Common Genetic Polymorphisms Influence Blood Biomarker Measurements in COPD

Implementing precision medicine for complex diseases such as chronic obstructive lung disease (COPD) will require extensive use of biomarkers and an in-depth understanding of how genetic, epigenetic, and environmental variations contribute to phenotypic diversity and disease progression. A meta-analysis from two large cohorts of current and former smokers with and without COPD [SPIROMICS (N = 750); COPDGene (N = 590)] was used to identify single nucleotide polymorphisms (SNPs) associated with measurement of 88 blood proteins (protein quantitative trait loci; pQTLs). PQTLs consistently replicated between the two cohorts. Features of pQTLs were compared to previously reported expression QTLs (eQTLs). Inference of causal relations of pQTL genotypes, biomarker measurements, and four clinical COPD phenotypes (airflow obstruction, emphysema, exacerbation history, and chronic bronchitis) were explored using conditional independence tests. We identified 527 highly significant (p 10% of measured variation in 13 protein biomarkers, with a single SNP (rs7041; p = 10−392) explaining 71%-75% of the measured variation in vitamin D binding protein (gene = GC). Some of these pQTLs [e.g., pQTLs for VDBP, sRAGE (gene = AGER), surfactant protein D (gene = SFTPD), and TNFRSF10C] have been previously associated with COPD phenotypes. Most pQTLs were local (cis), but distant (trans) pQTL SNPs in the ABO blood group locus were the top pQTL SNPs for five proteins. The inclusion of pQTL SNPs improved the clinical predictive value for the established association of sRAGE and emphysema, and the explanation of variance (R2) for emphysema improved from 0.3 to 0.4 when the pQTL SNP was included in the model along with clinical covariates. Causal modeling provided insight into specific pQTL-disease relationships for airflow obstruction and emphysema. In conclusion, given the frequency of highly significant local pQTLs, the large amount of variance potentially explained by pQTL, and the differences observed between pQTLs and eQTLs SNPs, we recommend that protein biomarker-disease association studies take into account the potential effect of common local SNPs and that pQTLs be integrated along with eQTLs to uncover disease mechanisms. Large-scale blood biomarker studies would also benefit from close attention to the ABO blood group

Segmentation and Quantitative Analysis of Intrathoracic Airway Trees from Computed Tomography Images

The segmentation of the human airway tree from volumetric multidetector-row computed tomography images is an important prerequisite for many clinical applications and physiologic studies. We present a new airway segmentation method based on fuzzy connectivity. Small adaptive regions of interest are used that follow the airway branches as they are segmented. This method works on various types of scans (low dose and regular dose, normal subjects and diseased subjects) without the need for the user to manually adjust any parameters. Comparison with a commonly used region-growing segmentation algorithm shows that this method retrieves a significantly higher count of airway branches. In an additional processing step, this method provides accurate cross-sectional airway measurements that are conducted in the original gray-level volume. Validation on a phantom shows that subvoxel accuracy is achieved for all airway sizes and airway orientations. The utility of the reported method is demonstrated in a comparative analysis of normal and cystic fibrosis airway trees

Intrathoracic airway trees: Segmentation and airway morphology analysis from lowdose ct scans

Abstract—The segmentation of the human airway tree from volumetric computed tomography (CT) images builds an important step for many clinical applications and for physiological studies. Previously proposed algorithms suffer from one or several problems: leaking into the surrounding lung parenchyma, the need for the user to manually adjust parameters, excessive runtime. Lowdose CT scans are increasingly utilized in lung screening studies, but segmenting them with traditional airway segmentation algorithms often yields less than satisfying results. In this paper, a new airway segmentation method based on fuzzy connectivity is presented. Small adaptive regions of interest are used that follow the airway branches as they are segmented. This has several advantages. It makes it possible to detect leaks early and avoid them, the segmentation algorithm can automatically adapt to changing image parameters, and the computing time is kept within moderate values. The new method is robust in the sense that it works on various types of scans (low-dose and regular dose, normal subjects and diseased subjects) without the need for the user to manually adjust any parameters. Comparison with a commonly used region-grow segmentation algorithm shows that the newly proposed method retrieves a significantly higher count of airway branches. A method that conducts accurate cross-sectional airway measurements on airways is presented as an additional processing step. Measurements are conducted in the original gray-level volume. Validation on a phantom shows that subvoxel accuracy is achieved for all airway sizes and airway orientations. Index Terms—Adaptive region of interest, airway tree segmentation, fuzzy connectivity, pulmonary imaging, quantitative analysis. I

Matching and anatomical labeling of human airway tree

Abstract — Matching of corresponding branchpoints between two human airway trees, as well as assigning anatomical names to the segments and branchpoints of the human airway tree, are of significant interest for clinical applications and physiological studies. In the past these tasks were often performed manually due to the lack of automated algorithms that can tolerate false branches and anatomical variability typical for in vivo trees. In this paper we present algorithms that perform both matching of branchpoints and anatomical labeling of in vivo trees without any human intervention and within a short computing time. No hand-pruning of false branches is required. The results from the automated methods show a high degree of accuracy when validated against reference data provided by human experts. 92.9 % of the verifiable branchpoint matches found by the computer agree with experts ’ results. For anatomical labeling, 97.1 % of the automatically assigned segment labels were found to be correct. Index Terms — Airway tree, branchpoint matching, anatomical labeling