Catechol-O-methyl-transferase functional polymorphism and nicotine dependence: an evaluation of nonreplicated results.

Review articles have focused attention on and cited possible reasons for the nonreplication of genetic association studies. Herein, we illustrate how one might work through these possible reasons to make a judgment about the most plausible reason(s) when faced with two or more studies which yield seemingly inconsistent results. In the first study, 342 treatment-seeking smokers were genotyped for the Val108Met polymorphism in the functional catechol-O-methyl-transferase (COMT) locus.

Bayesian model selection for genome-wide epistatic quantitative trait loci analysis.

The problem of identifying complex epistatic quantitative trait loci (QTL) across the entire genome continues to be a formidable challenge for geneticists. The complexity of genome-wide epistatic analysis results mainly from the number of QTL being unknown and the number of possible epistatic effects being huge. In this article, we use a composite model space approach to develop a Bayesian model selection framework for identifying epistatic QTL for complex traits in experimental crosses from two inbred lines.

Intentional weight loss reduces mortality rate in a rodent model of dietary obesity.

Objective: We used a rodent model of dietary obesity to evaluate effects of caloric restriction-induced weight loss on mortality rate. Research Measures and Procedures: In a randomized parallel-groups design, 312 outbred Sprague-Dawley rats (one-half males) were assigned at age 10 weeks to one of three diets: low fat (LF; 18.7% calories as fat) with caloric intake adjusted to maintain body weight 10% below that for ad libitum (AL)-fed rat food, high fat (HF; 45% calories as fat) fed at the same level, or HF fed AL.

Dietary supplements in weight reduction.

We summarize evidence on the role of dietary supplements in weight reduction, with particular attention to their safety and benefits. Dietary supplements are used for two purposes in weight reduction: (a) providing nutrients that may be inadequate in calorie-restricted diets and (b) for their potential benefits in stimulating weight loss. The goal in planning weight-reduction diets is that total intake from food and supplements should meet recommended dietary allowance/adequate intake levels without greatly exceeding them for all nutrients, except energy.

HDBStat!: a platform-independent software suite for statistical analysis of high dimensional biology data.

Background: Many efforts in microarray data analysis are focused on providing tools and methods for the qualitative analysis of microarray data. HDBStat! (High-Dimensional Biology-Statistics) is a software package designed for analysis of high dimensional biology data such as microarray data. It was initially developed for the analysis of microarray gene expression data, but it can also be used for some applications in proteomics and other aspects of genomics.

Peering into the future of American longevity.

Extract: The trend in the life expectancy of humans during the past thousand years has been generally characterized by a slow, steady increase -- though this pattern is frequently punctuated by volatility in death rates caused by epidemic and pandemic infectious diseases, famines, and war. This volatility was dramatically curtailed in the mid-19th century as infectious agents swiftly succumbed to improved living conditions, advances in public health, and medical interventions. During the past 30 years in the United States, the rise in life expectancy at birth has decelerated relative to this historic pattern, and gains in life expectancy at older ages are now much smaller than they were in previous decades.

A potential decline in life expectancy in the United States in the 21st century.

Forecasts of life expectancy are an important component of public policy that influence age-based entitlement programs such as Social Security and Medicare. Although the Social Security Administration recently raised its estimates of how long Americans are going to live in the 21st century, current trends in obesity in the United States suggest that these estimates may not be accurate. From our analysis of the effect of obesity on longevity, we conclude that the steady rise in life expectancy during the past two centuries may soon come to an end.

The effects of intentional weight loss as a latent variable problem.

Although obesity is associated with increased mortality rate and short-term weight loss improves risk factors for mortality, it has not been convincingly shown that weight loss among obese people results in reduced mortality rate. When considering the human literature, it has been pointed out that weight loss is often a sign of illness and that investigators therefore need to separate intentional from unintentional weight loss. It has generally been assumed that among people who state that they do not intend to lose weight, weight change subsequently observed is unintentional.

