scholarly journals Missing value estimation methods for DNA methylation data

2019 ◽  
Vol 35 (19) ◽  
pp. 3786-3793 ◽  
Author(s):  
Pietro Di Lena ◽  
Claudia Sala ◽  
Andrea Prodi ◽  
Christine Nardini
Keyword(s):  
Dna Methylation ◽  
Linear Regression ◽  
Missing Values ◽  
Supplementary Information ◽  
Estimation Methods ◽  
Accurate Estimation ◽  
Epigenetic Mark ◽  
Methylation Data ◽  
Imputation Methods ◽  
The Impact

Abstract Motivation DNA methylation is a stable epigenetic mark with major implications in both physiological (development, aging) and pathological conditions (cancers and numerous diseases). Recent research involving methylation focuses on the development of molecular age estimation methods based on DNA methylation levels (mAge). An increasing number of studies indicate that divergences between mAge and chronological age may be associated to age-related diseases. Current advances in high-throughput technologies have allowed the characterization of DNA methylation levels throughout the human genome. However, experimental methylation profiles often contain multiple missing values that can affect the analysis of the data and also mAge estimation. Although several imputation methods exist, a major deficiency lies in the inability to cope with large datasets, such as DNA methylation chips. Specific methods for imputing missing methylation data are therefore needed. Results We present a simple and computationally efficient imputation method, metyhLImp, based on linear regression. The rationale of the approach lies in the observation that methylation levels show a high degree of inter-sample correlation. We performed a comparative study of our approach with other imputation methods on DNA methylation data of healthy and disease samples from different tissues. Performances have been assessed both in terms of imputation accuracy and in terms of the impact imputed values have on mAge estimation. In comparison to existing methods, our linear regression model proves to perform equally or better and with good computational efficiency. The results of our analysis provide recommendations for accurate estimation of missing methylation values. Availability and implementation The R-package methyLImp is freely available at https://github.com/pdilena/methyLImp. Supplementary information Supplementary data are available at Bioinformatics online.

scholarly journals Imputation benchmark of β-value and M-value from DNA methylation data under different missing data mechanisms.

2020 ◽  
Author(s):  
Pietro Di Lena ◽  
Claudia Sala ◽  
Andrea Prodi ◽  
Christine Nardini
Keyword(s):  
Dna Methylation ◽  
Missing Data ◽  
Missing Values ◽  
Imputation Accuracy ◽  
Missing At Random ◽  
Cost Effective ◽  
Methylation Data ◽  
Imputation Methods ◽  
Value Range ◽  
The Cost

Abstract Background: High-throughput technologies enable the cost-effective collection and analysis of DNA methylation data throughout the human genome. This naturally entails missing values management that can complicate the analysis of the data. Several general and specific imputation methods are suitable for DNA methylation data. However, there are no detailed studies of their performances under different missing data mechanisms -(completely) at random or not- and different representations of DNA methylation levels (β and M-value). Results: We make an extensive analysis of the imputation performances of seven imputation methods on simulated missing completely at random (MCAR), missing at random (MAR) and missing not at random (MNAR) methylation data. We further consider imputation performances on the β- and M-value popular representations of methylation levels. Overall, β -values enable better imputation performances than M-values. Imputation accuracy is lower for mid-range β -values, while it is generally more accurate for values at the extremes of the β -value range. The MAR values distribution is on the average more dense in the mid-range in comparison to the expected β -value distribution. As a consequence, MAR values are on average harder to impute. Conclusions: The results of the analysis provide guidelines for the most suitable imputation approaches for DNA methylation data under different representations of DNA methylation levels and different missing data mechanisms.

scholarly journals Methylation data imputation performances under different representations and missingness patterns

2020 ◽  
Author(s):  
Pietro Di Lena ◽  
Claudia Sala ◽  
Andrea Prodi ◽  
Christine Nardini
Keyword(s):  
Dna Methylation ◽  
Missing Data ◽  
Missing Values ◽  
Imputation Accuracy ◽  
Missing At Random ◽  
Cost Effective ◽  
Methylation Data ◽  
Imputation Methods ◽  
Value Range ◽  
The Cost

