Plasma Proteomic Markers of Iron and Risk of Diabetes in a Cohort of African American and White American Current and Former Smokers.

Background: Little information is available on iron with diabetes risk among African Americans, a population where both anemia and elevated ferritin are common. We tested whether plasma proteomic measurements of ferritin and transferrin were associated with increased diabetes risk in a cohort of current and former African American (NHB) and Non-Hispanic White (NHW) smokers.

Methods: NHB and NHW participants from the COPDGene study who were free of diabetes (n = 4693) at baseline were followed for incident diabetes.

A novel application of data-consistent inversion to overcome spurious inference in genome-wide association studies.

The genome-wide association studies (GWAS) typically use linear or logistic regression models to identify associations between phenotypes (traits) and genotypes (genetic variants) of interest. However, the use of regression with the additive assumption has potential limitations. First, the normality assumption of residuals is the one that is rarely seen in practice, and deviation from normality increases the Type-I error rate.

Longitudinal Assessment of Multimorbidity Medication Patterns among Smokers in the COPDGene Cohort.

: Chronic obstructive pulmonary disease (COPD) is usually comorbid with other chronic diseases. We aimed to assess the multimorbidity medication patterns and explore if the patterns are similar for phase 1 (P1) and 5-year follow-up phase 2 (P2) in the COPDGene cohort. Materials and Methods: A total of 5564 out of 10,198 smokers from the COPDGene cohort who completed 2 visits, P1 and P2 visits, with complete medication use history were included in the study.

Predicting COPD Progression in Current and Former Smokers Using a Joint Model for Forced Expiratory Volume in 1 Second and Forced Expiratory Volume in 1 Second to Forced Vital Capacity Ratio.

Understanding baseline characteristics that can predict the progression of lung disease such as chronic obstructive pulmonary disease (COPD) for current or former smokers may allow for therapeutic intervention, particularly for individuals at high risk of rapid disease progression or transition from non-COPD to COPD. Classic diagnostic criteria for COPD and disease severity such as the Global Initiative for Chronic Obstructive Lung Disease document are based on forced expiratory volume in 1 second (FEV) and FEV to forced vital capacity (FVC) ratio. Modeling changes in these outcomes jointly is beneficial given that they are correlated, and they are both required for specific disease classifications.

Modeling of an alternative reimbursement method for palliative care.

Objectives: Patient and Caregiver Support for Serious Illness (PACSSI), a per-member per-month (PMPM) alternative reimbursement structure for palliative care (PC) services, has been described as overly generous by HHS. We developed a modified version, PACSSI-Flexible (PACSSI-F), by modeling reimbursement for PC based on the changes in patient functional status. We estimated reimbursement for the first year that an organization might implement the PACSSI-F for PC services.

Genome-Wide Association Study of Peripheral Artery Disease.

Background: Peripheral artery disease (PAD) affects >200 million people worldwide and is associated with high mortality and morbidity. We sought to identify genomic variants associated with PAD overall and in the contexts of diabetes and smoking status.

Methods: We identified genetic variants associated with PAD and then meta-analyzed with published summary statistics from the Million Veterans Program and UK Biobank to replicate their findings.

10-Year Follow-Up of Lung Function, Respiratory Symptoms, and Functional Capacity in the COPDGene Study.

The course of lung function, respiratory symptoms, and functional status over time in people who smoke cigarettes is still incompletely understood. The COPDGene (Genetic Epidemiology of Chronic Obstructive Pulmonary Disease [COPD]) study provides a unique cohort to examine these trajectories, and now 10-year follow-up data are available. This study aims to provide insight into the progression of spirometric parameters, respiratory symptoms, and functional capacity over 10 years in current and former cigarette smokers.

Co-Morbidity Patterns Identified Using Latent Class Analysis of Medications Predict All-Cause Mortality Independent of Other Known Risk Factors: The COPDGene Study.

Purpose: Medication patterns include all medications in an individual's clinical profile. We aimed to identify chronic co-morbidity treatment patterns through medication use among COPDGene participants and determine whether these patterns were associated with mortality, acute exacerbations of chronic obstructive pulmonary disease (AECOPD) and quality of life.

