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Principal Investigator: Emily S Wan
Organization: VA BOSTON HEALTH CARE SYSTEM
Fiscal Year: 2024
Funding agency: Veterans Affairs
Chronic lung diseases (CLDs), including asthma, chronic obstructive pulmonary disease (COPD), and interstitial
lung disease (ILD), cause significant functional limitation and disability and were, collectively, the 4th leading
cause of death in the United States in 2019. Veterans are enriched for environmental exposures which contribute
to the pathogenesis of CLDs (e.g., smoking, environmental toxins) and have a higher burden of CLD relative to
the general population. However, significant heterogeneity in CLD development and progression exists.
Investigations into the genomic contributions towards CLD susceptibility within the Veterans Health
Administration (VHA) have been limited by the lack of robust CLD phenotypes. Key challenges in [clinically-
based] CLD phenotyping include the lack of blood-based biomarkers, variable implementation of diagnostic
testing (e.g., underutilization of spirometry), and inconsistent availability of testing results in the VA electronic
health record (EHR). These barriers result in frequent misclassification and present challenges in identifying
controls as well as cases for large-scale epidemiological and genomic studies.
To address these knowledge gaps, we propose a multi-faceted approach to CLD phenotyping and
validation, followed by genome-wide association studies (GWAS), construction of polygenic risk scores, and
examinations of gene-by-environment interactions including pharmacogenomics within the Million Veteran
Program (MVP). First, we have developed a novel natural language processing (NLP)-boosted EHR-based
phenotyping algorithm which will generate quantitative probabilities for the presence and absence of multiple
CLDs (COPD, emphysema subtype, asthma, interstitial lung abnormalities (ILA), fibrosis subtype) for all VHA
users (~16.8 million) through 2018. Following algorithm optimization and internal validation against 500 gold
standard charts (already adjudicated in duplicate), prospective validation using mortality and respiratory-related
healthcare utilization data collected after 2018 will be performed (Aim 1). Second, we propose independent
phenotyping through quantitative imaging analysis (QIA) of chest computed tomography (CT) data available in
a subset of participants enrolled in MVP (Aim 2). In preliminary work, a secure prototype pipeline behind the VA
firewall for the analysis of archived clinical chest CT data using VA Technical Reference Manual (TRM)-approved
software platforms (3D Slicer, Chest Imaging Platform13,14) has been established. For the current proposal,
through a national network of collaborating VA pulmonary investigators (J. Curtis, VISN10; C. Wendt VISN23;
V. Fan VISN20; C. Wells VISN7; F. Kheradmand, VISN16), full-resolution clinical chest CT data from a subgroup
of individuals enrolled in MVP (n=6,000-9,000) will be analyzed to generate objective, quantitative
measurements of parenchymal lung disease (e.g., percent emphysema and ILA). Each of these QIA-based
phenotypes will be (i) validated against prospective mortality and healthcare utilization outcomes (available from
Aim 1) (ii) utilized as an independent secondary validation of EHR algorithm-derived emphysema, ILA, and
fibrosis (from Aim 1), and (iii) as a distinct, quantitative phenotype in genomic investigations (Aim 3). Third, we
propose to (i) conduct genome-wide association studies (GWAS) within the MVP using EHR-algorithm assigned
CLD case-control status (Aim 1) and QIA-phenotypes (Aim 2), (ii) construct polygenic risk scores (PRS) for each
CLD, and (iii) examine gene-by-environment [and pharmacogenomic] interactions in CLDs (Aim 3). Findings will
be replicated in independent cohorts: International COPD Genetics Consortium (ICGC) and UK Biobank (COPD,
emphysema), Genetic Epidemiology Research in Adult Health (GERA) and Mass General Brigham Biobank
(asthma), and an international cohort investigating idiopathic pulmonary fibrosis (ILA, fibrosis). Upon successful
completion of the project, we will have developed and validated robust phenotypes and identified risk loci for
CLDs which will shed light on disease mechanisms and have the potential to serve as the foundation of
personalized medicine initiatives for CLD management within the VHA.