Abstract Background: High-throughput technologies enable the cost-effective collection and analysis of DNA methylation data throughout the human genome. This naturally entails missing values management that can complicate the analysis of the data. Several general and specific imputation methods are suitable for DNA methylation data. However, there are no detailed studies of their performances under different missing data mechanisms –(completely) at random or not- and different representations of DNA methylation levels ($\beta$ and $M$-value). Results: We make an extensive analysis of the imputation performances of seven imputation methods on simulated missing completely at random (MCAR), missing at random (MAR) and missing not at random (MNAR) methylation data. We further consider imputation performances on the β- and M-value popular representations of methylation levels. Overall, β -values enable better imputation performances than M-values. Imputation accuracy is lower for mid-range β -values, while it is generally more accurate for values at the extremes of the β -value range. The MAR values distribution is on the average more dense in the mid-range in comparison to the expected β -value distribution. As a consequence, MAR values are on average harder to impute. Conclusions: The results of the analysis provide guidelines for the most suitable imputation approaches for DNA methylation data under different representations of DNA methylation levels and different missing data mechanisms.

scholarly journals Epiclomal: probabilistic clustering of sparse single-cell DNA methylation data

2018 ◽  
Author(s):  
Camila P.E. de Souza ◽  
Mirela Andronescu ◽  
Tehmina Masud ◽  
Farhia Kabeer ◽  
Justina Biele ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Single Cell ◽  
Missing Values ◽  
Clonal Analysis ◽  
Probabilistic Methods ◽  
Methylation Data ◽  
Genome Sequences ◽  
Probabilistic Clustering ◽  
Sequencing Method ◽  
Important Form

AbstractWe present Epiclomal, a probabilistic clustering method arising from a hierarchical mixture model to simultaneously cluster sparse single-cell DNA methylation data and impute missing values. Using synthetic and published single-cell CpG datasets we show that Epiclomal outperforms non-probabilistic methods and is able to handle the inherent missing data feature which dominates single-cell CpG genome sequences. Using a recently published single-cell 5mCpG sequencing method (PBAL), we show that Epiclomal discovers sub-clonal patterns of methylation in aneuploid tumour genomes, thus defining epiclones. We show that epiclones may transcend copy number determined clonal lineages, thus opening this important form of clonal analysis in cancer. Epiclomal is written in R and Python and is available at https://github.com/shahcompbio/Epiclomal.

scholarly journals Predicting gene expression using DNA methylation in three human populations

PeerJ ◽  
2019 ◽  
Vol 7 ◽  
pp. e6757 ◽  
Author(s):  
Huan Zhong ◽  
Soyeon Kim ◽  
Degui Zhi ◽  
Xiangqin Cui
Keyword(s):  
Gene Expression ◽  
Dna Methylation ◽  
Linear Regression ◽  
Human Population ◽  
Penalized Regression ◽  
Superior Performance ◽  
Gene Region ◽  
Human Populations ◽  
Epigenetic Mark ◽  
Lasso Regression

Background DNA methylation, an important epigenetic mark, is well known for its regulatory role in gene expression, especially the negative correlation in the promoter region. However, its correlation with gene expression across genome at human population level has not been well studied. In particular, it is unclear if genome-wide DNA methylation profile of an individual can predict her/his gene expression profile. Previous studies were mostly limited to association analyses between single CpG site methylation and gene expression. It is not known whether DNA methylation of a gene has enough prediction power to serve as a surrogate for gene expression in existing human study cohorts with DNA samples other than RNA samples. Results We examined DNA methylation in the gene region for predicting gene expression across individuals in non-cancer tissues of three human population datasets, adipose tissue of the Multiple Tissue Human Expression Resource Projects (MuTHER), peripheral blood mononuclear cell (PBMC) from Asthma and normal control study participates, and lymphoblastoid cell lines (LCL) from healthy individuals. Three prediction models were investigated, single linear regression, multiple linear regression, and least absolute shrinkage and selection operator (LASSO) penalized regression. Our results showed that LASSO regression has superior performance among these methods. However, the prediction power is generally low and varies across datasets. Only 30 and 42 genes were found to have cross-validation R2 greater than 0.3 in the PBMC and Adipose datasets, respectively. A substantially larger number of genes (258) were identified in the LCL dataset, which was generated from a more homogeneous cell line sample source. We also demonstrated that it gives better prediction power not to exclude any CpG probe due to cross hybridization or SNP effect. Conclusion In our three population analyses DNA methylation of CpG sites at gene region have limited prediction power for gene expression across individuals with linear regression models. The prediction power potentially varies depending on tissue, cell type, and data sources. In our analyses, the combination of LASSO regression and all probes not excluding any probe on the methylation array provides the best prediction for gene expression.

