Dataset Information

Multivariate generalized linear model for genetic pleiotropy.

ABSTRACT: When a single gene influences more than one trait, known as pleiotropy, it is important to detect pleiotropy to improve the biological understanding of a gene. This can lead to improved screening, diagnosis, and treatment of diseases. Yet, most current multivariate methods to evaluate pleiotropy test the null hypothesis that none of the traits are associated with a variant; departures from the null could be driven by just one associated trait. A formal test of pleiotropy should assume a null hypothesis that one or fewer traits are associated with a genetic variant. We recently developed statistical methods to analyze pleiotropy for quantitative traits having a multivariate normal distribution. We now extend this approach to traits that can be modeled by generalized linear models, such as analysis of binary, ordinal, or quantitative traits, or a mixture of these types of traits. Based on methods from estimating equations, we developed a new test for pleiotropy. We then extended the testing framework to a sequential approach to test the null hypothesis that $k+1$ traits are associated, given that the null of $k$ associated traits was rejected. This provides a testing framework to determine the number of traits associated with a genetic variant, as well as which traits, while accounting for correlations among the traits. By simulations, we illustrate the Type-I error rate and power of our new methods, describe how they are influenced by sample size, the number of traits, and the trait correlations, and apply the new methods to a genome-wide association study of multivariate traits measuring symptoms of major depression. Our new approach provides a quantitative assessment of pleiotropy, enhancing current analytic practice.

SUBMITTER: Schaid DJ

PROVIDER: S-EPMC6296339 | biostudies-literature | 2019 Jan

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Multivariate generalized linear model for genetic pleiotropy.

Schaid Daniel J DJ Tong Xingwei X Batzler Anthony A Sinnwell Jason P JP Qing Jiang J Biernacka Joanna M JM

Biostatistics (Oxford, England) 20190101 1

When a single gene influences more than one trait, known as pleiotropy, it is important to detect pleiotropy to improve the biological understanding of a gene. This can lead to improved screening, diagnosis, and treatment of diseases. Yet, most current multivariate methods to evaluate pleiotropy test the null hypothesis that none of the traits are associated with a variant; departures from the null could be driven by just one associated trait. A formal test of pleiotropy should assume a null hyp ...[more]

PMID: 29267957

Similar Datasets

Project description:BACKGROUND:Renal transplant patients are mandated to have continuous assessment of their kidney function over time to monitor disease progression determined by changes in blood urea nitrogen (BUN), serum creatinine (Cr), and estimated glomerular filtration rate (eGFR). Multivariate analysis of these outcomes that aims at identifying the differential factors that affect disease progression is of great clinical significance. Thus our study aims at demonstrating the application of different joint modeling approaches with random coefficients on a cohort of renal transplant patients and presenting a comparison of their performance through a pseudo-simulation study. The objective of this comparison is to identify the model with best performance and to determine whether accuracy compensates for complexity in the different multivariate joint models. METHODS AND RESULTS:We propose a novel application of multivariate Generalized Linear Mixed Models (mGLMM) to analyze multiple longitudinal kidney function outcomes collected over 3 years on a cohort of 110 renal transplantation patients. The correlated outcomes BUN, Cr, and eGFR and the effect of various covariates such patient's gender, age and race on these markers was determined holistically using different mGLMMs. The performance of the various mGLMMs that encompass shared random intercept (SHRI), shared random intercept and slope (SHRIS), separate random intercept (SPRI) and separate random intercept and slope (SPRIS) was assessed to identify the one that has the best fit and most accurate estimates. A bootstrap pseudo-simulation study was conducted to gauge the tradeoff between the complexity and accuracy of the models. Accuracy was determined using two measures; the mean of the differences between the estimates of the bootstrapped datasets and the true beta obtained from the application of each model on the renal dataset, and the mean of the square of these differences. The results showed that SPRI provided most accurate estimates and did not exhibit any computational or convergence problem. CONCLUSION:Higher accuracy was demonstrated when the level of complexity increased from shared random coefficient models to the separate random coefficient alternatives with SPRI showing to have the best fit and most accurate estimates.

Dataset Information

Multivariate generalized linear model for genetic pleiotropy.

Publications

Multivariate generalized linear model for genetic pleiotropy.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets