Subject(s)
Hepatitis B Vaccines/administration & dosage , Hepatitis B Vaccines/immunology , Hepatitis B/prevention & control , Immunosuppressive Agents/administration & dosage , Immunosuppressive Agents/adverse effects , Inflammatory Bowel Diseases/drug therapy , Inflammatory Bowel Diseases/immunology , Tumor Necrosis Factor-alpha/antagonists & inhibitors , Female , Humans , MaleABSTRACT
Menopausal hormone treatment (MHT) may limit progression of cardiovascular disease (CVD) but poses a thrombosis risk. To test targeted candidate gene variation for association with subclinical CVD defined by carotid artery intima-media thickness (CIMT) and coronary artery calcification (CAC), 610 women participating in the Kronos Early Estrogen Prevention Study (KEEPS), a clinical trial of MHT to prevent progression of CVD, were genotyped for 13,229 single nucleotide polymorphisms (SNPs) within 764 genes from anticoagulant, procoagulant, fibrinolytic, or innate immunity pathways. According to linear regression, proportion of European ancestry correlated negatively, but age at enrollment and pulse pressure correlated positively with CIMT. Adjusting for these variables, two SNPs, one on chromosome 2 for MAP4K4 gene (rs2236935, ß = 0.037, P value = 2.36 × 10(-06)) and one on chromosome 5 for IL5 gene (rs739318, ß = 0.051, P value = 5.02 × 10(-05)), associated positively with CIMT; two SNPs on chromosome 17 for CCL5 (rs4796119, ß = -0.043, P value = 3.59 × 10(-05); rs2291299, ß = -0.032, P value = 5.59 × 10(-05)) correlated negatively with CIMT; only rs2236935 remained significant after correcting for multiple testing. Using logistic regression, when we adjusted for waist circumference, two SNPs (rs11465886, IRAK2, chromosome 3, OR = 3.91, P value = 1.10 × 10(-04); and rs17751769, SERPINA1, chromosome 14, OR = 1.96, P value = 2.42 × 10(-04)) associated positively with a CAC score of >0 Agatston unit; one SNP (rs630014, ABO, OR = 0.51, P value = 2.51 × 10(-04)) associated negatively; none remained significant after correcting for multiple testing. Whether these SNPs associate with CIMT and CAC in women randomized to MHT remains to be determined.
Subject(s)
Calcinosis/genetics , Carotid Intima-Media Thickness , Coronary Artery Disease/genetics , Polymorphism, Single Nucleotide/genetics , Adult , Female , Genetic Predisposition to Disease , Humans , Interleukin-5/genetics , Intracellular Signaling Peptides and Proteins/genetics , Middle Aged , Protein Serine-Threonine Kinases/geneticsABSTRACT
OBJECTIVE: To illustrate the effects of failing to account for model uncertainty when modelling is used to estimate the global burden of disease, with specific application to childhood deaths from rotavirus infection. METHODS: To estimate the global burden of rotavirus infection, different random-effects meta-analysis and meta-regression models were constructed by varying the stratification criteria and including different combinations of covariates. Bayesian model averaging was used to combine the results across models and to provide a measure of uncertainty that reflects the choice of model and the sampling variability. FINDINGS: In the models examined, the estimated number of child deaths from rotavirus infection varied between 492,000 and 664,000. While averaging over the different models' estimates resulted in a modest increase in the estimated number of deaths (541,000 as compared with the World Health Organization's estimate of 527,000), the width of the 95% confidence interval increased from 105,000 to 198,000 deaths when model uncertainty was taken into account. CONCLUSION: Sampling variability explains only a portion of the overall uncertainty in a modelled estimate. The uncertainty owing to both the sampling variability and the choice of model(s) should be given when disease burden results are presented. Failure to properly account for uncertainty in disease burden estimates may lead to inappropriate uses of the estimates and inaccurate prioritization of global health needs.
