Publications by authors named "Erin Austin"

35 Publications

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

Clin Epidemiol 2020 27;12:1171-1181. Epub 2020 Oct 27.

Department of Epidemiology, Colorado School of Public Health, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.

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. Latent class analysis (LCA) was used to identify medication patterns and assign individuals into unobserved LCA classes. Mortality, AECOPD, and the St. George's Respiratory Questionnaire (SGRQ) health status were compared in different LCA classes through survival analysis, logistic regression, and Kruskal-Wallis test, respectively.

Results: LCA identified 8 medication patterns from 32 classes of chronic comorbid medications. A total of 8110 out of 10,127 participants with complete covariate information were included. Survival analysis adjusted for covariates showed, compared to a low medication use class, mortality was highest in participants with hypertension+diabetes+statin+antiplatelet medication group. Participants in hypertension+SSRI+statin medication group had the highest odds of AECOPD and the highest SGRQ score at both P1 and P2.

Conclusion: Medication pattern can serve as a good indicator of an individual's comorbidities profile and improves models predicting clinical outcomes.
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http://dx.doi.org/10.2147/CLEP.S279075DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7602898PMC
October 2020

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

Chronic Obstr Pulm Dis 2020 Oct;7(4):346-361

University of Pittsburgh, Pittsburgh, Pennsylvania.

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.

Methods: We obtained extensive data on current and former smokers from the COPD Genetic Epidemiology (COPDGene) study at enrollment. Based on physician input and model goodness-of-fit measures, a subset of variables was selected to fit final Weibull survival models separately for men and women. Coefficients and predictors were translated into a point system, allowing for easy computation of mortality risk scores and probabilities. We then used the SubPopulations and InteRmediate Outcome Measures In COPD Study (SPIROMICS) cohort for external validation of our model.

Results: Of 9867 COPDGene participants with standard baseline data, 17.6% died over 10 years of follow-up, and 9074 of these participants had the full set of baseline predictors (standard plus 6-minute walk distance and computed tomography variables) available for full model fits. The average age of participants in the cohort was 60 for both men and women, and the average predicted 10-year mortality risk was 18% for women and 25% for men. Model time-integrated area under the receiver operating characteristic curve statistics demonstrated good predictive model accuracy (0.797 average), validated in the external cohort (0.756 average). Risk of mortality was impacted most by 6-minute walk distance, forced expiratory volume in 1 second and age, for both men and women.

Conclusions: Current and former smokers exhibited a wide range of mortality risk over a 10- year period. Our models can identify higher risk individuals who can be targeted for interventions to reduce risk of mortality, for participants with or without chronic obstructive pulmonary disease (COPD) using current Global initiative for obstructive Lung Disease (GOLD) criteria.
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http://dx.doi.org/10.15326/jcopdf.7.4.2020.0146DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7883903PMC
October 2020

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

Dev Neuropsychol 2020 08 7;45(5):297-308. Epub 2020 Jul 7.

Department of Kinesiology, University of Texas at Arlington , Arlington, TX, USA.

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. For MI accuracy, between-subject effects showed that young adults had higher scores than children on three of the four subscales and the action subscale significantly predicted motor proficiency. These findings indicate that MI ability continues to develop into adulthood.
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http://dx.doi.org/10.1080/87565641.2020.1788034DOI Listing
August 2020

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

Chronic Obstr Pulm Dis 2019 Nov;6(5):414-429

Department of Epidemiology, Colorado School of Public Health, University of Colorado Anschutz Medical Campus, Aurora.

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). Individuals could express increased risk for mortality on one or both of the primary subtype axes (airway-predominant or emphysema-predominant) and thus they were further classified into 6 groups: high-risk airway-predominant disease only (APD-only), moderate-risk airway-predominant disease only (MR-APD-only), high-risk emphysema-predominant disease only (EPD-only), combined high-risk airway- and emphysema-predominant disease (combined APD-EPD), combined moderate-risk airway- and emphysema-predominant disease (combined MR-APD-EPD), and no high-risk pulmonary subtype. Outcomes were dichotomized for GOLD spirometry stage progression from Phase 1 to Phase 2. Logistic regression of the progression outcomes on the pulmonary subtypes were adjusted for age, sex, race, and change in smoking status.

Results: The MR-APD-only group was associated with conversion from GOLD 0 to preserved ratio-impaired spirometry (PRISm) status (odds ratio [OR] 11.3, 95% confidence interval [CI] 5.7-22.1) and GOLD 0 to GOLD 2-4 (OR 6.0, 95% CI 2.0-18.0). The EPD-only group was associated with conversion from GOLD 0 to GOLD 1 (OR 2.4, 95% CI 1.2-4.6), and GOLD 1 to GOLD 2-4 (OR 2.6, 95% CI 1.0-6.9). Conversion between PRISm and GOLD 2-4 (31%-38%) occurred in both the APD-only and the MR-APD-only groups.

Conclusion: Differential conversion occurs from GOLD 0 to PRISm and GOLD 0 to GOLD 1 based on groups expressing airway-predominant disease or emphysema-predominant disease independently or in combination. Airway-predominant and emphysema-predominant subtypes are highly important in determining patterns of early disease progression.
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http://dx.doi.org/10.15326/jcopdf.6.5.2019.0155DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7020848PMC
November 2019

COPDGene 2019: Redefining the Diagnosis of Chronic Obstructive Pulmonary Disease.

Chronic Obstr Pulm Dis 2019 Nov;6(5):384-399

Northeastern University, Boston, Massachusetts.

