Level of confidence evaluation and its usage for Roll-back Recovery with Checkpointing optimization

Increasing soft error rates for semiconductor devices manu- factured in later technologies enforces the use of fault tolerant techniques such as Roll-back Recovery with Checkpointing (RRC). However, RRC introduces time overhead that increases the completion (execution) time. For non-real-time systems, research have focused on optimizing RRC and shown that it is possible to find the optimal number of checkpoints such that the average execution time is minimal. While minimal average execution time is important, it is for real-time systems important to provide a high probability that deadlines are met. Hence, there is a need of probabilistic guarantees that jobs employing RRC complete before a given deadline. First, we present a mathematical framework for the evaluation of level of confidence, the probability that a given deadline is met, when RRC is employed. Second, we present an optimization method for RRC that finds the number of checkpoints that results in the minimal completion time while the minimal com- pletion time satisfies a given level of confidence requirement. Third, we use the proposed framework to evaluate probabilistic guarantees for RRC optimization in non-real-time systems

Impact of BMI and the Metabolic Syndrome on the Risk of Diabetes in Middle-Aged Men

OBJECTIVE The existence of an obese subgroup with a healthy metabolic profile and low diabetes risk has been proposed; yet long-term data are lacking. We aimed to investigate associations between combinations of BMI categories and metabolic syndrome and risk of type 2 diabetes in middle-aged men. RESEARCH DESIGN AND METHODS At age 50, cardiovascular risk factors were assessed in 1,675 participants without diabetes in the community-based Uppsala Longitudinal Study of Adult Men (ULSAM) study. According to BMI/metabolic syndrome status, they were categorized as normal weight (BMI &amp;lt;25 kg/m2) without metabolic syndrome (National Cholesterol Education Program criteria, n = 853), normal weight with metabolic syndrome (n = 60), overweight (BMI 25–30 kg/m2) without metabolic syndrome (n = 557), overweight with metabolic syndrome (n = 117), obese (BMI &amp;gt;30 kg/m2) without metabolic syndrome (n = 28), and obese with metabolic syndrome (n = 60). We investigated the associations between BMI/metabolic syndrome categories at baseline and diabetes incidence. RESULTS After 20 years, 160 participants had developed diabetes. In logistic regression models adjusting for age, smoking, and physical activity, increased risks for diabetes were observed in the normal weight with metabolic syndrome (odds ratio 3.28 [95% CI] 1.38–7.81; P = 0.007), overweight without metabolic syndrome (3.49 [2.26–5.42]; P &amp;lt; 0.001), overweight with metabolic syndrome (7.77 [4.44–13.62]; P &amp;lt; 0.001), obese without metabolic syndrome (11.72 [4.88–28.16]; P &amp;lt; 0.001), and obese with metabolic syndrome (10.06 [5.19–19.51]; P &amp;lt; 0.001) categories compared with the normal weight without metabolic syndrome category. CONCLUSIONS Overweight or obese men without metabolic syndrome were at increased risk for diabetes. Our data provide further evidence that overweight and obesity in the absence of the metabolic syndrome should not be considered a harmless condition. </jats:sec

Urinary Albumin, Sodium, and Potassium and Cardiovascular Outcomes in the UK Biobank: Observational and Mendelian Randomization Analyses.

Urinary biomarkers are associated with cardiovascular disease, but the nature of these associations is not well understood. We performed multivariable-adjusted regression models to assess associations of random spot measurements of the urine sodium-potassium ratio (UNa/UK) and urine albumin adjusted for creatinine with cardiovascular risk factors, cardiovascular disease, and type 2 diabetes mellitus (T2D) in 478 311 participants of the UK Biobank. Further, we assessed the causal relationships of these kidney biomarkers, used as proxies for kidney function, with cardiovascular outcomes using the 2-sample Mendelian randomization approach. In observational analyses, UNa/UK showed significant inverse associations with atrial fibrillation, coronary artery disease, ischemic stroke, lipid-lowering medication, and T2D. In contrast, urine albumin adjusted for creatinine showed significant positive associations with atrial fibrillation, coronary artery disease, heart failure, hemorrhagic stroke, lipid-lowering medication, and T2D. We found a positive association between UNa/UK and albumin with blood pressure (BP), as well as with adiposity-related measures. After correcting for potential horizontal pleiotropy, we found evidence of causal associations of UNa/UK and albumin with BP (β systolic BP ≥2.63; β diastolic BP ≥0.85 SD increase in BP per SD change in UNa/UK and urine albumin adjusted for creatinine; P≤0.04), and of albumin with T2D (odds ratio=1.33 per SD change in albumin, P=0.02). Our comprehensive study of urinary biomarkers performed using state-of-the-art analyses of causality mirror and extend findings from randomized interventional trials which have established UNa/UK as a risk factor for hypertension. In addition, we detect a causal feedback loop between albumin and hypertension, and our finding of a bidirectional causal association between albumin and T2D reflects the well-known nephropathy in T2D