Terms: <21+ years old><3-D><3-Dimensional><3D><Address><Adult><Adult Human><Algorithms><Archives><Asthma><Bronchial Asthma><CAT scan><COPD><CT X Ray><CT Xray><CT imaging><CT scan><Cause of Death><Chest><Chest imaging><Chronic Obstruction Pulmonary Disease><Chronic Obstructive Lung Disease><Chronic Obstructive Pulmonary Disease><Chronic lung disease><Clinical><Collaborations><Computed Tomography><Computer software><Computerized Medical Record><Data><Development><Diagnosis><Diagnostic tests><Diathesis><Disease><Disease Management><Disease susceptibility><Disorder><Disorder Management><Electronic Health Record><Electronic Medical Record><Elements><Emphysema><Enrollment><Environment><Environmental Exposure><Environmental Toxin><Epidemiologic Research><Epidemiologic Studies><Epidemiological Studies><Epidemiological data><Epidemiology><Epidemiology Research><Epidemiology data><Exposure to><Fibrosing Alveolitis><Fibrosis><Foundations><Funding><Future><GWA study><GWAS><Gene variant><Gene x Environment Interaction><General Population><General Public><Genes><Genetic Diseases><Genetic Markers><Genetic study><Genomics><GxE interaction><Health><Health Care Utilization><Heterogeneity><ICD Code><Image><Individual><Inhalation><Inhaling><International><International Classification of Disease Codes><Interstitial Lung Diseases><Investigation><Investigators><Knowledge><Lung><Lung Diseases><Lung Respiratory System><Manuals><Measurement><Medical Imaging><Methods><Modernization><Natural Language Processing><Outcome><Pathogenesis><Pathologic><Patient Self-Report><Persons><Pharmacogenomics><Phenotype><Population Heterogeneity><Probability><Pulmonary Diseases><Pulmonary Disorder><Pulmonary Emphysema><Radiography><Reporting><Research><Research Personnel><Researchers><Resolution><Retrieval><Risk><Risk-associated variant><Roentgenography><Secure><Self-Report><Smoking><Smoking Status><Software><Spirometry><Subgroup><System><Technology><Test Result><Testing><Thorace><Thoracic><Thoracic imaging><Thorax><Tomodensitometry><Toxic Environmental Agents><Toxic Environmental Substances><Toxin><United States><Validation><Veterans><Veterans Health Administration><Veterans Health Affairs><Visual><Work><X-Ray CAT Scan><X-Ray Computed Tomography><X-Ray Computerized Tomography><Xray CAT scan><Xray Computed Tomography><Xray computerized tomography><adjudication><adjudicative process and procedure><adulthood><allele variant><allelic variant><biobank><biorepository><blood-based biomarker><blood-based marker><case control><case-controlled><catscan><chest CT><chest computed tomography><chronic obstructive pulmonary disorder><chronic pulmonary disease><cohort><computed axial tomography><computer program><computer programming><computer tomography><computerized axial tomography><computerized tomography><developmental><diffuse interstitial pulmonary fibrosis><disability><disease diagnosis><disease of the lung><disease phenotype><disorder of the lung><diverse populations><electronic health care record><electronic health medical record><electronic health plan record><electronic health registry><electronic medical health record><electronic structure><emphysematous><enroll><environment effect on gene><environment enrichment><environment enrichment for laboratory animals><environmental enrichment><environmental enrichment for laboratory animals><environmental toxicant><epidemiologic><epidemiologic data><epidemiologic investigation><epidemiological><epidemiology study><ethnic diversity><ethnically diverse><firewall><gene biomarker><gene environment interaction><gene expression biomarker><gene marker><gene signature biomarker><genetic biomarker><genetic condition><genetic disorder><genetic epidemiologic study><genetic epidemiology><genetic variant><genome wide association><genome wide association scan><genome wide association studies><genome wide association study><genomewide association scan><genomewide association studies><genomewide association study><genomic variant><health care service use><health care service utilization><healthcare service use><healthcare service utilization><healthcare utilization><heterogeneous population><idiopathic pulmonary fibrosis><image-based method><imaging><imaging method><imaging modality><imaging platform><information gathering><interstitial><liability to disease><lung disorder><military veteran><mortality><multi-ethnic><multi-modality><multiethnic><multimodality><natural language understanding><non-contrast CT><noncontrast CT><noncontrast computed tomography><novel><participant enrollment><patient enrollment><personalization of treatment><personalized medicine><personalized therapy><personalized treatment><pharmacologic><phenotyping algorithm><polygenic risk score><population diversity><programs><prospective><prototype><pulmonary><quantitative imaging><radiologic imaging><radiological imaging><radiologist><resolutions><respiratory><risk allele><risk gene><risk genotype><risk loci><risk locus><risk stratification><risk variant><stratify risk><three dimensional><tool><validations><veteran population><whole genome association analysis><whole genome association studies><whole genome association study>