Background: Chronic obstructive pulmonary disease (COPD) remains a major cause of morbidity and mortality. Present-day diagnostic criteria are largely based solely on spirometric criteria. Accumulating evidence has identified a substantial number of individuals without spirometric evidence of COPD who suffer from respiratory symptoms and/or increased morbidity and mortality. There is a clear need for an expanded definition of COPD that is linked to physiologic, structural (computed tomography [CT]) and clinical evidence of disease. Using data from the COPD Genetic Epidemiology study (COPDGene), we hypothesized that an integrated approach that includes environmental exposure, clinical symptoms, chest CT imaging and spirometry better defines disease and captures the likelihood of progression of respiratory obstruction and mortality.

Methods: Four key disease characteristics - environmental exposure (cigarette smoking), clinical symptoms (dyspnea and/or chronic bronchitis), chest CT imaging abnormalities (emphysema, gas trapping and/or airway wall thickening), and abnormal spirometry - were evaluated in a group of 8784 current and former smokers who were participants in COPDGene Phase 1. Using these 4 disease characteristics, 8 categories of participants were identified and evaluated for odds of spirometric disease progression (FEV > 350 ml loss over 5 years), and the hazard ratio for all-cause mortality was examined.

Results: Using smokers without symptoms, CT imaging abnormalities or airflow obstruction as the reference population, individuals were classified as Possible COPD, Probable COPD and Definite COPD. Current Global initiative for obstructive Lung Disease (GOLD) criteria would diagnose 4062 (46%) of the 8784 study participants with COPD. The proposed COPDGene 2019 diagnostic criteria would add an additional 3144 participants. Under the new criteria, 82% of the 8784 study participants would be diagnosed with Possible, Probable or Definite COPD. These COPD groups showed increased risk of disease progression and mortality. Mortality increased in patients as the number of their COPD characteristics increased, with a maximum hazard ratio for all cause-mortality of 5.18 (95% confidence interval [CI]: 4.15-6.48) in those with all 4 disease characteristics.

Conclusions: A substantial portion of smokers with respiratory symptoms and imaging abnormalities do not manifest spirometric obstruction as defined by population normals. These individuals are at significant risk of death and spirometric disease progression. We propose to redefine the diagnosis of COPD through an integrated approach using environmental exposure, clinical symptoms, CT imaging and spirometric criteria. These expanded criteria offer the potential to stimulate both current and future interventions that could slow or halt disease progression in patients before disability or irreversible lung structural changes develop.
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http://dx.doi.org/10.15326/jcopdf.6.5.2019.0149DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7020846PMC
November 2019

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

Arterioscler Thromb Vasc Biol 2019 06;39(6):1227-1233

From the Department of Cardiovascular Medicine (M.S.S., X.F., E.E.A., I.J.K.), Mayo Clinic, Rochester, MN.

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. PAD cases had a resting/postexercise ankle-brachial index ≤0.9, or history of lower extremity revascularization; controls had no history of PAD. We tested the association of common (defined as minor allele frequency ≥5%) variants with PAD assuming an additive genetic model with adjustment for age and sex. To identify low-frequency/rare variants (minor allele frequency <5%) associated with PAD, we conducted gene-level analyses using sequence kernel association test and permutation test. After Bonferroni correction, we found common variants in SH2B3, ABO, and ZEB2 to be associated with PAD ( P<4.5×10). At the gene level, the strongest associations were for LPL and SH2B3. Conclusions- Targeted sequencing of 41 genomic regions associated with CHD revealed several common variants/genes to be associated with PAD, highlighting the basis of shared genetic susceptibility between CHD and PAD.
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http://dx.doi.org/10.1161/ATVBAHA.118.312128DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6531315PMC
June 2019

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

NPJ Genom Med 2019 11;4. Epub 2019 Feb 11.

20Center for Human Genetics, Marshfield Clinic Research Foundation, Marshfield, WI 54449 USA.

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 ( < 0.3), and association with LDL-C levels, yielding a set of two , three , and five variants in EA but no variants in AA. Cases and controls were defined for each phecode using the PheWAS package in R. Logistic regression assuming an additive genetic model was used with adjustment for age, sex, and the first two principal components. Significant associations were tested in additional cohorts from Vanderbilt University ( = 29,713), the Marshfield Clinic Personalized Medicine Research Project ( = 9562), and UK Biobank ( = 408,455). We identified one , two , and two variants significantly associated with an examined phecode. Only one of the variants was associated with a non-lipid disease phecode, ("myopia") but this association was not significant in the replication cohorts. In this large-scale PheWAS we did not find LDL-C-related variants in , , and to be associated with non-lipid-related phenotypes including diabetes, neurocognitive disorders, or cataracts.
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http://dx.doi.org/10.1038/s41525-019-0078-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6370860PMC
February 2019

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

J Investig Med 2017 10 11;65(7):1077-1082. Epub 2017 Jul 11.

Department of Cardiovascular Diseases and the Gonda Vascular Center, Mayo Clinic, Rochester, Minnesota, USA.

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. Women had a mean aneurysm expansion 0.41 mm/year greater than men after adjustment for baseline AAA size. In addition to baseline size, mean arterial pressure (MAP), non-diabetic status, rs599839[G] and rs7025486[A] were associated with greater aneurysm expansion (all p<0.05). The associations of MAP and rs599839[G] were similar in both sexes, while the associations of baseline size, pulse pressure (PP) and rs7025486[A] were stronger in women than men (all p ≤0.02). A three-way interaction of PP*sex* rs7025486[A] was noted in a full-factorial analysis (p=0.007) independent of baseline size and MAP. In the high PP group (≥median), women had a mean growth rate 0.68 mm/year greater per [A] of rs7025486 than men (p =0.003), whereas there was no difference in the low PP group (p =0.8). We demonstrate that variants rs7025486[A] and rs599839[G] are associated with AAA expansion. The association of rs7025486[A] is stronger in women than men and amplified by high PP, contributing to sex differences in aneurysm expansion.
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http://dx.doi.org/10.1136/jim-2016-000404DOI Listing
October 2017

Motivation, Perception, and Treatment Beliefs in the Myocardial Infarction Genes (MI-GENES) Randomized Clinical Trial.

