122 research outputs found
Measurement of the Remaining In-Plane Polarization Transfer Coefficients for the 10-B(p,p') 10-B Reaction at 200 MeV
This research was sponsored by the National Science Foundation Grant NSF PHY-931478
Medium Effects in the Normal Component Polarization Observables for the 13-C(p,p')13-C, (1/2)- → (9/2)+ Reaction at 200 MeV
This research was sponsored by the National Science Foundation Grant NSF PHY-931478
Cost-effectiveness of Evolocumab therapy for reducing cardiovascular events in patients with atherosclerotic cardiovascular disease
Importance: The proprotein convertase subtilisin/kexin type 9 inhibitor evolocumab has been demonstrated to reduce the composite of myocardial infarction, stroke, or cardiovascular death in patients with established atherosclerotic cardiovascular disease. To our knowledge, long-term cost-effectiveness of this therapy has not been evaluated using clinical trial efficacy data. Objective: To evaluate the cost-effectiveness of evolocumab in patients with atherosclerotic cardiovascular disease when added to standard background therapy. Design, Setting, and Participants: A Markov cohort state-transition model was used, integrating US population-specific demographics, risk factors, background therapy, and event rates along with trial-based event risk reduction. Costs, including price of drug, utilities, and transitional probabilities, were included from published sources. Exposures: Addition of evolocumab to standard background therapy including statins. Main Outcomes and Measures: Cardiovascular events including myocardial infarction, ischemic stroke and cardiovascular death, quality-adjusted life-year (QALY), incremental cost-effectiveness ratio (ICER), and net value-based price. Results: In the base case, using US clinical practice patients with atherosclerotic cardiovascular disease with low-density lipoprotein cholesterol levels of at least 70 mg/dL (to convert to millimoles per liter, multiply by 0.0259) and an annual events rate of 6.4 per 100 patient-years, evolocumab was associated with increased cost and improved QALY: incremental cost, 268 637 per QALY gained (10 311 based on mean rebate of 29% for branded pharmaceuticals). Sensitivity and scenario analyses demonstrated ICERs ranging from 488 642 per QALY, with ICER of 270 192 with discounted price of 483 800 if no cardiovascular mortality reduction emerges. Evolocumab treatment exceeded 9669 (10 311 in patients with low-density lipoprotein cholesterol levels of at least 80 mg/dL. Conclusions and Relevance: At its current list price of 150 000 per QALY, the annual net price would need to be substantially lower (6780 for trial participants), or a higher-risk population would need to be treated
The Physiology of Vasodilatation
Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/68237/2/10.1177_000331976101200602.pd
Identification of a novel proinsulin-associated SNP and demonstration that proinsulin is unlikely to be a causal factor in subclinical vascular remodelling using Mendelian randomisation
Background and aims Increased proinsulin relative to insulin levels have been associated with subclinical atherosclerosis (measured by carotid intima-media thickness (cIMT)) and are predictive of future cardiovascular disease (CVD), independently of established risk factors. The mechanisms linking proinsulin to atherosclerosis and CVD are unclear. A genome-wide meta-analysis has identified nine loci associated with circulating proinsulin levels. Using proinsulin-associated SNPs, we set out to use a Mendelian randomisation approach to test the hypothesis that proinsulin plays a causal role in subclinical vascular remodelling. Methods We studied the high CVD-risk IMPROVE cohort (n = 3345), which has detailed biochemical phenotyping and repeated, state-of-the-art, high-resolution carotid ultrasound examinations. Genotyping was performed using Illumina Cardio-Metabo and Immuno arrays, which include reported proinsulin-associated loci. Participants with type 2 diabetes (n = 904) were omitted from the analysis. Linear regression was used to identify proinsulin-associated genetic variants. Results We identified a proinsulin locus on chromosome 15 (rs8029765) and replicated it in data from 20,003 additional individuals. An 11-SNP score, including the previously identified and the chromosome 15 proinsulin-associated loci, was significantly and negatively associated with baseline IMTmean and IMTmax (the primary cIMT phenotypes) but not with progression measures. However, MR-Eggers refuted any significant effect of the proinsulin-associated 11-SNP score, and a non-pleiotropic SNP score of three variants (including rs8029765) demonstrated no effect on baseline or progression cIMT measures. Conclusions We identified a novel proinsulin-associated locus and demonstrated that whilst proinsulin levels are associated with cIMT measures, proinsulin per se is unlikely to have a causative effect on cIMT
Identification and Functional Characterization of G6PC2 Coding Variants Influencing Glycemic Traits Define an Effector Transcript at the G6PC2-ABCB11 Locus
