated with reduced lung function and chronic airflow obstruction.