J Genet Couns 2017 Oct 6;26(5):1153-1161. Epub 2017 Apr 6.

Department of Cardiovascular Diseases, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA.

Little is known about individuals' motivation, perception, and treatment beliefs towards the use of genetic information in risk estimates for coronary heart disease (CHD). In this study, participants at intermediate 10-year risk of CHD were randomized to receive either their estimated conventional risk score (CRS) alone, or a CRS and a genetic risk score (GRS), by a genetic counselor. Surveys on motivation to participate in and perception of genetic testing for CHD were administered at 3 months and treatment beliefs at 6 months following risk disclosure. Survey responses used Likert scales. Linear and logistic regression were used for analysis. Overall, motivation to participate in genomic clinical trials was favorable and did not differ between the CRS and GRS groups (16.95 ± 0.82 vs. 17.58 ± 0.83, p = 0.091), but participants who initially received their GRS indicated a greater desire to find ways to improve health as a reason for participation (OR: 0.53 (95%CI: 0.29, 0.94), p = 0.028). Perception of genetic testing was also favorable in both groups (15.29 ± 0.39 vs. 15.12 ± 0.40, p = 0.835). Participants who initially received their GRS were more inclined to recommend genetic testing to family and friends (9.95 ± 1.88 vs. 10.52 ± 2.17, p = 0.023). In the MI-GENES study, motivation to participate in and perception of genetic testing among study participants were overall favorable. Genetic risk disclosure was associated with increased motivation to recommend genetic testing to family and friends.
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http://dx.doi.org/10.1007/s10897-017-0092-9DOI Listing
October 2017

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

Development 2017 04 20;144(7):1242-1248. Epub 2017 Feb 20.

Department of Cell Biology, University of Pittsburgh Medical School, Pittsburgh, PA 15261, USA

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. In addition, several phospho-mutations dramatically reduced the biosynthetic turnover rate of DE-Cad during apical-basal polarization, and such biosynthetically stable DE-Cad mutants specifically rescued the polarity defects in embryonic epithelia lacking the polarity proteins Stardust and Crumbs.
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http://dx.doi.org/10.1242/dev.141598DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5399621PMC
April 2017

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

J Investig Med 2017 03 19;65(3):681-688. Epub 2016 Dec 19.

Division of Cardiovascular Diseases, Department of Medicine, Mayo Clinic, Rochester, Minnesota, USA.

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. A novel decision aid was used in both encounters to disclose the CHD risk estimates and facilitate SDM regarding statin use. Patients reported their decision quality and physician visit satisfaction using validated surveys. There were no statistically significant differences between the two groups in the SDM score, satisfaction with the clinical encounter, perception of the quality of the discussion or of participation in decision-making and physician visit satisfaction scores. Quantitative analyses of a random subset of 80 video-recorded encounters using the OPTION5 scale also showed no significant difference in SDM between the two groups. Disclosure of CHD genetic risk using an electronic health record-linked decision aid did not adversely affect SDM or patients' satisfaction with the clinical encounter.

Trial Registration Number: NCT01936675; Results.
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http://dx.doi.org/10.1136/jim-2016-000318DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5325770PMC
March 2017

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

PLoS Genet 2016 Oct 28;12(10):e1006367. Epub 2016 Oct 28.

INSERM, UMR970 Paris Cardiovascular Research Center (PARCC), Paris F-75015, FRANCE.

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>0.05) generated by exome-chip arrays in 249 FMD patients and 689 controls. We replicated 13 loci (P<10-4) in 402 cases and 2,537 controls and confirmed an association between FMD and a variant in the phosphatase and actin regulator 1 gene (PHACTR1). Three additional case control cohorts including 512 cases and 669 replicated this result and overall reached the genomic level of significance (OR = 1.39, P = 7.4×10-10, 1,154 cases and 3,895 controls). The top variant, rs9349379, is intronic to PHACTR1, a risk locus for coronary artery disease, migraine, and cervical artery dissection. The analyses of geometrical parameters of carotids from ~2,500 healthy volunteers indicate higher intima media thickness (P = 1.97×10-4) and wall to lumen ratio (P = 0.002) in rs9349379-A carriers, suggesting indices of carotid hypertrophy previously described in carotids of FMD patients. Immunohistochemistry detected PHACTR1 in endothelium and smooth muscle cells of FMD and normal human carotids. The expression of PHACTR1 by genotypes in primary human fibroblasts showed higher expression in rs9349379-A carriers (N = 86, P = 0.003). Phactr1 knockdown in zebrafish resulted in dilated vessels indicating subtle impaired vascular development. We report the first susceptibility locus for FMD and provide evidence for a complex genetic pattern of inheritance and indices of shared pathophysiology between FMD and other cardiovascular and neurovascular diseases.
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http://dx.doi.org/10.1371/journal.pgen.1006367DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5085032PMC
October 2016

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

Am J Cardiol 2016 Nov 23;118(10):1497-1502. Epub 2016 Aug 23.

