Testing an optimally weighted combination of common and/or rare variants with multiple traits.

Recently, joint analysis of multiple traits has become popular because it can increase statistical power to identify genetic variants associated with complex diseases. In addition, there is increasing evidence indicating that pleiotropy is a widespread phenomenon in complex diseases. Currently, most of existing methods test the association between multiple traits and a single genetic variant. However, these methods by analyzing one variant at a time may not be ideal for rare variant association studies because of the allelic heterogeneity as well as the extreme rarity of rare variants. In this article, we developed a statistical method by testing an optimally weighted combination of variants with multiple traits (TOWmuT) to test the association between multiple traits and a weighted combination of variants (rare and/or common) in a genomic region. TOWmuT is robust to the directions of effects of causal variants and is applicable to different types of traits. Using extensive simulation studies, we compared the performance of TOWmuT with the following five existing methods: gene association with multiple traits (GAMuT), multiple sequence kernel association test (MSKAT), adaptive weighting reverse regression (AWRR), single-TOW, and MANOVA. Our results showed that, in all of the simulation scenarios, TOWmuT has correct type I error rates and is consistently more powerful than the other five tests. We also illustrated the usefulness of TOWmuT by analyzing a whole-genome genotyping data from a lung function study.

Analysis of Surface Water Pollution Accidents in China: Characteristics and Lessons for Risk Management.

Understanding historical accidents is important for accident prevention and risk mitigation; however, there are no public databases of pollution accidents in China, and no detailed information regarding such incidents is readily available. Thus, 653 representative cases of surface water pollution accidents in China were identified and described as a function of time, location, materials involved, origin, and causes. The severity and other features of the accidents, frequency and quantities of chemicals involved, frequency and number of people poisoned, frequency and number of people affected, frequency and time for which pollution lasted, and frequency and length of pollution zone were effectively used to value and estimate the accumulated probabilities. The probabilities of occurrences of various types based on origin and causes were also summarized based on these observations. The following conclusions can be drawn from these analyses: (1) There was a high proportion of accidents involving multi-district boundary regions and drinking water crises, indicating that more attention should be paid to environmental risk prevention and the mitigation of such incidents. (2) A high proportion of accidents originated from small-sized chemical plants, indicating that these types of enterprises should be considered during policy making. (3) The most common cause (49.8% of the total) was intentional acts (illegal discharge); accordingly, efforts to increase environmental consciousness in China should be enhanced.

Detecting association of rare and common variants by testing an optimally weighted combination of variants with longitudinal data.

Increasing evidence shows that complex diseases are caused by both common and rare variants. Recently, several statistical methods for detecting associations of rare variants have been developed, including the test for testing the effect of an optimally weighted combination of variants (TOW) developed by our group in 2012. These methodologies consider phenotype measurement at only one time point. Because many sequence data have been developed on population cohorts that contain phenotype measurements at multiple time points, such as the data set provided in the Genetic Analysis Workshop 18 (GAW18), we extend TOW from phenotype measurement at one time point to phenotype measurements at multiple time points. We then apply the newly proposed method to the GAW18 data set and compare the power of the new method with TOW using only one phenotype measurement. The application results show that the newly proposed method jointly modeling phenotype measurements at all time points has increased power over TOW.

Detecting association of rare variants by testing an optimally weighted combination of variants for quantitative traits in general families.

Although next-generation sequencing technology allows sequencing the whole genome of large groups of individuals, the development of powerful statistical methods for rare variant association studies is still underway. Even though many statistical methods have been developed for mapping rare variants, most of these methods are for unrelated individuals only, whereas family data have been shown to improve power to detect rare variants. The majority of the existing methods for unrelated individuals is essentially testing the effect of a weighted combination of variants with different weighting schemes. The performance of these methods depends on the weights being used. Recently, researchers proposed a test for Testing the effect of an Optimally Weighted combination of variants (TOW) for unrelated individuals. In this article, we extend our previously developed TOW for unrelated individuals to family-based data and propose a novel test for Testing the effect of an Optimally Weighted combination of variants for Family-based designs (TOW-F). The optimal weights are analytically derived. The results of extensive simulation studies show that TOW-F is robust to population stratification in a wide range of population structures, is robust to the direction and magnitude of the effects of causal variants, and is relatively robust to the percentage of neutral variants.

Two adaptive weighting methods to test for rare variant associations in family-based designs.

Although next-generation DNA sequencing technologies have made rare variant association studies feasible and affordable, the development of powerful statistical methods for rare variant association studies is still under way. Most of the existing methods for rare variant association studies compare the number of rare mutations in a group of rare variants (in a gene or a pathway) between cases and controls. However, these methods assume that all causal variants are risk to diseases. Recently, several methods that are robust to the direction and magnitude of effects of causal variants have been proposed. However, they are applicable to unrelated individuals only, whereas family data have been shown to improve power to detect rare variants. In this article, we propose two adaptive weighting methods for rare variant association studies based on family data for quantitative traits. Using extensive simulation studies, we evaluate and compare our proposed methods with two methods based on the weights proposed by Madsen and Browning. Our results show that both proposed methods are robust to population stratification, robust to the direction and magnitude of the effects of causal variants, and more powerful than the methods using weights suggested by Madsen and Browning, especially when both risk and protective variants are present.