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Direct prediction of regulatory elements from partial data without imputation.

ABSTRACT: Genome segmentation approaches allow us to characterize regulatory states in a given cell type using combinatorial patterns of histone modifications and other regulatory signals. In order to analyze regulatory state differences across cell types, current genome segmentation approaches typically require that the same regulatory genomics assays have been performed in all analyzed cell types. This necessarily limits both the numbers of cell types that can be analyzed and the complexity of the resulting regulatory states, as only a small number of histone modifications have been profiled across many cell types. Data imputation approaches that aim to estimate missing regulatory signals have been applied before genome segmentation. However, this approach is computationally costly and propagates any errors in imputation to produce incorrect genome segmentation results downstream. We present an extension to the IDEAS genome segmentation platform which can perform genome segmentation on incomplete regulatory genomics dataset collections without using imputation. Instead of relying on imputed data, we use an expectation-maximization approach to estimate marginal density functions within each regulatory state. We demonstrate that our genome segmentation results compare favorably with approaches based on imputation or other strategies for handling missing data. We further show that our approach can accurately impute missing data after genome segmentation, reversing the typical order of imputation/genome segmentation pipelines. Finally, we present a new 2D genome segmentation analysis of 127 human cell types studied by the Roadmap Epigenomics Consortium. By using an expanded set of chromatin marks that have been profiled in subsets of these cell types, our new segmentation results capture a more complex picture of combinatorial regulatory patterns that appear on the human genome.

SUBMITTER: Zhang Y

PROVIDER: S-EPMC6855516 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

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Direct prediction of regulatory elements from partial data without imputation.

Zhang Yu Y Mahony Shaun S

PLoS computational biology 20191104 11

Genome segmentation approaches allow us to characterize regulatory states in a given cell type using combinatorial patterns of histone modifications and other regulatory signals. In order to analyze regulatory state differences across cell types, current genome segmentation approaches typically require that the same regulatory genomics assays have been performed in all analyzed cell types. This necessarily limits both the numbers of cell types that can be analyzed and the complexity of the resul ...[more]

PMID: 31682602

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Project description:In modern scientific research, data are often collected from multiple modalities. Since different modalities could provide complementary information, statistical prediction methods using multi-modality data could deliver better prediction performance than using single modality data. However, one special challenge for using multi-modality data is related to block-missing data. In practice, due to dropouts or the high cost of measures, the observations of a certain modality can be missing completely for some subjects. In this paper, we propose a new DIrect Sparse regression procedure using COvariance from Multi-modality data (DISCOM). Our proposed DISCOM method includes two steps to find the optimal linear prediction of a continuous response variable using block-missing multi-modality predictors. In the first step, rather than deleting or imputing missing data, we make use of all available information to estimate the covariance matrix of the predictors and the cross-covariance vector between the predictors and the response variable. The proposed new estimate of the covariance matrix is a linear combination of the identity matrix, the estimates of the intra-modality covariance matrix and the cross-modality covariance matrix. Flexible estimates for both the sub-Gaussian and heavy-tailed cases are considered. In the second step, based on the estimated covariance matrix and the estimated cross-covariance vector, an extended Lasso-type estimator is used to deliver a sparse estimate of the coefficients in the optimal linear prediction. The number of samples that are effectively used by DISCOM is the minimum number of samples with available observations from two modalities, which can be much larger than the number of samples with complete observations from all modalities. The effectiveness of the proposed method is demonstrated by theoretical studies, simulated examples, and a real application from the Alzheimer's Disease Neuroimaging Initiative. The comparison between DISCOM and some existing methods also indicates the advantages of our proposed method.

Project description:BackgroundA complete understanding of the regulatory mechanisms of gene expression is the next important issue of genomics. Many bioinformaticians have developed methods and algorithms for predicting transcriptional regulatory mechanisms from sequence, gene expression, and binding data. However, most of these studies involved the use of yeast which has much simpler regulatory networks than human and has many genome wide binding data and gene expression data under diverse conditions. Studies of genome wide transcriptional networks of human genomes currently lag behind those of yeast.ResultsWe report herein a new method that combines gene expression data analysis with promoter analysis to infer transcriptional regulatory elements of human genes. The Z scores from the application of gene set analysis with gene sets of transcription factor binding sites (TFBSs) were successfully used to represent the activity of TFBSs in a given microarray data set. A significant correlation between the Z scores of gene sets of TFBSs and individual genes across multiple conditions permitted successful identification of many known human transcriptional regulatory elements of genes as well as the prediction of numerous putative TFBSs of many genes which will constitute a good starting point for further experiments. Using Z scores of gene sets of TFBSs produced better predictions than the use of mRNA levels of a transcription factor itself, suggesting that the Z scores of gene sets of TFBSs better represent diverse mechanisms for changing the activity of transcription factors in the cell. In addition, cis-regulatory modules, combinations of co-acting TFBSs, were readily identified by our analysis.ConclusionBy a strategic combination of gene set level analysis of gene expression data sets and promoter analysis, we were able to identify and predict many transcriptional regulatory elements of human genes. We conclude that this approach will aid in decoding some of the important transcriptional regulatory elements of human genes.

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Direct prediction of regulatory elements from partial data without imputation.

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Direct prediction of regulatory elements from partial data without imputation.

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