Cardiovascular Division, Department of Medicine, University of Minnesota, Minneapolis, Minnesota. Electronic address:

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. The primary outcome was a composite of appropriate shock, acute coronary syndrome, ischemic stroke, coronary revascularization, heart failure exacerbation, CV hospitalization, or all-cause death. We used Cox proportional hazards model and a stepwise selection method to fit the most parsimonious model to predict the primary outcome in all patients and separately for G1 and G2 patients. We followed 223 (184 G1 and 39 G2, mean age 61 years) patients through December 31, 2012; 141 (63.2%) developed the primary outcome. In all patients, atrial fibrillation (AF; hazard ratio 6.72, 95% CI 4.20 to 10.75; p <0.001), use of antiarrhythmic drug (1.55, 1.02 to 2.36; p = 0.04), and lower estimated glomerular filtration rate (0.99, 0.98 to 0.997; p = 0.01) were associated with increased risk of the primary outcome; the attributable risks were 21.6%, 16.0%, and 15.9%, respectively. In G1, AF, hypertension, and lower estimated glomerular filtration rate were associated with increased risk, whereas in G2, AF, use of antiarrhythmic drug, and nonischemic cardiomyopathy were associated with increased risk. In conclusion, although risk factors are different for primary and secondary prevention patients, AF is a strong and consistent risk factor for adverse outcomes in both populations.
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http://dx.doi.org/10.1016/j.amjcard.2016.08.016DOI Listing
November 2016

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

PLoS One 2016 10;11(6):e0156965. Epub 2016 Jun 10.

Department of Cardiovascular Diseases, Mayo Clinic, Rochester, Minnesota, United States of America.

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 64.5 ± 8.1 years, 81% men) by a sandwich chemiluminescent assay (coefficient of variation = 4.1%). OPN levels were natural log (Ln) transformed prior to analyses. We assessed whether Ln OPN levels were associated with the composite primary endpoint of cardiovascular death, non-fatal myocardial infarction and hospitalization for heart failure using multiple event multivariable Cox proportional hazards regression. Adjustment was performed for: (a) age and sex; (b) additional potential confounders; and (c) a parsimonious set of statistically significant 10 variates. During a median follow-up of 4.8 years, 416 adverse cardiovascular outcomes occurred in 366 patients. Ln OPN was significantly associated with the primary endpoint; HR (95% CI) = 1.56 (1.27, 1.92); P <0.001, and remained significant after adjustment for age and sex [1.31 (1.06, 1.61); P = 0.01] and after adjustment for relevant covariates [1.24 (1.01, 1.52); P = 0.04]. In a secondary analysis of the individual event types, Ln OPN was significantly associated with incident hospitalization for heart failure: HR (95% CI) = 2.04 (1.44, 2.89); P <0.001, even after adjustment for age, sex and additional relevant covariates. In conclusion, in patients with stable CAD and preserved EF on optimal medical therapy, plasma OPN levels were independently associated with the composite incident endpoint of adverse cardiovascular outcomes as well as incident hospitalization for heart failure.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0156965PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4902195PMC
July 2017

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

Circulation 2016 Mar 25;133(12):1181-8. Epub 2016 Feb 25.

From the Division of Cardiovascular Diseases, Department of Medicine, Mayo Clinic, Rochester, MN (I.J.K., H.J., E.E.A., S.-A.B., T.M.K., I.N.I., R.A.H., T.S.M., K.S.); Department of Health Sciences Research, Mayo Clinic, Rochester, MN (J.E.O., D.J.S., K.R.B.); Department of Pediatrics, Medicine and Physiology, Medical College of Wisconsin, Milwaukee (U.B.); Division of Genetics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA (R.C.G.); and Knowledge and Evaluation Research Unit, Mayo Clinic, Rochester, MN (V.M.M.).

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). Participants in the (+)GRS group were stratified as having high or average/low GRS. Risk was disclosed by a genetic counselor followed by shared decision making regarding statin therapy with a physician. We compared the primary end point of LDL-C levels at 6 months and assessed whether any differences were attributable to changes in dietary fat intake, physical activity levels, or statin use. Participants (mean age, 59.4±5 years; 48% men; mean 10-year CHD risk, 8.5±4.1%) were allocated to receive either CRS (n=100) or (+)GRS (n=103). At the end of the study period, the (+)GRS group had a lower LDL-C than the CRS group (96.5±32.7 versus 105.9±33.3 mg/dL; P=0.04). Participants with high GRS had lower LDL-C levels (92.3±32.9 mg/dL) than CRS participants (P=0.02) but not participants with low GRS (100.9±32.2 mg/dL; P=0.18). Statins were initiated more often in the (+)GRS group than in the CRS group (39% versus 22%, P<0.01). No significant differences in dietary fat intake and physical activity levels were noted.

Conclusions: Disclosure of CHD risk estimates that incorporated genetic risk information led to lower LDL-C levels than disclosure of CHD risk based on conventional risk factors alone.

Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01936675.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.115.020109DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4803581PMC
March 2016

A multi-locus genetic risk score for abdominal aortic aneurysm.

Atherosclerosis 2016 Mar 5;246:274-9. Epub 2016 Jan 5.

Division of Cardiovascular Diseases and the Gonda Vascular Center, Mayo Clinic, Rochester, MN, USA. Electronic address:

Background: We investigated whether a multi-locus genetic risk scores (GRS) was associated with presence and progression of abdominal aortic aneurysm (AAA) in a case - control study.

Methods And Results: The study comprised of 1124 patients with AAA (74 ± 8 years, 83% men, 52% of them with a maximal AAA size ≤ 5 cm) and 6524 non-cases (67 ± 11 years, 58% men) from the Mayo Vascular Disease Biorepository. AAA was defined as infrarenal abdominal aorta diameter ≥ 3.0 cm or history of AAA repair. Non-cases were participants without known AAA. A GRS was calculated using 4 SNPs associated with AAA at genome-wide significance (P ≤ 10(-8)). The GRS was associated with the presence of AAA after adjustment for age, sex, cardiovascular risk factors, atherosclerotic cardiovascular diseases and family history of aortic aneurysm: odds ratio (OR, 95% confidence interval, CI) 1.06 (1.04-1.09, p < 0.001). Adding GRS to conventional risk factors improved the association of presence of AAA (net reclassification index 14%, p < 0.001). In a subset of patients with AAA who had ≥ 2 imaging studies (n = 651, mean (SE) growth rate 2.47 (0.11) mm/year during a mean time interval of 5.41 years), GRS, baseline size, diabetes and family history were each associated with aneurysm growth rate in univariate association (all p < 0.05). The estimated mean aneurysm growth rate was 0.50 mm/year higher in those with GRS > median (5.78) than those with GRS ≤ median (p = 0.01), after adjustment for baseline size (p < 0.001), diabetes (p = 0.046) and family history of aortic aneurysm (p = 0.02).