Materials And Methods: Participants analyzed here completed Phase 1 (P1) and/or Phase 2 (P2) of COPDGene.

A Risk Prediction Model for Mortality Among Smokers in the COPDGene® Study.

Background: Risk factor identification is a proven strategy in advancing treatments and preventive therapy for many chronic conditions. Quantifying the impact of those risk factors on health outcomes can consolidate and focus efforts on individuals with specific high-risk profiles. Using multiple risk factors and longitudinal outcomes in 2 independent cohorts, we developed and validated a risk score model to predict mortality in current and former cigarette smokers.

Accuracy and Vividness in Motor Imagery Ability: Differences between Children and Young Adults.

Motor imagery (MI) refers to the imagination of a motor task without actual movement execution. The purpose of this study was to compare MI accuracy and vividness, and motor proficiency between children ( = 101; 7-12 years) and young adults ( = 140; 18-25 years). Results indicated that young adults were significantly more accurate and rated their MI significantly more vivid than children.

A New Semiparametric Approach to Finite Mixture of Regressions using Penalized Regression via Fusion.

For some modeling problems a population may be better assessed as an aggregate of unknown subpopulations, each with a distinct relationship between a response and associated variables. The finite mixture of regressions (FMR) model, in which an outcome is derived from one of a finite number of linear regression models, is a natural tool in this setting. In this article, we first propose a new penalized regression approach.

Pulmonary Subtypes Exhibit Differential Global Initiative for Chronic Obstructive Lung Disease Spirometry Stage Progression: The COPDGene® Study.

Rationale: We classified individuals into pulmonary disease subtypes based on 2 underlying pathophysiologic disease axes (airway-predominant and emphysema-predominant) and their increased mortality risk. Our next objective was to determine whether some subcomponents of these subtypes are additionally associated with unique patterns of Global initiative for chronic Obstructive Lung Disease (GOLD) spirometry stage progression.

Methods: After accounting for intra-individual measurement variability in spirometry measures between baseline (Phase 1) and the 5-year follow up (Phase 2) of the COPD Genetic Epidemiology (COPDGene) study, 4615 individuals had complete data that would characterize patterns of disease progression over 5 years (2033 non-Hispanic whites; 827 African Americans; 48% female).

Targeted Sequencing Study to Uncover Shared Genetic Susceptibility Between Peripheral Artery Disease and Coronary Heart Disease-Brief Report.

Objective- It is unclear to what extent genetic susceptibility variants are shared between peripheral artery disease (PAD) and coronary heart disease (CHD), both manifestations of atherosclerotic vascular disease. We investigated whether common and low-frequency/rare variants in loci associated with CHD are also associated with PAD. Approach and Results- Targeted sequencing of 41 genomic regions associated with CHD in genome-wide association studies was performed in 1749 PAD cases (65±11 years, 61% men) and 1855 controls (60±11 years, 56% men) of European ancestry.

A phenome-wide association study to discover pleiotropic effects of , , and .

We conducted an electronic health record (EHR)-based phenome-wide association study (PheWAS) to discover pleiotropic effects of variants in three lipoprotein metabolism genes , , and . Using high-density genotype data, we tested the associations of variants in the three genes with 1232 EHR-derived binary phecodes in 51,700 European-ancestry (EA) individuals and 585 phecodes in 10,276 African-ancestry (AA) individuals; 457 , 730 , and 720 variants were filtered by imputation quality (  > 0.4), minor allele frequency (>1%), linkage disequilibrium (  < 0.

A genotype: sex interaction is associated with abdominal aortic aneurysm expansion.

A faster expansion rate of abdominal aortic aneurysm (AAA) increases the risk of rupture. Women are at higher risk of rupture than men, but the mechanisms underlying this increased risk are unknown. We investigated whether genetic variants that influence susceptibility for AAA (, , , and ) are associated with AAA expansion and whether these associations differ by sex in 650 patients with AAA (mean age 70±8 years, 17% women) enrolled in the Mayo Clinic Vascular Disease Biorepository.