Birthweight, Type 2 Diabetes Mellitus, and Cardiovascular Disease: Addressing the Barker Hypothesis With Mendelian Randomization.

BACKGROUND: Low birthweight has been associated with a higher risk of hypertension, type 2 diabetes mellitus (T2D), and cardiovascular disease. The Barker hypothesis posits that intrauterine growth restriction resulting in lower birthweight is causal for these diseases, but causality is difficult to infer from observational studies. METHODS: We performed regression analyses to assess associations of birthweight with cardiovascular disease and T2D in 237 631 individuals from the UK Biobank. Further, we assessed the causal relationship of such associations using Mendelian randomization. RESULTS: In the observational analyses, birthweight showed inverse associations with systolic and diastolic blood pressure (β, -0.83 and -0.26; per raw unit in outcomes and SD change in birthweight; 95% confidence interval [CI], -0.90 to -0.75 and -0.31 to -0.22, respectively), T2D (odds ratio, 0.83; 95% CI, 0.79-0.87), lipid-lowering treatment (odds ratio, 0.84; 95% CI, 0.81-0.86), and coronary artery disease (hazard ratio, 0.85; 95% CI, 0.78-0.94), whereas the associations with adult body mass index and body fat (β, 0.04 and 0.02; per SD change in outcomes and birthweight; 95% CI, 0.03-0.04 and 0.01-0.02, respectively) were positive. The Mendelian randomization analyses indicated inverse causal associations of birthweight with low-density lipoprotein cholesterol, 2-hour glucose, coronary artery disease, and T2D and positive causal association with body mass index but no associations with blood pressure. CONCLUSIONS: Our study indicates that lower birthweight, used as a proxy for intrauterine growth retardation, is causally related with increased susceptibility to coronary artery disease and T2D. This causal relationship is not mediated by adult obesity or hypertension

Genetic and methylation variation in the CYP2B6 gene is related to circulating p,p′-dde levels in a population-based sample

AbstractObjectivesSince the metabolism of the organochlorine pesticide dichlorodiphenyltrichloroethane (DDT) is not fully known in humans, we evaluated if circulating levels of a major breakdown product of DDT, p,p′-DDE, were related to genome-wide genetic and methylation variation in a population-based sample.MethodsIn the population-based Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) study (1016 subjects all aged 70), circulating levels of p,p′-DDE were analyzed by high-resolution chromatography coupled to high-resolution mass spectrometry (HRGC/HRMS). Genetic variants were genotyped and imputed (1000 Genomes reference, March 2012 release). Methylation sites were assayed using the Illumina HumanMethylation450 array in whole blood. A genome-wide association study (GWAS) approach was applied.ResultsEvidence for genome-wide significant association with p,p′-DDE levels was observed only for a locus at chromosome 19 corresponding to the CYP2B6 gene (lead SNP rs7260538). Subjects being homozygote for the G allele showed a median level of 472ng/g lipid, while the corresponding level for those being homozygote for the T allele was 192ng/g lipid (p=1.5×10−31). An analysis conditioned on the lead SNP disclosed a distinct signal in the same gene (rs7255374, position chr19:41520351; p=2.2×10−8).A whole-genome methylation analysis showed one significant relationship vs. p,p′-DDE levels (p=6.2×10−9) located 7kb downstream the CYP2B6 gene (cg27089200, position chr19:41531976). This CpG-site was also related to the lead SNP (p=3.8×10−35), but mediated only 4% of the effect of the lead SNP on p,p′-DDE levels.ConclusionCirculating levels of p,p′-DDE were related to genetic variation in the CYP2B6 gene in the general elderly population. DNA methylation in this gene is not closely linked to the p,p′-DDE levels