Conclusions: A multi-locus GRS was associated with presence of AAA and greater aneurysm expansion.
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http://dx.doi.org/10.1016/j.atherosclerosis.2015.12.031DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5507075PMC
March 2016

Family history of atherosclerotic vascular disease is associated with the presence of abdominal aortic aneurysm.

Vasc Med 2016 Feb 12;21(1):41-6. Epub 2015 Nov 12.

Division of Cardiovascular Diseases and the Gonda Vascular Center, Mayo Clinic, Rochester, MN, USA

We investigated whether family history (FHx) of atherosclerotic cardiovascular disease (ASCVD) was associated with presence of abdominal aortic aneurysm (AAA). The study cohort comprised of 696 patients with AAA (70±8 years, 84% men) and 2686 controls (68±10 years, 61% men) recruited from noninvasive vascular and stress electrocardiogram (ECG) laboratories at Mayo Clinic. AAA was defined as a transverse diameter of abdominal aorta ⩾ 3 cm or history of AAA repair. Controls were not known to have AAA. FHx was defined as having at least one first-degree relative with aortic aneurysm or with onset of ASCVD (coronary, cerebral or peripheral artery disease) before age 65 years. FHx of aortic aneurysm or ASCVD were each associated with presence of AAA after adjustment for age, sex, conventional risk factors and ASCVD: adjusted odds ratios (OR; 95% confidence interval): 2.17 (1.66-2.83, p < 0.01) and 1.31 (1.08-1.59, p < 0.01), respectively. FHx of ASCVD remained associated with AAA after additional adjustment for FHx of aortic aneurysm: adjusted OR: 1.27 (1.05-1.55, p = 0.01). FHx of ASCVD in multiple arterial locations was associated with higher odds of having AAA: the adjusted odds were 1.23 times higher for each additionally affected arterial location reported in the FHx (1.08-1.40, p = 0.01). Our results suggest both unique and shared environmental and genetic factors mediating susceptibility to AAA and ASCVD.
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http://dx.doi.org/10.1177/1358863X15611758DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6652204PMC
February 2016

A conserved polybasic domain mediates plasma membrane targeting of Lgl and its regulation by hypoxia.

J Cell Biol 2015 Oct 19;211(2):273-86. Epub 2015 Oct 19.

Department of Cell Biology, University of Pittsburgh Medical School, Pittsburgh, PA 15261

Lethal giant larvae (Lgl) plays essential and conserved functions in regulating both cell polarity and tumorigenesis in Drosophila melanogaster and vertebrates. It is well recognized that plasma membrane (PM) or cell cortex localization is crucial for Lgl function in vivo, but its membrane-targeting mechanisms remain poorly understood. Here, we discovered that hypoxia acutely and reversibly inhibits Lgl PM targeting through a posttranslational mechanism that is independent of the well-characterized atypical protein kinase C (aPKC) or Aurora kinase-mediated phosphorylations. Instead, we identified an evolutionarily conserved polybasic (PB) domain that targets Lgl to the PM via electrostatic binding to membrane phosphatidylinositol phosphates. Such PB domain-mediated PM targeting is inhibited by hypoxia, which reduces inositol phospholipid levels on the PM through adenosine triphosphate depletion. Moreover, Lgl PB domain contains all the identified phosphorylation sites of aPKC and Aurora kinases, providing a molecular mechanism by which phosphorylations neutralize the positive charges on the PB domain to inhibit Lgl PM targeting.
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http://dx.doi.org/10.1083/jcb.201503067DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4621827PMC
October 2015

A Novel Statistic for Global Association Testing Based on Penalized Regression.

Genet Epidemiol 2015 Sep;39(6):415-26

Division of Biostatistics, School of Public Health, University of Minnesota, Minneapolis, Minnesota, United States of America.

Natural genetic structures like genes may contain multiple variants that work as a group to determine a biologic outcome. The effect of rare variants, mutations occurring in less than 5% of samples, is hypothesized to be explained best as groups collectively associated with a biologic function. Therefore, it is important to develop powerful association tests to identify a true association between an outcome of interest and a group of variants, in particular a group with many rare variants. In this article we first delineate a novel penalized regression-based global test for the association between sets of variants and a disease phenotype. Next, we use Genetic Analysis Workshop 18 (GAW18) data to assess the power of the new global association test to capture a relationship between an aggregated group of variants and a simulated hypertension status. Rare variant only, common variant only, and combined variant groups are studied. The power values are compared to those obtained from eight well-regarded global tests (Score, Sum, SSU, SSUw, UminP, aSPU, aSPUw, and sequence kernel association test (SKAT)) that do not use penalized regression and a set of tests using either the SSU or score statistics and least absolute shrinkage and selection operator penalty (LASSO) logistic regression. Association testing of rare variants with our method was the top performer when there was low linkage disequilibrium (LD) between and within causal variants. This was similarly true when simultaneously testing rare and common variants in low LD scenarios. Finally, our method was able to provide meaningful variant-specific association information.
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http://dx.doi.org/10.1002/gepi.21915DOI Listing
September 2015

Plasma mid-regional pro-atrial natriuretic peptide and N-terminal pro-brain natriuretic peptide improve discrimination of lone atrial fibrillation.

Int J Cardiol 2015 Jun 31;188:10-2. Epub 2015 Mar 31.

Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, 5 Lower Kent Ridge Road, Singapore; Cardiac Department, 5 Lower Kent Ridge Road, National University Heart Centre, Singapore.

