Citations

ABSTRACTMany important complex diseases are composed of a series of phenotypes, which makes the disease diagnosis and its genetic dissection difficult. The standard procedures to determine heritability in such complex diseases are either applied for single phenotype analyses or to compare findings across phenotypes or multidimensional reduction procedures, such as principal components analysis using all phenotypes. However each method has its own problems and the challenges are even more complex for extended family data and categorical phenotypes. In this paper, we propose a methodology to determine a scale for complex outcomes involving multiple categorical phenotypes in extended pedigrees using item response theory (IRT) models that take all categorical phenotypes into account, allowing informative comparison among individuals. An advantage of the IRT framework is that a straightforward joint heritability parameter can be estimated for categorical phenotypes. Furthermore, our methodology allows many possible extensions such as the inclusion of covariates and multiple variance components. We use Markov Chain Monte Carlo algorithm for the parameter estimation and validate our method through simulated data. As an application we consider the metabolic syndrome as the multiple phenotype disease using data from the Baependi Heart Study consisting of 1,696 individuals in 95 families. We adjust IRT models without covariates and include age and age squared as covariates. The results showed that adjusting for covariates yields a higher joint heritability () than without co variates () indicating that the covariates absorbed some of the error variance.

ABSTRACTVenous thromboembolism (VTE) is a common, heritable disease resulting in high rates of hospitalization and mortality. Yet few associations between VTE and genetic variants, all in the coagulation pathway, have been established. To identify additional genetic determinants of VTE, we conducted a two‐stage genome‐wide association study (GWAS) among individuals of European ancestry in the extended cohorts for heart and aging research in genomic epidemiology (CHARGE) VTE consortium. The discovery GWAS comprised 1,618 incident VTE cases out of 44,499 participants from six community‐based studies. Genotypes for genome‐wide single‐nucleotide polymorphisms (SNPs) were imputed to approximately 2.5 million SNPs in HapMap and association with VTE assessed using study‐design appropriate regression methods. Meta‐analysis of these results identified two known loci, in F5 and ABO. Top 1,047 tag SNPs (P ≤ 0.0016) from the discovery GWAS were tested for association in an additional 3,231 cases and 3,536 controls from three case‐control studies. In the combined data from these two stages, additional genome‐wide significant associations were observed on 4q35 at F11 (top SNP rs4253399, intronic to F11) and on 4q28 at FGG (rs6536024, 9.7 kb from FGG; P < 5.0 × 10−13 for both). The associations at the FGG locus were not completely explained by previously reported variants. Loci at or near SUSD1 and OTUD7A showed borderline yet novel associations (P < 5.0 × 10−6) and constitute new candidate genes. In conclusion, this large GWAS replicated key genetic associations in F5 and ABO, and confirmed the importance of F11 and FGG loci for VTE. Future studies are warranted to better characterize the associations with F11 and FGG and to replicate the new candidate associations.

BACKGROUNDApproximately 1.7 million individuals per year are affected with health care‐associated infections (HAIs) in the United States. The authors examined trends in the incidence of HAI after major cancer surgery (MCS) and risk factors for HAI to describe the effects of HAI on mortality after MCS.METHODSPatients undergoing 1 of 8 MCS procedures within the Nationwide Inpatient Sample between 1999 and 2009 were identified (n = 2,502,686). Generalized linear regression models were used to estimate the impact of the primary predictors (procedure type, age, sex, race, insurance status, Charlson comorbidity index, hospital volume, and hospital bed size) on the odds of HAI and in‐hospital mortality. Trends in incidence were evaluated with linear regression.RESULTSOverall, MCS‐associated HAI incidence increased 2.7% per year (P < .001), whereas mortality decreased 1.3% per year (P < .001). Male gender (odds ratio [OR], 1.12, 95% confidence interval [CI], 1.10‐1.14), advancing age (OR, 1.02; 95% CI, 1.02‐1.02), black race (OR, 1.26; 95% CI, 1.21‐1.31), ≥1 comorbidities (OR, from 1.08 [95% CI, 1.04‐1.13] to 1.31 [95% CI, 1.27‐1.35]), and nonprivate insurance (OR, from 1.18 [95% CI, 1.15‐1.22] to 1.67 [95% CI, 1.59‐1.76]) were associated with an increased odds of HAI on multivariable analysis. Conversely, increasing hospital volume was associated with lower odds of HAI (OR, 0.999; 95% CI, 0.99‐0.99). Patients with MCS‐associated HAI had increased odds of mortality (OR, 8.66; 95% CI, 8.51‐8.82).CONCLUSIONSBetween 1999 and 2009, the incidence of MCS‐associated HAI events increased; however, HAI‐associated mortality decreased. That said, significant disparities exist in the hospital and demographic attributes associated with MCS‐associated HAI, with attendant health policy implications. Moreover, HAI remains detrimentally linked to mortality during hospitalization. Cancer 2013;119:2317–2324. © 2013 American Cancer Society.