Phosphorylation potential of E-Cadherin intracellular domain is essential for development and adherens junction biosynthetic dynamics regulation.

Phosphorylation of a highly conserved serine cluster in the intracellular domain of E-Cadherin is essential for binding to β-Catenin In cultured cells, phosphorylation of specific serine residues within the cluster is also required for regulation of adherens junction (AJ) stability and dynamics. However, much less is known about how such phosphorylation of E-Cadherin regulates AJ formation and dynamics In this report, we generated an extensive array of E-Cadherin (DE-Cad) endogenous knock-in alleles that carry mutations targeting this highly conserved serine cluster. Analyses of these mutations suggest that the overall phosphorylation potential, rather than the potential site-specific phosphorylation, of the serine cluster enhances the recruitment of β-Catenin by DE-Cad Moreover, phosphorylation potential of the serine cluster only moderately increases the level of β-Catenin in AJs and is in fact dispensable for AJ formation Nonetheless, phosphorylation-dependent recruitment of β-Catenin is essential for development, probably by enhancing the interactions between DE-Cad and α-Catenin.

Shared decision-making following disclosure of coronary heart disease genetic risk: results from a randomized clinical trial.

Unlabelled: Whether disclosure of genetic risk for coronary heart disease (CHD) influences shared decision-making (SDM) regarding use of statins to reduce CHD risk is unknown. We randomized 207 patients, age 45-65 years, at intermediate CHD risk, and not on statins, to receive the 10-year risk of CHD based on conventional risk factors alone (n=103) or in combination with a genetic risk score (n=104). A genetic counselor disclosed this information followed by a physician visit for SDM regarding statin therapy.

PHACTR1 Is a Genetic Susceptibility Locus for Fibromuscular Dysplasia Supporting Its Complex Genetic Pattern of Inheritance.

Fibromuscular dysplasia (FMD) is a nonatherosclerotic vascular disease leading to stenosis, dissection and aneurysm affecting mainly the renal and cerebrovascular arteries. FMD is often an underdiagnosed cause of hypertension and stroke, has higher prevalence in females (~80%) but its pathophysiology is unclear. We analyzed ~26K common variants (MAF>0.

Usefulness of Atrial Fibrillation as a Marker for Adverse Cardiovascular Outcomes in Both Primary and Secondary Prevention in Patients With Implantable Cardioverter-Defibrillators.

Whether the risk factors for cardiovascular (CV) outcomes are different in primary versus secondary prevention implantable cardioverter-defibrillator (ICD) patients is unclear. We sought to identify predictors of CV outcomes in ICD recipients for primary (G1) versus secondary prevention (G2). Consecutive patients who had ICD implanted during August 2005 to December 2009 were included.

Plasma Osteopontin Levels and Adverse Cardiovascular Outcomes in the PEACE Trial.

Osteopontin (OPN) is a secreted glycophosphoprotein that has a role in inflammation, immune response and calcification. We hypothesized that plasma OPN levels are associated with adverse cardiovascular outcomes in patients with stable coronary artery disease (CAD) and preserved ejection fraction (EF) enrolled in the PEACE trial. We measured plasma OPN levels at baseline in 3567 CAD patients (mean age 64.

Incorporating a Genetic Risk Score Into Coronary Heart Disease Risk Estimates: Effect on Low-Density Lipoprotein Cholesterol Levels (the MI-GENES Clinical Trial).

Background: Whether knowledge of genetic risk for coronary heart disease (CHD) affects health-related outcomes is unknown. We investigated whether incorporating a genetic risk score (GRS) in CHD risk estimates lowers low-density lipoprotein cholesterol (LDL-C) levels.

Methods And Results: Participants (n=203, 45-65 years of age, at intermediate risk for CHD, and not on statins) were randomly assigned to receive their 10-year probability of CHD based either on a conventional risk score (CRS) or CRS + GRS ((+)GRS).