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http://dx.doi.org/10.1016/j.ijcard.2015.03.415DOI Listing
June 2015

Structure-based design of inhibitors of coagulation factor XIa with novel P1 moieties.

Bioorg Med Chem Lett 2015 Apr 4;25(7):1635-42. Epub 2015 Feb 4.

Bristol-Myers Squibb Company, Research and Development, 311 Pennington-Rocky Hill Rd., Pennington, NJ 08534, United States.

Compound 2 was previously identified as a potent inhibitor of factor XIa lacking oral bioavailability. A structure-based approach was used to design analogs of 2 with novel P1 moieties with good selectivity profiles and oral bioavailability. Further optimization of the P1 group led to the identification of a 4-chlorophenyltetrazole P1 analog, which when combined with further modifications to the linker and P2' group provided compound 32 with FXIa Ki=6.7 nM and modest oral exposure in dogs.
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http://dx.doi.org/10.1016/j.bmcl.2015.01.028DOI Listing
April 2015

Does the inclusion of rare variants improve risk prediction?

BMC Proc 2014 17;8(Suppl 1):S94. Epub 2014 Jun 17.

School of Statistics, University of Minnesota, Minneapolis, MN 55455, USA.

Every known link between a genetic variant and blood pressure improves the understanding and potentially the risk assessment of related diseases such as hypertension. Genetic data have become increasingly comprehensive and available for an increasing number of samples. The availability of whole-genome sequencing data means that statistical genetic models must evolve to meet the challenge of using both rare variants (RVs) and common variants (CVs) to link previously unidentified genome loci to disease-related traits. Penalized regression has two features, variable selection and proportional coefficient shrinkage, that allow researchers to build models tailored to hypothesized characteristics of the genotype-phenotype map. The following work uses the Genetic Analysis Workshop 18 data to investigate the performance of a spectrum of penalized regressions using at first only CVs or only RVs to predict systolic blood pressure (SBP). Next, combinations of CVs and RVs are used to model SBP, and the impact on prediction is quantified. The study demonstrates that penalized regression improves blood pressure prediction for any combination of CVs and RVs compared with maximum likelihood estimation. More significantly, models using both types of variants provide better predictions of SBP than those using only CVs or only RVs. The predictive mean squared error was reduced by up to 11.5% when RVs were added to CV-only penalized regression models. Elastic net regression with equally weighted LASSO and ridge components, in particular, can use large numbers of single-nucleotide polymorphisms to improve prediction.
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http://dx.doi.org/10.1186/1753-6561-8-S1-S94DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4143761PMC
December 2014

Inactivating mutations in NPC1L1 and protection from coronary heart disease.

N Engl J Med 2014 Nov 12;371(22):2072-82. Epub 2014 Nov 12.

Cardiovascular Division, Department of Medicine, Division of Statistical Genomics, Washington University School of Medicine, St. Louis, MO, USA.

Background: Ezetimibe lowers plasma levels of low-density lipoprotein (LDL) cholesterol by inhibiting the activity of the Niemann-Pick C1-like 1 (NPC1L1) protein. However, whether such inhibition reduces the risk of coronary heart disease is not known. Human mutations that inactivate a gene encoding a drug target can mimic the action of an inhibitory drug and thus can be used to infer potential effects of that drug.

Methods: We sequenced the exons of NPC1L1 in 7364 patients with coronary heart disease and in 14,728 controls without such disease who were of European, African, or South Asian ancestry. We identified carriers of inactivating mutations (nonsense, splice-site, or frameshift mutations). In addition, we genotyped a specific inactivating mutation (p.Arg406X) in 22,590 patients with coronary heart disease and in 68,412 controls. We tested the association between the presence of an inactivating mutation and both plasma lipid levels and the risk of coronary heart disease.

Results: With sequencing, we identified 15 distinct NPC1L1 inactivating mutations; approximately 1 in every 650 persons was a heterozygous carrier for 1 of these mutations. Heterozygous carriers of NPC1L1 inactivating mutations had a mean LDL cholesterol level that was 12 mg per deciliter (0.31 mmol per liter) lower than that in noncarriers (P=0.04). Carrier status was associated with a relative reduction of 53% in the risk of coronary heart disease (odds ratio for carriers, 0.47; 95% confidence interval, 0.25 to 0.87; P=0.008). In total, only 11 of 29,954 patients with coronary heart disease had an inactivating mutation (carrier frequency, 0.04%) in contrast to 71 of 83,140 controls (carrier frequency, 0.09%).

Conclusions: Naturally occurring mutations that disrupt NPC1L1 function were found to be associated with reduced plasma LDL cholesterol levels and a reduced risk of coronary heart disease. (Funded by the National Institutes of Health and others.).
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http://dx.doi.org/10.1056/NEJMoa1405386DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4335708PMC
November 2014

Fitness change effects on midlife metabolic outcomes.

Med Sci Sports Exerc 2015 May;47(5):967-73

1University of Minnesota, Minneapolis, MN; 2Northwestern University, Evanston, IL; 3Pennington Biomedical Research Center, Baton Rouge, LA; and 4Kaiser Permanente Division of Research, Oakland, CA.

Purpose: Fitness decline, high body mass index (BMI), and insulin resistance (IR) are associated with worsening cardiometabolic risk factors prospectively; modification of the fitness change effect by BMI and IR remains unknown.

Methods: Participants from the Coronary Artery Risk Development in Young Adults study without diabetes at year 0 (Y0) (n = 2048, 43.4% men; mean age, 25 yr) had fitness quantified by treadmill at Y0 and Y20. Y0 BMI was normal (nBMI <25 kg·m) or high (hBMI ≥25 kg·m). Y0 IR status was insulin sensitive (IS) (homeostatic model assessment IR <1.84 (75th percentile)) or insulin resistant (IR) (homeostatic model assessment IR ≥1.84). Four groups were established: nBMI/IS, hBMI/IS, nBMI/IR, and hBMI/IR. Y0 fitness was low (<33rd percentile for sex) or average high (≥33rd percentile for sex). Fitness change (treadmill time: Y20-Y0) was maintained (increase or decline ≤20th percentile for sex) or decreased (decline >20th percentile for sex). The outcomes were incident diabetes and percentage change over 25 yr in weight, waist girth, blood pressure, and lipid profile. Analysis was by multiple linear regression and proportional hazards regression with adjustment for individual characteristics.

Results: Maintained fitness after 20 yr was associated with greater increase in HDL cholesterol and less increase in weight, waist girth, blood pressure, and triglycerides than decreased fitness, similarly for the groups defined by BMI and IR. Maintained fitness reduced the rate of incident diabetes in IS but not IR participants.

Conclusions: Maintained fitness after 20 yr was associated with more favorable middle-age cardiometabolic risk factors than decreased fitness; this benefit might be blunted by baseline IR.
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http://dx.doi.org/10.1249/MSS.0000000000000481DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4340823PMC
May 2015

Applications of machine learning and data mining methods to detect associations of rare and common variants with complex traits.

Genet Epidemiol 2014 Sep;38 Suppl 1:S81-5

Department of Human Genetics, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, California, United States of America.

Machine learning methods (MLMs), designed to develop models using high-dimensional predictors, have been used to analyze genome-wide genetic and genomic data to predict risks for complex traits. We summarize the results from six contributions to our Genetic Analysis Workshop 18 working group; these investigators applied MLMs and data mining to analyses of rare and common genetic variants measured in pedigrees. To develop risk profiles, group members analyzed blood pressure traits along with single-nucleotide polymorphisms and rare variant genotypes derived from sequence and imputation analyses in large Mexican American pedigrees. Supervised MLMs included penalized regression with varying penalties, support vector machines, and permanental classification. Unsupervised MLMs included sparse principal components analysis and sparse graphical models. Entropy-based components analyses were also used to mine these data. None of the investigators fully capitalized on the genetic information provided by the complete pedigrees. Their approaches either corrected for the nonindependence of the individuals within the pedigrees or analyzed only those who were independent. Some methods allowed for covariate adjustment, whereas others did not. We evaluated these methods using a variety of metrics. Four contributors conducted primary analyses on the real data, and the other two research groups used the simulated data with and without knowledge of the underlying simulation model. One group used the answers to the simulated data to assess power and type I errors. Although the MLMs applied were substantially different, each research group concluded that MLMs have advantages over standard statistical approaches with these high-dimensional data.
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http://dx.doi.org/10.1002/gepi.21830DOI Listing
September 2014

Cost effectiveness of radioembolization compared with conventional transarterial chemoembolization for treatment of hepatocellular carcinoma.

J Vasc Interv Radiol 2014 Jul 24;25(7):1075-84. Epub 2014 May 24.

Department of Radiology, MD Anderson Cancer Center, University of Texas, Houston, Texas.

Purpose: To assess cost effectiveness of radioembolization versus conventional transarterial chemoembolization.

Materials And Methods: The cost of radioembolization versus conventional transarterial chemoembolization was determined based on Medicare reimbursements. Three patient subgroups were defined based on the Barcelona Clinic Liver Cancer (BCLC) classification system (A, B, or C). Efficacy and safety outcomes after each procedure were obtained from the literature. A Monte Carlo case-based simulation was designed for 60 months in 250 patients in each subgroup. Survival was calculated based on average survival from the literature and the Monte Carlo model. The primary outcome was the cost effectiveness of radioembolization over transarterial chemoembolization by considering calculated survival.

Results: The costs approached $17,000 for transarterial chemoembolization versus $31,000 or $48,000 for unilobar or bilobar radioembolization, respectively. Based on the simulation, median estimated survival was greater with transarterial chemoembolization than radioembolization in BCLC-A and BCLC-B subgroups (40 months vs 30 months and 23 months vs 16 months, respectively, P = .001). However, in the BCLC-C subgroup, survival was greater with radioembolization than transarterial chemoembolization (13 months vs 17 months, P = .001). The incremental cost-effectiveness ratio of radioembolization over transarterial chemoembolization in the BCLC-C subgroup was $360 per month. The results were dependent on bilobar versus unilobar radioembolization and the total number of radioembolization procedures.

Conclusions: The model suggests radioembolization costs may be justified for patients with BCLC-C disease, whereas radioembolization may not be cost effective in patients with BCLC-A disease; however, many patients with BCLC-C disease have extensive disease precluding locoregional therapies. Secondary considerations may determine treatment choice in more borderline patients (BCLC-B disease) because there is no persistent survival benefit with radioembolization.
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http://dx.doi.org/10.1016/j.jvir.2014.04.014DOI Listing
July 2014

Training status diverges muscle diacylglycerol accumulation during free fatty acid elevation.

Am J Physiol Endocrinol Metab 2014 Jul 20;307(1):E124-31. Epub 2014 May 20.

Department of Medicine, Mayo Clinic College of Medicine, Rochester, Minnesota.