Genome wide association studies (GWAS) for fasting glucose (FG) and insulin (FI) have identified common variant signals which explain 4.8% and 1.2% of trait variance, respectively. It is hypothesized that low-frequency and rare variants could contribute substantially to unexplained genetic variance. To test this, we analyzed exome-array data from up to 33,231 non-diabetic individuals of European ancestry. We found exome-wide significant (P<5×10-7) evidence for two loci not previously highlighted by common variant GWAS: GLP1R (p.Ala316Thr, minor allele frequency (MAF)=1.5%) influencing FG levels, and URB2 (p.Glu594Val, MAF = 0.1%) influencing FI levels. Coding variant associations can highlight potential effector genes at (non-coding) GWAS signals. At the G6PC2/ABCB11 locus, we identified multiple coding variants in G6PC2 (p.Val219Leu, p.His177Tyr, and p.Tyr207Ser) influencing FG levels, conditionally independent of each other and the non-coding GWAS signal. In vitro assays demonstrate that these associated coding alleles result in reduced protein abundance via proteasomal degradation, establishing G6PC2 as an effector gene at this locus. Reconciliation of single-variant associations and functional effects was only possible when haplotype phase was considered. In contrast to earlier reports suggesting that, paradoxically, glucose-raising alleles at this locus are protective against type 2 diabetes (T2D), the p.Val219Leu G6PC2 variant displayed a modest but directionally consistent association with T2D risk. Coding variant associations for glycemic traits in GWAS signals highlight PCSK1, RREB1, and ZHX3 as likely effector transcripts. These coding variant association signals do not have a major impact on the trait variance explained, but they do provide valuable biological insights
A review of spatial causal inference methods for environmental and epidemiological applications
The scientific rigor and computational methods of causal inference have had
great impacts on many disciplines, but have only recently begun to take hold in
spatial applications. Spatial casual inference poses analytic challenges due to
complex correlation structures and interference between the treatment at one
location and the outcomes at others. In this paper, we review the current
literature on spatial causal inference and identify areas of future work. We
first discuss methods that exploit spatial structure to account for unmeasured
confounding variables. We then discuss causal analysis in the presence of
spatial interference including several common assumptions used to reduce the
complexity of the interference patterns under consideration. These methods are
extended to the spatiotemporal case where we compare and contrast the potential
outcomes framework with Granger causality, and to geostatistical analyses
involving spatial random fields of treatments and responses. The methods are
introduced in the context of observational environmental and epidemiological
studies, and are compared using both a simulation study and analysis of the
effect of ambient air pollution on COVID-19 mortality rate. Code to implement
many of the methods using the popular Bayesian software OpenBUGS is provided
Common variants near MC4R are associated with fat mass, weight and risk of obesity.
To identify common variants influencing body mass index (BMI), we analyzed genome-wide association data from 16,876 individuals of European descent. After previously reported variants in FTO, the strongest association signal (rs17782313, P = 2.9 x 10(-6)) mapped 188 kb downstream of MC4R (melanocortin-4 receptor), mutations of which are the leading cause of monogenic severe childhood-onset obesity. We confirmed the BMI association in 60,352 adults (per-allele effect = 0.05 Z-score units; P = 2.8 x 10(-15)) and 5,988 children aged 7-11 (0.13 Z-score units; P = 1.5 x 10(-8)). In case-control analyses (n = 10,583), the odds for severe childhood obesity reached 1.30 (P = 8.0 x 10(-11)). Furthermore, we observed overtransmission of the risk allele to obese offspring in 660 families (P (pedigree disequilibrium test average; PDT-avg) = 2.4 x 10(-4)). The SNP location and patterns of phenotypic associations are consistent with effects mediated through altered MC4R function. Our findings establish that common variants near MC4R influence fat mass, weight and obesity risk at the population level and reinforce the need for large-scale data integration to identify variants influencing continuous biomedical traits
Meta-analysis of type 2 Diabetes in African Americans Consortium
Type 2 diabetes (T2D) is more prevalent in African Americans than in Europeans. However, little is known about the genetic risk in African Americans despite the recent identification of more than 70 T2D loci primarily by genome-wide association studies (GWAS) in individuals of European ancestry. In order to investigate the genetic architecture of T2D in African Americans, the MEta-analysis of type 2 DIabetes in African Americans (MEDIA) Consortium examined 17 GWAS on T2D comprising 8,284 cases and 15,543 controls in African Americans in stage 1 analysis. Single nucleotide polymorphisms (SNPs) association analysis was conducted in each study under the additive model after adjustment for age, sex, study site, and principal components. Meta-analysis of approximately 2.6 million genotyped and imputed SNPs in all studies was conducted using an inverse variance-weighted fixed effect model. Replications were performed to follow up 21 loci in up to 6,061 cases and 5,483 controls in African Americans, and 8,130 cases and 38,987 controls of European ancestry. We identified three known loci (TCF7L2, HMGA2 and KCNQ1) and two novel loci (HLA-B and INS-IGF2) at genome-wide significance (4.15 × 10(-94)<P<5 × 10(-8), odds ratio (OR) = 1.09 to 1.36). Fine-mapping revealed that 88 of 158 previously identified T2D or glucose homeostasis loci demonstrated nominal to highly significant association (2.2 × 10(-23) < locus-wide P<0.05). These novel and previously identified loci yielded a sibling relative risk of 1.19, explaining 17.5% of the phenotypic variance of T2D on the liability scale in African Americans. Overall, this study identified two novel susceptibility loci for T2D in African Americans. A substantial number of previously reported loci are transferable to African Americans after accounting for linkage disequilibrium, enabling fine mapping of causal variants in trans-ethnic meta-analysis studies.Peer reviewe
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