Proper imputation of missing values in proteomics datasets for differential expression analysis

2020 ◽  
Author(s):  
Mingyi Liu ◽  
Ashok Dongre
Keyword(s):  
Differential Expression ◽  
Expression Analysis ◽  
Protein Identification ◽  
Missing Values ◽  
Tissue Sample ◽  
Differential Expression Analysis ◽  
Real Life ◽  
Label Free ◽  
Imputation Methods ◽  
The Impact

Abstract Label-free shotgun proteomics is an important tool in biomedical research, where tandem mass spectrometry with data-dependent acquisition (DDA) is frequently used for protein identification and quantification. However, the DDA datasets contain a significant number of missing values (MVs) that severely hinders proper analysis. Existing literature suggests that different imputation methods should be used for the two types of MVs: missing completely at random or missing not at random. However, the simulated or biased datasets utilized by most of such studies offer few clues about the composition and thus proper imputation of MVs in real-life proteomic datasets. Moreover, the impact of imputation methods on downstream differential expression analysis—a critical goal for many biomedical projects—is largely undetermined. In this study, we investigated public DDA datasets of various tissue/sample types to determine the composition of MVs in them. We then developed simulated datasets that imitate the MV profile of real-life datasets. Using such datasets, we compared the impact of various popular imputation methods on the analysis of differentially expressed proteins. Finally, we make recommendations on which imputation method(s) to use for proteomic data beyond just DDA datasets.

scholarly journals PEIS: a novel approach of tumor purity estimation by identifying information sites through integrating signal based on DNA methylation data

2019 ◽  
Vol 20 (S22) ◽  
Author(s):  
Shudong Wang ◽  
Lihua Wang ◽  
Yuanyuan Zhang ◽  
Shanchen Pang ◽  
Xinzeng Wang
Keyword(s):  
Dna Methylation ◽  
Strong Correlation ◽  
Estimation Methods ◽  
Methylation Data ◽  
Tumor Purity ◽  
Novel Approach ◽  
Highly Sensitive ◽  
Number Variation ◽  
High Consistency ◽  
Selection Of

Abstract Background Tumor purity plays an important role in understanding the pathogenic mechanism of tumors. The purity of tumor samples is highly sensitive to tumor heterogeneity. Due to Intratumoral heterogeneity of genetic and epigenetic data, it is suitable to study the purity of tumors. Among them, there are many purity estimation methods based on copy number variation, gene expression and other data, while few use DNA methylation data and often based on selected information sites. Consequently, how to choose methylation sites as information sites has an important influence on the purity estimation results. At present, the selection of information sites was often based on the differentially methylated sites that only consider the mean signal, without considering other possible signals and the strong correlation among adjacent sites. Results Considering integrating multi-signals and strong correlation among adjacent sites, we propose an approach, PEIS, to estimate the purity of tumor samples by selecting informative differential methylation sites. Application to 12 publicly available tumor datasets, it is shown that PEIS provides accurate results in the estimation of tumor purity which has a high consistency with other existing methods. Also, through comparing the results of different information sites selection methods in the evaluation of tumor purity, it shows the PEIS is superior to other methods. Conclusions A new method to estimate the purity of tumor samples is proposed. This approach integrates multi-signals of the CpG sites and the correlation between the sites. Experimental analysis shows that this method is in good agreement with other existing methods for estimating tumor purity.

scholarly journals A Benchmark for Data Imputation Methods

2021 ◽  
Vol 4 ◽  
Author(s):  
Sebastian Jäger ◽  
Arndt Allhorn ◽  
Felix Bießmann
Keyword(s):  
Data Quality ◽  
Missing Values ◽  
Predictive Performance ◽  
Heterogeneous Data ◽  
Learning Approaches ◽  
Imputation Methods ◽  
High Data ◽  
Software Applications ◽  
Incomplete Datasets ◽  
The Impact