How endurance training alters muscle lipid metabolism while preserving insulin sensitivity remains unclear. Because acute free fatty acid (FFA) elevation by lipid infusion reduces insulin sensitivity, we hypothesized that training status would alter accumulation of muscle triacylglycerol (TAG), diacylglycerol (DAG), ceramide, and acylcarnitine during acute FFA elevation. Trained (n = 15) and sedentary (n = 13) participants matched for age, sex, and BMI received either a 6-h infusion of lipid (20% Intralipid at 90 ml/h) or glycerol (2.25 g/100 ml at 90 ml/h) during a hyperinsulinemic euglycemic clamp. Muscle biopsies were taken at 0, 120, and 360 min after infusion initiation to measure intramyocellular concentrations of TAG, DAG, ceramides, and acylcarnitines by liquid chromatography-tandem mass spectrometry. Trained participants had a higher Vo2 max and insulin sensitivity than sedentary participants. The lipid infusion produced a comparable elevation of FFA (594 ± 90 μmol/l in trained, 721 ± 30 μmol/l in sedentary, P = 0.4) and a decline in insulin sensitivity (-44.7% trained vs. -47.2% sedentary, P = 0.89). In both groups, lipid infusion increased the linoleic and linolenic acid content of TAG without changing total TAG. In the sedentary group, lipid infusion increased total, oleic, and linoleic acid and linolenic acid content of DAG. Regardless of training status, lipid infusion did not alter total ceramide, saturated ceramide, palmitoyl-carnitine, or oleoyl-carnitine. We conclude that during acute FFA elevation, trained adults have a similar decline in insulin sensitivity with less accumulation of muscle DAG than sedentary adults, suggesting that lipid-induced insulin resistance can occur without elevation of total muscle DAG.
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http://dx.doi.org/10.1152/ajpendo.00166.2014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4080147PMC
July 2014

Penalized Regression and Risk Prediction in Genome-Wide Association Studies.

Stat Anal Data Min 2013 Aug;6(4)

School of Statistics, University of Minnesota, Minneapolis, MN 55455.

An important task in personalized medicine is to predict disease risk based on a person's genome, e.g. on a large number of single-nucleotide polymorphisms (SNPs). Genome-wide association studies (GWAS) make SNP and phenotype data available to researchers. A critical question for researchers is how to best predict disease risk. Penalized regression equipped with variable selection, such as LASSO and SCAD, is deemed to be promising in this setting. However, the sparsity assumption taken by the LASSO, SCAD and many other penalized regression techniques may not be applicable here: it is now hypothesized that many common diseases are associated with many SNPs with small to moderate effects. In this article, we use the GWAS data from the Wellcome Trust Case Control Consortium (WTCCC) to investigate the performance of various unpenalized and penalized regression approaches under true sparse or non-sparse models. We find that in general penalized regression outperformed unpenalized regression; SCAD, TLP and LASSO performed best for sparse models, while elastic net regression was the winner, followed by ridge, TLP and LASSO, for non-sparse models.
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http://dx.doi.org/10.1002/sam.11183DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3859439PMC
August 2013

Shorter minimum p-wave duration is associated with paroxysmal lone atrial fibrillation.

J Electrocardiol 2014 Jan-Feb;47(1):106-12. Epub 2013 Oct 21.

Cardiovascular Division, Department of Medicine, University of Minnesota, Minneapolis, MN, USA; Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore. Electronic address:

Background And Purpose: Prolonged P-wave dispersion (PWD) and P-wave duration (PWdur) have been found to be associated with common atrial fibrillation (AF), but the association of P-wave indices with lone atrial fibrillation (LAF) is unclear.

Methods: We enrolled 61 paroxysmal LAF cases and 150 controls without AF. P-wave indices were measured from a 12-lead ECG. Multivariable logistic regression was used to assess the association between P-wave indices and LAF.

Results: PWD was longer in LAF patients (median, IQR; 54.1 [42.9-63.2] ms) than controls (46.0 [38.5-57.7] ms), P=0.03. MinPWdur was shorter in LAF patients (60.5 [50.7-72.6] ms) than controls (66.0 [55.5-76.4] ms), P=0.03. In multivariable models, only the association between shorter minPWdur and LAF remained statistically significant (OR [95% CI] per tertile increment in minPWdur, 0.64 [0.42-0.95], P=0.03).

Conclusions: Unlike common AF, paroxysmal LAF is independently associated with shorter minPWdur. This finding suggests that both shorter and prolonged PWdur may be associated with increased risk of AF.
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http://dx.doi.org/10.1016/j.jelectrocard.2013.09.038DOI Listing
August 2014

Operative Technique and Atrial Tachyarrhythmias After Orthotopic Heart Transplantation.

J Atr Fibrillation 2012 Dec 16;5(4):690. Epub 2012 Dec 16.

Cardiac Arrhythmia Center, Cardiovascular Division, Department of Medicine, University of Minnesota Medical School, Minneapolis, MN 55455, USA.

There is conflicting evidence that operative technique affects the risk of atrial tachyarrhythmia after orthotopic heart transplantation (OHT). We sought to determine whether OHT by bicaval (BC) technique is associated with a lower risk of atrial tachyarrhythmia than biatrial (BA) technique. Consecutive patients who underwent OHT between 1997 and 2007 at the University of Minnesota were included in this retrospective cohort study with follow-up through December 31, 2011. We included 260 OHT recipients (BA, 155; BC, 105). Fifty-nine patients (22.7%) developed early atrial tachyarrhythmias. The multivariable odds ratio (95% confidence interval [CI]) of BC technique for early atrial tachyarrhythmias was 0.85 (0.46-1.57), P=0.59. After a median follow-up of 4.9 years, 40 (15.4%) patients developed late atrial tachyarrhythmias. The multivariable hazard ratio (HR) (95% CI) of BC technique for late atrial tachyarrhythmias was 0.99 (0.50-1.96), P=0.98. Graft rejection was found to be a multivariate predictor of late atrial tachyarrhythmias (HR, 2.89; 95% CI, 1.48-5.65; P=0.002). In contrast to prior reports, we did not find an association between operative technique and early or late atrial tachyarrhythmias after OHT. Graft rejection is a risk factor for late atrial tachyarrhythmias after OHT.
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http://dx.doi.org/10.4022/jafib.690DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5153158PMC
December 2012