Genome-wide fine-mapping identifies pleiotropic and functional variants that predict many traits across global cattle populations

The difficulty in finding causative mutations has hampered their use in genomic prediction. Here, we present a methodology to fine-map potentially causal variants genome-wide by integrating the functional, evolutionary and pleiotropic information of variants using GWAS, variant clustering and Bayesian mixture models. Our analysis of 17 million sequence variants in 44,000+ Australian dairy cattle for 34 traits suggests, on average, one pleiotropic QTL existing in each 50 kb chromosome-segment. We selected a set of 80k variants representing potentially causal variants within each chromosome segment to develop a bovine XT-50K genotyping array. The custom array contains many pleiotropic variants with biological functions, including splicing QTLs and variants at conserved sites across 100 vertebrate species. This biology-informed custom array outperformed the standard array in predicting genetic value of multiple traits across populations in independent datasets of 90,000+ dairy cattle from the USA, Australia and New Zealand.

Consensus clustering for Bayesian mixture models

MotivationCluster analysis is an integral part of precision medicine and systems biology, used to define groups of patients or biomolecules. However, problems such as choosing the number of clusters and issues with high dimensional data arise consistently. An ensemble approach, such as consensus clustering, can overcome some of the difficulties associated with high dimensional data, frequently exploring more relevant clustering solutions than individual models. Another tool for cluster analysis, Bayesian mixture modelling, has alternative advantages, including the ability to infer the number of clusters present and extensibility. However, inference of these models is often performed using Markov-chain Monte Carlo (MCMC) methods which can suffer from problems such as poor exploration of the posterior distribution and long runtimes. This makes applying Bayesian mixture models and their extensions to ‘omics data challenging. We apply consensus clustering to Bayesian mixture models to address these problems.ResultsConsensus clustering of Bayesian mixture models successfully finds generating structure in our simulation study and captures multiple modes in the likelihood surface. This approach also offers significant reductions in runtime compared to traditional Bayesian inference when a parallel environment is available. We propose a heuristic to decide upon ensemble size and then apply consensus clustering to Multiple Dataset Integration, an extension of Bayesian mixture models for integrative analyses, on three ‘omics datasets for budding yeast. We find clusters of genes that are co-expressed and have common regulatory proteins which we validate using external knowledge, showing consensus clustering can be applied to any MCMC-based clustering method.

Use of Bayesian Mixture Models in Analyzing Heterogeneous Survival Data: A Simulation Study

Background and Aim: One of the statistical methods used to analyze the time-to-event medical data is survival analysis. In survival models, the response variable is time to the occurrence of an event. The main characteristic of survival data is the existence of censored data. When we have the distribution of survival time, we can use parametric methods. Among the important and popular distributions that can be used, we can mention the Weibull distribution. If the data derives from a heterogeneous population, simple parametric models (such as Weibull) would not fit the data appropriately. One of the methods which have been introduced to overcome this problem is the use of mixture models. Methods: To assess the validity of the two-component Weibull mixture model, we use a simulation method on heterogeneous survival data. For this purpose, data with different sample sizes were produced in a batch of 1000. Then, the validity of the model is checked using root mean square error (RMSE) criterion Results: It is obtained that increasing the sample size would decrease the RMSE in the parameters. However the maximum observed RMSE in all the parameters was negligible. Conclusion: The Bayesian Weibull mixture model was a proper fit for the heterogeneous survival data