Background— The importance of complete revascularization remains unclear and contradictory. This current investigation compares the effect of complete revascularization on 10-year survival of patients with stable multivessel coronary artery disease (CAD) who were randomly assigned to percutaneous coronary intervention (PCI) or coronary artery bypass graft (CABG). Methods and Results— This is a post hoc analysis of the Second Medicine, Angioplasty, or Surgery Study (MASS II), which is a randomized trial comparing treatments in patients with stable multivessel CAD, and preserved systolic ventricular function. We analyzed patients who underwent surgery (CABG) or stent angioplasty (PCI). The survival free of overall mortality of patients who underwent complete (CR) or incomplete revascularization (IR) was compared. Of the 408 patients randomly assigned to mechanical revascularization, 390 patients (95.6%) underwent the assigned treatment; complete revascularization was achieved in 224 patients (57.4%), 63.8% of those in the CABG group and 36.2% in the PCI group ( P =0.001). The IR group had more prior myocardial infarction than the CR group (56.2%×39.2%, P =0.01). During a 10-year follow-up, the survival free of cardiovascular mortality was significantly different among patients in the 2 groups (CR, 90.6% versus IR, 84.4%; P =0.04). This was mainly driven by an increased cardiovascular specific mortality in individuals with incomplete revascularization submitted to PCI ( P =0.05). Conclusions— Our study suggests that in 10-year follow-up, CR compared with IR was associated with reduced cardiovascular mortality, especially due to a higher increase in cardiovascular-specific mortality in individuals submitted to PCI. Clinical Trial Registration Information— URL: http://www.controlled-trials.com . Registration number: ISRCTN66068876.

AbstractProtein synthesis determines sensitivity of differentiating and malignant plasma cells to proteasome inhibitors by saturating cellular proteolytic capacity.A previously unsuspected, considerable proportion of newly synthesized polypeptides are hydrolyzed rapidly by proteasomes, possibly competing with endogenous substrates and altering proteostasis. In view of the anti-cancer effects of PIs, we set out to achieve a quantitative assessment of proteasome workload in cells hallmarked by different PI sensitivity, namely, a panel of MM cells, and in a dynamic model of plasma cell differentiation, a process that confers exquisite PI sensitivity. Our results suggest that protein synthesis is a key determinant of proteasomal proteolytic burden and PI sensitivity. In different MM cells and in differentiating plasma cells, the average proteolytic work accomplished per proteasome ranges over different orders of magnitude, an unexpected degree of variability, with increased workload invariably associated to increased PI sensitivity. The unfavorable load-versus-capacity balance found in highly PI-sensitive MM lines is accounted for by a decreased total number of immunoproteasomes/cell coupled to enhanced generation of RDPs. Moreover, indicative of cause-effect relationships, attenuating general protein synthesis by the otherwise toxic agent CHX reduces PI sensitivity in activated B and in MM cells. Our data support the view that in plasma cells protein synthesis contributes to determine PI sensitivity by saturating the proteasomal degradative capacity. Quantitating protein synthesis and proteasome workload may thus prove crucial to design novel negative proteostasis regulators against cancer.