Early exposure to dogs and farm animals and the risk of childhood asthma

IMPORTANCE: The association between early exposure to animals and childhood asthma is not clear, and previous studies have yielded contradictory results. OBJECTIVE: To determine whether exposure to dogs and farm animals confers a risk of asthma. DESIGN, SETTING AND PARTICIPANTS: In a nationwide cohort study, the association between early exposure to dogs and farm animals and the risk of asthma was evaluated and included all children born in Sweden from January 1, 2001, to December 31, 2010 (N = 1,011,051), using registry data on dog and farm registration, asthma medication, diagnosis, and confounders for parents and their children. The association was assessed as the odds ratio (OR) for a current diagnosis of asthma at age 6 years for school-aged children and as the hazard ratio (HR) for incident asthma at ages 1 to 5 years for preschool-aged children. Data were analyzed from January 1, 2007, to September 30, 2012. EXPOSURES: Living with a dog or farm animal. MAIN OUTCOMES AND MEASURES: Childhood asthma diagnosis and medication used. RESULTS: Of the 1,011,051 children born during the study period, 376,638 preschool-aged (53,460 [14.2%] exposed to dogs and 1729 [0.5%] exposed to farm animals) and 276,298 school-aged children (22,629 [8.2%] exposed to dogs and 958 [0.3%] exposed to farm animals) were included in the analyses. Of these, 18,799 children (5.0%) in the preschool-aged children's cohort experienced an asthmatic event before baseline, and 28,511 cases of asthma and 906,071 years at risk were recorded during follow-up (incidence rate, 3.1 cases per 1000 years at risk). In the school-aged children's cohort, 11,585 children (4.2%) experienced an asthmatic event during the seventh year of life. Dog exposure during the first year of life was associated with a decreased risk of asthma in school-aged children (OR, 0.87; 95% CI, 0.81-0.93) and in preschool-aged children 3 years or older (HR, 0.90; 95% CI, 0.83-0.99) but not in children younger than 3 years (HR, 1.03; 95% CI, 1.00-1.07). Results were comparable when analyzing only first-born children. Farm animal exposure was associated with a reduced risk of asthma in both school-aged children and preschool-aged children (OR, 0.48; 95% CI, 0.31-0.76, and HR, 0.69; 95% CI, 0.56-0.84), respectively. CONCLUSIONS AND RELEVANCE: In this study, the data support the hypothesis that exposure to dogs and farm animals during the first year of life reduces the risk of asthma in children at age 6 years. This information might be helpful in decision making for families and physicians on the appropriateness and timing of early animal exposure.NonePublishe

Clinical Conditions and Their Impact on Utility of Genetic Scores for Prediction of Acute Coronary Syndrome

Background: Acute coronary syndrome (ACS) is a clinically significant presentation of coronary heart disease. Genetic information has been proposed to improve prediction beyond well-established clinical risk factors. While polygenic scores (PS) can capture an individual's genetic risk for ACS, its prediction performance may vary in the context of diverse correlated clinical conditions. Here, we aimed to test whether clinical conditions impact the association between PS and ACS. Methods: We explored the association between 405 clinical conditions diagnosed before baseline and 9080 incident cases of ACS in 387 832 individuals from the UK Biobank. Results were replicated in 6430 incident cases of ACS in 177 876 individuals from FinnGen. Results: We identified 80 conventional (eg, stable angina pectoris and type 2 diabetes) and unconventional (eg, diaphragmatic hernia and inguinal hernia) associations with ACS. The association between PS and ACS was consistent in individuals with and without most clinical conditions. However, a diagnosis of stable angina pectoris yielded a differential association between PS and ACS. PS was associated with a significantly reduced (interaction P=2.87x10(-8)) risk for ACS in individuals with stable angina pectoris (hazard ratio, 1.163 [95% CI, 1.082-1.251]) compared with individuals without stable angina pectoris (hazard ratio, 1.531 [95% CI, 1.497-1.565]). These findings were replicated in FinnGen (interaction P=1.38x10(-6)). Conclusions: In summary, while most clinical conditions did not impact utility of PS for prediction of ACS, we found that PS was substantially less predictive of ACS in individuals with prevalent stable coronary heart disease. PS may be more appropriate for prediction of ACS in asymptomatic individuals than symptomatic individuals with clinical suspicion for coronary heart disease.Peer reviewe