Dataset Information

Multivariate methods and software for association mapping in dose-response genome-wide association studies.

ABSTRACT: BACKGROUND:The large sample sizes, freedom of ethical restrictions and ease of repeated measurements make cytotoxicity assays of immortalized lymphoblastoid cell lines a powerful new in vitro method in pharmacogenomics research. However, previous studies may have over-simplified the complex differences in dose-response profiles between genotypes, resulting in a loss of power. METHODS:The current study investigates four previously studied methods, plus one new method based on a multivariate analysis of variance (MANOVA) design. A simulation study was performed using differences in cancer drug response between genotypes for biologically meaningful loci. These loci also showed significance in separate genome-wide association studies. This manuscript builds upon a previous study, where differences in dose-response curves between genotypes were constructed using the hill slope equation. CONCLUSION:Overall, MANOVA was found to be the most powerful method for detecting real signals, and was also the most robust method for detection using alternatives generated with the previous simulation study. This method is also attractive because test statistics follow their expected distributions under the null hypothesis for both simulated and real data. The success of this method inspired the creation of the software program MAGWAS. MAGWAS is a computationally efficient, user-friendly, open source software tool that works on most platforms and performs GWASs for individuals having multivariate responses using standard file formats.

SUBMITTER: Brown CC

PROVIDER: S-EPMC3661384 | biostudies-literature | 2012 Dec

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Multivariate methods and software for association mapping in dose-response genome-wide association studies.

Brown Chad C CC Havener Tammy M TM Medina Marisa Wong MW Krauss Ronald M RM McLeod Howard L HL Motsinger-Reif Alison A AA

BioData mining 20121212 1

<h4>Background</h4>The large sample sizes, freedom of ethical restrictions and ease of repeated measurements make cytotoxicity assays of immortalized lymphoblastoid cell lines a powerful new in vitro method in pharmacogenomics research. However, previous studies may have over-simplified the complex differences in dose-response profiles between genotypes, resulting in a loss of power.<h4>Methods</h4>The current study investigates four previously studied methods, plus one new method based on a mul ...[more]

PMID: 23234571

Similar Datasets

Project description:Multivariate quantitative traits arise naturally in recent neuroimaging genetics studies, in which both structural and functional variability of the human brain is measured non-invasively through techniques such as magnetic resonance imaging (MRI). There is growing interest in detecting genetic variants associated with such multivariate traits, especially in genome-wide studies. Random forests (RFs) classifiers, which are ensembles of decision trees, are amongst the best performing machine learning algorithms and have been successfully employed for the prioritisation of genetic variants in case-control studies. RFs can also be applied to produce gene rankings in association studies with multivariate quantitative traits, and to estimate genetic similarities measures that are predictive of the trait. However, in studies involving hundreds of thousands of SNPs and high-dimensional traits, a very large ensemble of trees must be inferred from the data in order to obtain reliable rankings, which makes the application of these algorithms computationally prohibitive.We have developed a parallel version of the RF algorithm for regression and genetic similarity learning tasks in large-scale population genetic association studies involving multivariate traits, called PaRFR (Parallel Random Forest Regression). Our implementation takes advantage of the MapReduce programming model and is deployed on Hadoop, an open-source software framework that supports data-intensive distributed applications. Notable speed-ups are obtained by introducing a distance-based criterion for node splitting in the tree estimation process. PaRFR has been applied to a genome-wide association study on Alzheimer's disease (AD) in which the quantitative trait consists of a high-dimensional neuroimaging phenotype describing longitudinal changes in the human brain structure. PaRFR provides a ranking of SNPs associated to this trait, and produces pair-wise measures of genetic proximity that can be directly compared to pair-wise measures of phenotypic proximity. Several known AD-related variants have been identified, including APOE4 and TOMM40. We also present experimental evidence supporting the hypothesis of a linear relationship between the number of top-ranked mutated states, or frequent mutation patterns, and an indicator of disease severity.The Java codes are freely available at http://www2.imperial.ac.uk/~gmontana.

Dataset Information

Multivariate methods and software for association mapping in dose-response genome-wide association studies.

Publications

Multivariate methods and software for association mapping in dose-response genome-wide association studies.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets