Correction: Light intensity physical activity and sedentary behavior in relation to body mass index and grip strength in older adults: Cross-sectional findings from the lifestyle interventions and independence for elders (LIFE) study

[This corrects the article DOI: 10.1371/journal.pone.0116058.]

Statistical Power of Model Selection Strategies for Genome-Wide Association Studies

Genome-wide association studies (GWAS) aim to identify genetic variants related to diseases by examining the associations between phenotypes and hundreds of thousands of genotyped markers. Because many genes are potentially involved in common diseases and a large number of markers are analyzed, it is crucial to devise an effective strategy to identify truly associated variants that have individual and/or interactive effects, while controlling false positives at the desired level. Although a number of model selection methods have been proposed in the literature, including marginal search, exhaustive search, and forward search, their relative performance has only been evaluated through limited simulations due to the lack of an analytical approach to calculating the power of these methods. This article develops a novel statistical approach for power calculation, derives accurate formulas for the power of different model selection strategies, and then uses the formulas to evaluate and compare these strategies in genetic model spaces. In contrast to previous studies, our theoretical framework allows for random genotypes, correlations among test statistics, and a false-positive control based on GWAS practice. After the accuracy of our analytical results is validated through simulations, they are utilized to systematically evaluate and compare the performance of these strategies in a wide class of genetic models. For a specific genetic model, our results clearly reveal how different factors, such as effect size, allele frequency, and interaction, jointly affect the statistical power of each strategy. An example is provided for the application of our approach to empirical research. The statistical approach used in our derivations is general and can be employed to address the model selection problems in other random predictor settings. We have developed an R package markerSearchPower to implement our formulas, which can be downloaded from the Comprehensive R Archive Network (CRAN) or http://bioinformatics.med.yale.edu/group/

Common variants of the beta and gamma subunits of the epithelial sodium channel and their relation to plasma renin and aldosterone levels in essential hypertension

BACKGROUND: Rare mutations of the epithelial sodium channel (ENaC) result in the monogenic hypertension form of Liddle's syndrome. We decided to screen for common variants in the ENaC βand γ subunits in patients with essential hypertension and to relate their occurrence to the activity of circulating renin-angiotensin-aldosterone system. METHODS: Initially, DNA samples from 27 patients with low renin/low aldosterone hypertension were examined. The DNA variants were subsequently screened for in 347 patients with treatment-resistant hypertension, 175 male subjects with documented long-lasting normotension and 301 healthy Plasma renin and aldosterone levels were measured under baseline conditions and during postural and captopril challenge tests. RESULTS: Two commonly occurring βENaC variants (G589S and a novel intronic i12-17CT substitution) and one novel γENaC variant (V546I) were detected. One of these variants occurred in a heterozygous form in 32 patients, a prevalence (9.2%) significantly higher than that in normotensive males (2.9%, p = 0.007) and blood donors (3.0%, p = 0.001). βENaC i12-17CT was significantly more prevalent in the hypertension group than in the two control groups combined (4.6% vs. 1.1%, p = 0.001). When expressed in Xenopus oocytes, neither of the two ENaC amino acid-changing variants showed a significant difference in activity compared with ENaC wild-type. No direct evidence for a mRNA splicing defect could be obtained for the βENaC intronic variant. The ratio of daily urinary potassium excretion to upright and mean (of supine and upright values) plasma renin activity was higher in variant allele carriers than in non-carriers (p = 0.034 and p = 0.048). CONCLUSIONS: At least 9% of Finnish patients with hypertension admitted to a specialized center carry genetic variants of β and γENaC, a three times higher prevalence than in the normotensive individuals or in random healthy controls. Patients with the variant alleles showed an increased urinary potassium excretion rate in relation to their renin levels

Worldwide population differentiation at disease-associated SNPs

<p>Abstract</p> <p>Background</p> <p>Recent genome-wide association (GWA) studies have provided compelling evidence of association between genetic variants and common complex diseases. These studies have made use of cases and controls almost exclusively from populations of European ancestry and little is known about the frequency of risk alleles in other populations. The present study addresses the transferability of disease associations across human populations by examining levels of population differentiation at disease-associated single nucleotide polymorphisms (SNPs).</p> <p>Methods</p> <p>We genotyped ~1000 individuals from 53 populations worldwide at 25 SNPs which show robust association with 6 complex human diseases (Crohn's disease, type 1 diabetes, type 2 diabetes, rheumatoid arthritis, coronary artery disease and obesity). Allele frequency differences between populations for these SNPs were measured using Fst. The Fst values for the disease-associated SNPs were compared to Fst values from 2750 random SNPs typed in the same set of individuals.</p> <p>Results</p> <p>On average, disease SNPs are not significantly more differentiated between populations than random SNPs in the genome. Risk allele frequencies, however, do show substantial variation across human populations and may contribute to differences in disease prevalence between populations. We demonstrate that, in some cases, risk allele frequency differences are unusually high compared to random SNPs and may be due to the action of local (i.e. geographically-restricted) positive natural selection. Moreover, some risk alleles were absent or fixed in a population, which implies that risk alleles identified in one population do not necessarily account for disease prevalence in all human populations.</p> <p>Conclusion</p> <p>Although differences in risk allele frequencies between human populations are not unusually large and are thus likely not due to positive local selection, there is substantial variation in risk allele frequencies between populations which may account for differences in disease prevalence between human populations.</p

Rapid increases in obesity in Jamaica, compared to Nigeria and the United States

<p>Abstract</p> <p>Background</p> <p>Weight gain in adulthood is now common in many populations, ranging from modest gains in developing countries to a substantial percentage of body weight in some Western societies. To examine the rate of change across the spectrum of low to high-income countries we compared rates of weight change in samples drawn from three countries, Nigeria, Jamaica and the United States.</p> <p>Methods</p> <p>Population samples from Nigeria (n = 1,242), Jamaica (n = 1,409), and the US (n = 809) were selected during the period 1995–1999 in adults over the age of 19; participation rates in the original survey were 96%, 60%, and 60%, respectively. Weight in (kg) was measured on 3 different occasions, ending in 2005. Multi-level regression models were used to estimate weight change over time and pattern-mixture models were applied to assess the potential effect of missing data on estimates of the model parameters.</p> <p>Results</p> <p>The unadjusted weight gain rate (standard error) was 0.34(0.06), 1.26(0.12), 0.34(0.19) kg/year among men and 0.43(0.06), 1.28(0.10), 0.40(0.15) kg/year among women in Nigeria, Jamaica, US, respectively. Regression-adjusted weight change rates were significantly different across country, sex, and baseline BMI. Adjusted weight gain in Nigeria, Jamaica and US was 0.31(0.05), 1.37(.04), and 0.52(0.05) kg/year respectively. Women in Nigeria and the US had higher weight gains than men, with the converse observed among Jamaicans. The obese experienced weight loss across all three samples, whereas the normal weight (BMI < 25) had significant weight gains. Missing data patterns had an effect on the rates of weight change.</p> <p>Conclusion</p> <p>Weight change in sample cohorts from a middle-income country was greater than in cohorts from either of the low- or high-income countries. The steep trajectory of weight gain in Jamaica, relative to Nigeria and the US, is most likely attributable to the accelerating effects of the cultural and behavioral shifts which have come to bear on transitional societies.</p

Intensive glycemic control is not associated with fractures or falls in the ACCORD randomized trial

OBJECTIVE - Older adults with type 2 diabetes are at high risk of fractures and falls, but the effect of glycemic control on these outcomes is unknown. To determine the effect of intensive versus standard glycemic control, we assessed fractures and falls