Adaptive Set-Based Methods for Association Testing.

With a typical sample size of a few thousand subjects, a single genome-wide association study (GWAS) using traditional one single nucleotide polymorphism (SNP)-at-a-time methods can only detect genetic variants conferring a sizable effect on disease risk. Set-based methods, which analyze sets of SNPs jointly, can detect variants with smaller effects acting within a gene, a pathway, or other biologically relevant sets. Although self-contained set-based methods (those that test sets of variants without regard to variants not in the set) are generally more powerful than competitive set-based approaches (those that rely on comparison of variants in the set of interest with variants not in the set), there is no consensus as to which self-contained methods are best. In particular, several self-contained set tests have been proposed to directly or indirectly "adapt" to the a priori unknown proportion and distribution of effects of the truly associated SNPs in the set, which is a major determinant of their power. A popular adaptive set-based test is the adaptive rank truncated product (ARTP), which seeks the set of SNPs that yields the best-combined evidence of association. We compared the standard ARTP, several ARTP variations we introduced, and other adaptive methods in a comprehensive simulation study to evaluate their performance. We used permutations to assess significance for all the methods and thus provide a level playing field for comparison. We found the standard ARTP test to have the highest power across our simulations followed closely by the global model of random effects (GMRE) and a least absolute shrinkage and selection operator (LASSO)-based test.

Indoor time-microenvironment-activity patterns in seven regions of Europe.

Personal exposure to environmental substances is largely determined by time-microenvironment-activity patterns while moving across locations or microenvironments. Therefore, time-microenvironment-activity data are particularly useful in modeling exposure. We investigated determinants of workday time-microenvironment-activity patterns of the adult urban population in seven European cities. The EXPOLIS study assessed workday time-microenvironment-activity patterns among a total of 1427 subjects (age 19-60 years) in Helsinki (Finland), Athens (Greece), Basel (Switzerland), Grenoble (France), Milan (Italy), Prague (Czech Republic), and Oxford (UK). Subjects completed time-microenvironment-activity diaries during two working days. We present time spent indoors--at home, at work, and elsewhere, and time exposed to tobacco smoke indoors for all cities. The contribution of sociodemographic factors has been assessed using regression models. More than 90% of the variance in indoor time-microenvironment-activity patterns originated from differences between and within subjects rather than between cities. The most common factors that were associated with indoor time-microenvironment-activity patterns, with similar contributions in all cities, were the specific work status, employment status, whether the participants were living alone, and whether the participants had children at home. Gender and season were associated with indoor time-microenvironment-activity patterns as well but the effects were rather heterogeneous across the seven cities. Exposure to second-hand tobacco smoke differed substantially across these cities. The heterogeneity of these factors across cities may reflect city-specific characteristics but selection biases in the sampled local populations may also explain part of the findings. Determinants of time-microenvironment-activity patterns need to be taken into account in exposure assessment, epidemiological analyses, exposure simulations, as well as in the development of preventive strategies that focus on time-microenvironment-activity patterns that ultimately determine exposures.