AbstractThe endothelial protein C receptor (EPCR) limits thrombus formation by enhancing activation of the protein C anticoagulant pathway, and therefore may play a role in the etiology of thrombotic disorders. The rs867186 single-nucleotide polymorphism in the PROCR gene (g.6936A > G, c.4600A > G), resulting in a serine-to-glycine substitution at codon 219, has been associated with reduced activation of the protein C pathway, although its association with thrombosis risk remains unclear. The present study is a highly comprehensive systematic review and meta-analysis, including unpublished genome-wide association study results, conducted to evaluate the evidence for an association between rs867186 and 2 common thrombotic outcomes, venous thromboembolism (VTE) and myocardial infarction (MI), which are hypothesized to share some etiologic pathways. MEDLINE, EMBASE, and HuGE Navigator were searched through July 2011 to identify relevant epidemiologic studies, and data were summarized using random-effects meta-analysis. Twelve candidate genes and 13 genome-wide association studies were analyzed (11 VTE and 14 MI, including 37 415 cases and 84 406 noncases). Under the additive genetic model, the odds of VTE increased by a factor of 1.22 (95% confidence interval, 1.11-1.33, P < .001) for every additional copy of the G allele. No evidence for association with MI was observed.

Background— Coronary artery bypass graft surgery with cardiopulmonary bypass is a safe, routine procedure. Nevertheless, significant morbidity remains, mostly because of the body’s response to the nonphysiological nature of cardiopulmonary bypass. Few data are available on the effects of off-pump coronary artery bypass graft surgery (OPCAB) on cardiac events and long-term clinical outcomes. Methods and Results— In a single-center randomized trial, 308 patients undergoing coronary artery bypass graft surgery were randomly assigned: 155 to OPCAB and 153 to on-pump CAB (ONCAB). Primary composite end points were death, myocardial infarction, further revascularization (surgery or angioplasty), or stroke. After 5-year follow-up, the primary composite end point was not different between groups (hazard ratio 0.71, 95% CI 0.41 to 1.22; P =0.21). A statistical difference was found between OPCAB and ONCAB groups in the duration of surgery (240±65 versus 300±87.5 minutes; P <0.001), in the length of ICU stay (19.5±17.8 versus 43±17.0 hours; P <0.001), time to extubation (4.6±6.8 versus 9.3±5.7 hours; P <0.001), hospital stay (6±2 versus 9±2 days; P <0.001), higher incidence of atrial fibrillation (35 versus 4% of patients; P <0.001), and blood requirements (31 versus 61% of patients; P <0.001), respectively. The number of grafts per patient was higher in the ONCAB than the OPCAB group (2.97 versus 2.49 grafts/patient; P <0.001). Conclusions— No difference was found between groups in the primary composite end point at 5-years follow-up. Although OPCAB surgery was related to a lower number of grafts and higher episodes of atrial fibrillation, it had no significant implications related to long-term outcomes. Clinical Trial Registration— URL: http://www.controlled-trials.com. Unique identifier: ISRCTN66068876.

Background— This study compared the 10-year follow-up of percutaneous coronary intervention (PCI), coronary artery surgery (CABG), and medical treatment (MT) in patients with multivessel coronary artery disease, stable angina, and preserved ventricular function. Methods and Results— The primary end points were overall mortality, Q-wave myocardial infarction, or refractory angina that required revascularization. All data were analyzed according to the intention-to-treat principle. At a single institution, 611 patients were randomly assigned to CABG (n=203), PCI (n=205), or MT (n=203). The 10-year survival rates were 74.9% with CABG, 75.1% with PCI, and 69% with MT ( P =0.089). The 10-year rates of myocardial infarction were 10.3% with CABG, 13.3% with PCI, and 20.7% with MT ( P <0.010). The 10-year rates of additional revascularizations were 7.4% with CABG, 41.9% with PCI, and 39.4% with MT ( P <0.001). Relative to the composite end point, Cox regression analysis showed a higher incidence of primary events in MT than in CABG (hazard ratio 2.35, 95% confidence interval 1.78 to 3.11) and in PCI than in CABG (hazard ratio 1.85, 95% confidence interval 1.39 to 2.47). Furthermore, 10-year rates of freedom from angina were 64% with CABG, 59% with PCI, and 43% with MT ( P <0.001). Conclusions— Compared with CABG, MT was associated with a significantly higher incidence of subsequent myocardial infarction, a higher rate of additional revascularization, a higher incidence of cardiac death, and consequently a 2.29-fold increased risk of combined events. PCI was associated with an increased need for further revascularization, a higher incidence of myocardial infarction, and a 1.46-fold increased risk of combined events compared with CABG. Additionally, CABG was better than MT at eliminating anginal symptoms. Clinical Trial Registration Information— URL: http://www.controlled-trials.com. Registration number: ISRCTN66068876.