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Flexible model-based clustering of mixed binary and continuous data: application to genetic regulation and cancer.

ABSTRACT: Clustering is used widely in 'omics' studies and is often tackled with standard methods, e.g. hierarchical clustering. However, the increasing need for integration of multiple data sets leads to a requirement for clustering methods applicable to mixed data types, where the straightforward application of standard methods is not necessarily the best approach. A particularly common problem involves clustering entities characterized by a mixture of binary data (e.g. presence/absence of mutations, binding, motifs and epigenetic marks) and continuous data (e.g. gene expression, protein abundance, metabolite levels). Here, we present a generic method based on a probabilistic model for clustering this type of data, and illustrate its application to genetic regulation and the clustering of cancer samples. We show that the resulting clusters lead to useful hypotheses: in the case of genetic regulation these concern regulation of groups of genes by specific sets of transcription factors and in the case of cancer samples combinations of gene mutations are related to patterns of gene expression. The clusters have potential mechanistic significance and in the latter case are significantly linked to survival. The method is available as a stand-alone software package (GNU General Public Licence) from http://github.com/BioToolsLeeds/FlexiCoClusteringPackage.git.

SUBMITTER: Zainul Abidin FN

PROVIDER: S-EPMC5399749 | biostudies-literature | 2017 Apr

REPOSITORIES: biostudies-literature

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Flexible model-based clustering of mixed binary and continuous data: application to genetic regulation and cancer.

Zainul Abidin Fatin N FN Westhead David R DR

Nucleic acids research 20170401 7

Clustering is used widely in 'omics' studies and is often tackled with standard methods, e.g. hierarchical clustering. However, the increasing need for integration of multiple data sets leads to a requirement for clustering methods applicable to mixed data types, where the straightforward application of standard methods is not necessarily the best approach. A particularly common problem involves clustering entities characterized by a mixture of binary data (e.g. presence/absence of mutations, bi ...[more]

PMID: 27994031

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Project description:BackgroundIn clinical trials and epidemiological research, mixed-effects models are commonly used to examine population-level and subject-specific trajectories of biomarkers over time. Despite their increasing popularity and application, the specification of these models necessitates a great deal of care when analysing longitudinal data with non-linear patterns and asymmetry. Parametric (linear) mixed-effect models may not capture these complexities flexibly and adequately. Additionally, assuming a Gaussian distribution for random effects and/or model errors may be overly restrictive, as it lacks robustness against deviations from symmetry.MethodsThis paper presents a semiparametric mixed-effects model with flexible distributions for complex longitudinal data in the Bayesian paradigm. The non-linear time effect on the longitudinal response was modelled using a spline approach. The multivariate skew-t distribution, which is a more flexible distribution, is utilized to relax the normality assumptions associated with both random-effects and model errors.ResultsTo assess the effectiveness of the proposed methods in various model settings, simulation studies were conducted. We then applied these models on chronic kidney disease (CKD) data and assessed the relationship between covariates and estimated glomerular filtration rate (eGFR). First, we compared the proposed semiparametric partially linear mixed-effect (SPPLM) model with the fully parametric one (FPLM), and the results indicated that the SPPLM model outperformed the FPLM model. We then further compared four different SPPLM models, each assuming different distributions for the random effects and model errors. The model with a skew-t distribution exhibited a superior fit to the CKD data compared to the Gaussian model. The findings from the application revealed that hypertension, diabetes, and follow-up time had a substantial association with kidney function, specifically leading to a decrease in GFR estimates.ConclusionsThe application and simulation studies have demonstrated that our work has made a significant contribution towards a more robust and adaptable methodology for modeling intricate longitudinal data. We achieved this by proposing a semiparametric Bayesian modeling approach with a spline smoothing function and a skew-t distribution.

Project description:Analysis of data measured on different scales is a relevant challenge. Biomedical studies often focus on high-throughput datasets of, e.g., quantitative measurements. However, the need for integration of other features possibly measured on different scales, e.g. clinical or cytogenetic factors, becomes increasingly important. The analysis results (e.g. a selection of relevant genes) are then visualized, while adding further information, like clinical factors, on top. However, a more integrative approach is desirable, where all available data are analyzed jointly, and where also in the visualization different data sources are combined in a more natural way. Here we specifically target integrative visualization and present a heatmap-style graphic display. To this end, we develop and explore methods for clustering mixed-type data, with special focus on clustering variables. Clustering of variables does not receive as much attention in the literature as does clustering of samples. We extend the variables clustering methodology by two new approaches, one based on the combination of different association measures and the other on distance correlation. With simulation studies we evaluate and compare different clustering strategies. Applying specific methods for mixed-type data proves to be comparable and in many cases beneficial as compared to standard approaches applied to corresponding quantitative or binarized data. Our two novel approaches for mixed-type variables show similar or better performance than the existing methods ClustOfVar and bias-corrected mutual information. Further, in contrast to ClustOfVar, our methods provide dissimilarity matrices, which is an advantage, especially for the purpose of visualization. Real data examples aim to give an impression of various kinds of potential applications for the integrative heatmap and other graphical displays based on dissimilarity matrices. We demonstrate that the presented integrative heatmap provides more information than common data displays about the relationship among variables and samples. The described clustering and visualization methods are implemented in our R package CluMix available from https://cran.r-project.org/web/packages/CluMix.

Dataset Information

Flexible model-based clustering of mixed binary and continuous data: application to genetic regulation and cancer.

Publications

Flexible model-based clustering of mixed binary and continuous data: application to genetic regulation and cancer.

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