Glucose metabolism in patients with schizophrenia treated with atypical antipsychotic agents: a frequently sampled intravenous glucose tolerance test and minimal model analysis.

Background: While the incidence of new-onset diabetes mellitus may be increasing in patients with schizophrenia treated with certain atypical antipsychotic agents, it remains unclear whether atypical agents are directly affecting glucose metabolism or simply increasing known risk factors for diabetes.

Objective: To study the 2 drugs most clearly implicated (clozapine and olanzapine) and risperidone using a frequently sampled intravenous glucose tolerance test.

Design: A cross-sectional design in stable, treated patients with schizophrenia evaluated using a frequently sampled intravenous glucose tolerance test and the Bergman minimal model analysis.

New joint covariance- and marginal-based tests for association and linkage for quantitative traits for random and non-random sampling.

We develop novel statistical tests for transmission disequilibrium testing (tests of linkage in the presence of association) for quantitative traits using parents and offspring. These joint tests utilize information in both the covariance (or more generally, dependency) between genotype and phenotype and the marginal distribution of genotype. Using computer simulation we test the validity (Type I error rate control) and power of the proposed methods, for additive, dominant, and recessive modes of inheritance, locus-specific heritability of the trait 0.

Insufficient production and tissue delivery of CD4+ memory T cells in rapidly progressive simian immunodeficiency virus infection.

The mechanisms linking human immunodeficiency virus replication to the progressive immunodeficiency of acquired immune deficiency syndrome are controversial, particularly the relative contribution of CD4+ T cell destruction. Here, we used the simian immunodeficiency virus (SIV) model to investigate the relationship between systemic CD4+ T cell dynamics and rapid disease progression. Of 18 rhesus macaques (RMs) infected with CCR5-tropic SIVmac239 (n=14) or CXCR4-tropic SIVmac155T3 (n=4), 4 of the former group manifested end-stage SIV disease by 200 d after infection.

Overweight, obesity, and colorectal cancer screening: disparity between men and women.

Background: To estimate the association between body-mass index (BMI: kg/m2) and colorectal cancer (CRC) screening among US adults aged >or= 50 years.

Methods: Population-based data from the 2001 Behavioral Risk Factor Surveillance Survey. Adults (N = 84,284) aged >or= 50 years were classified by BMI as normal weight (18.

Clinical implications of obesity with specific focus on cardiovascular disease: a statement for professionals from the American Heart Association Council on Nutrition, Physical Activity, and Metabolism: endorsed by the American College of Cardiology Foundation.

Obesity adversely affects cardiac function, increases the risk factors for coronary heart disease, and is an independent risk factor for cardiovascular disease. The risk of developing coronary heart disease is directly related to the concomitant burden of obesity-related risk factors. Modest weight loss can improve diastolic function and affect the entire cluster of coronary heart disease risk factors simultaneously.

Joint tests for quantitative trait loci in experimental crosses.

Selective genotyping is common because it can increase the expected correlation between QTL genotype and phenotype and thus increase the statistical power of linkage tests (i.e., regression-based tests).

Statistical methods for testing effects on "maximum lifespan".

It has been noted that certain interventions such as caloric restriction may increase maximum lifespan, whereas other interventions may increase mean or median lifespan but not maximum lifespan. Here the term "maximum lifespan" is used to refer to the upper percentiles of the distribution of lifespan. This is of great interest because increasing maximum lifespan may be an indicator that an intervention is slowing the general process of aging and not merely retarding the development of specific diseases.

Waist circumference percentiles in nationally representative samples of African-American, European-American, and Mexican-American children and adolescents.

Objective: To describe and provide estimates of the distribution of waist circumference (WC) according to percentiles in African-, European-, and Mexican-American children, and to test for group differences at different percentiles.

Study Design: Cross-sectional data from the Third National Health and Nutrition Examination Survey (NHANES III) were examined. The sample evaluated included 9713 nonpregnant persons 2 to 18 years of age with measured values of WCs.

Metabolic and behavioral characteristics of metabolically obese but normal-weight women.

A unique subset of individuals termed metabolically obese but normal weight (MONW) has been identified. These young women are potentially at increased risk for development of the metabolic syndrome despite their young age and normal body mass index. We seek to determine metabolic and behavioral factors that could potentially distinguish MONW women from young women with a normal metabolic profile.

Empirical Bayes estimation of gene-specific effects in micro-array research.

Micro-array technology allows investigators the opportunity to measure expression levels of thousands of genes simultaneously. However, investigators are also faced with the challenge of simultaneous estimation of gene expression differences for thousands of genes with very small sample sizes. Traditional estimators of differences between treatment means (ordinary least squares estimators or OLS) are not the best estimators if interest is in estimation of gene expression differences for an ensemble of genes.

Dual-energy x-ray absorptiometry-measured lean soft tissue mass: differing relation to body cell mass across the adult life span.

Lean soft tissue (LST) measured by dual-energy X-ray absorptiometry (DEXA) is used as a metabolic measure in aging research despite evidence of extracellular fluid expansion and a corresponding reduction in body cell mass (BCM) in older participants. We investigated the hypothesis that the fraction of LST as BCM is smaller with greater age. Men and women (n = 2043) had DEXA and 40K-counting for body potassium and BCM measured on the same day.

Towards sound epistemological foundations of statistical methods for high-dimensional biology.

A sound epistemological foundation for biological inquiry comes, in part, from application of valid statistical procedures. This tenet is widely appreciated by scientists studying the new realm of high-dimensional biology, or 'omic' research, which involves multiplicity at unprecedented scales. Many papers aimed at the high-dimensional biology community describe the development or application of statistical techniques.

Epistatic interaction between two nonstructural loci on chromosomes 7 and 3 influences hepatic lipase activity in BSB mice.

BSB mice exhibit a wide range of obesity despite being produced by a backcross of lean C57BL/6J (B) x lean Mus spretus (SPRET/Pt) F1 animals x B. Previous linkage studies identified a quantitative trait locus (QTL) on mouse chromosome 7 with coincident peaks for hepatic lipase activity, obesity, and plasma cholesterol. However, these mice were not analyzed for gene x gene epistasis.

A simple significance test for quantile regression.

Where OLS regression seeks to model the mean of a random variable as a function of observed variables, quantile regression seeks to model the quantiles of a random variable as functions of observed variables. Tests for the dependence of the quantiles of a random variable upon observed variables have only been developed through the use of computer resampling or based on asymptotic approximations resting on distributional assumptions. We propose an exceedingly simple but heretofore undocumented likelihood ratio test within a logistic regression framework to test the dependence of a quantile of a random variable upon observed variables.

Characterization of epistasis influencing complex spontaneous obesity in the BSB model.

There is growing awareness that complex interactions among multiple genes and environmental factors play an important role in controlling obesity traits. The BSB mouse, which is produced by the backcross of (lean C57BL/6J x lean Mus spretus) x C57BL/6J, provides an excellent model of epistatic obesity. To evaluate potential epistatic interactions among six chromosomal regions previously determined to influence obesity phenotypes, we performed novel Bayesian analyses on the basis of both epistatic and nonepistatic models for four obesity traits: percentage of body fat, adiposity index, total fat mass, and body weight, and also for plasma total cholesterol.

Rimonabant Sanofi-Synthélabo.

Rimonabant, an antagonist of central cannabinoid type 1 (CB1) receptors, is being developed by Sanofi-Synthélabo for the potential treatment of obesity and as a potential smoking cessation agent. Phase III trials were initiated for obesity in August 2001 and were ongoing in September 2003. By September 2002, the compound had entered phase III trials for smoking cessation, and these trials were ongoing in September 2003.