With the increasing importance and complexity of data pipelines, data quality became one of the key challenges in modern software applications. The importance of data quality has been recognized beyond the field of data engineering and database management systems (DBMSs). Also, for machine learning (ML) applications, high data quality standards are crucial to ensure robust predictive performance and responsible usage of automated decision making. One of the most frequent data quality problems is missing values. Incomplete datasets can break data pipelines and can have a devastating impact on downstream ML applications when not detected. While statisticians and, more recently, ML researchers have introduced a variety of approaches to impute missing values, comprehensive benchmarks comparing classical and modern imputation approaches under fair and realistic conditions are underrepresented. Here, we aim to fill this gap. We conduct a comprehensive suite of experiments on a large number of datasets with heterogeneous data and realistic missingness conditions, comparing both novel deep learning approaches and classical ML imputation methods when either only test or train and test data are affected by missing data. Each imputation method is evaluated regarding the imputation quality and the impact imputation has on a downstream ML task. Our results provide valuable insights into the performance of a variety of imputation methods under realistic conditions. We hope that our results help researchers and engineers to guide their data preprocessing method selection for automated data quality improvement.

scholarly journals Predicting gene expression using DNA methylation in two human populations

2018 ◽  
Author(s):  
Huan Zhong ◽  
Soyeon Kim ◽  
Degui Zhi ◽  
Xiangqin Cui
Keyword(s):  
Gene Expression ◽  
Dna Methylation ◽  
Linear Regression ◽  
Penalized Regression ◽  
Superior Performance ◽  
Gene Region ◽  
Human Populations ◽  
Epigenetic Mark ◽  
Lasso Regression ◽  
Cpg Sites

Background. DNA methylation, an important epigenetic mark, is well known for its regulatory role in gene expression, especially the negative regulation in the promoter region. However, its correlation with gene expression at population level has not been well studied. In particular, it is unclear if genome-wide DNA methylation profile of an individual can predict her/his gene expression profile. Previous studies were mostly limited to association analyses between single CpG site methylation and gene expression. It is not known whether DNA methylation of a gene has enough prediction power to serve as a surrogate for gene expression in existing human study cohorts with DNA samples but not RNA samples. Results. We studied two human population datasets, Multiple Tissue Human Expression Resource Projects (MuTHER)’s Adipose tissue as well as asthma and normal peoples’ peripheral blood mononuclear cell (PBMC), for predicting gene expression using methylation of all CpG sites from the gene region. Three prediction models were investigated; single linear regression, multiple linear regression, and least absolute shrinkage and selection operator (LASSO) penalized regression. Our results showed that LASSO regression has superior performance among these methods. However, even with LASSO regression, very small prediction R2 was obtained for the majority of genes and only about one thousand genes had prediction R2 greater than 0.1. GO term and pathway analyses of these more predictable genes showed that they are enriched for immune and defense genes. Conclusion. In human populations, DNA methylation of CpG sites at gene region have weak prediction power for gene expression. The relatively more predictable genes tend to be defense and immune genes.

scholarly journals Weighted elastic net for unsupervised domain adaptation with application to age prediction from DNA methylation data

2019 ◽  
Vol 35 (14) ◽  
pp. i154-i163 ◽  
Author(s):  
Lisa Handl ◽  
Adrin Jalali ◽  
Michael Scherer ◽  
Ralf Eggeling ◽  
Nico Pfeifer
Keyword(s):  
Dna Methylation ◽  
Computational Biology ◽  
Domain Adaptation ◽  
Real Data ◽  
Elastic Net ◽  
Training Data ◽  
Supplementary Information ◽  
Methylation Data ◽  
Unsupervised Domain Adaptation ◽  
Age Prediction

Abstract Motivation Predictive models are a powerful tool for solving complex problems in computational biology. They are typically designed to predict or classify data coming from the same unknown distribution as the training data. In many real-world settings, however, uncontrolled biological or technical factors can lead to a distribution mismatch between datasets acquired at different times, causing model performance to deteriorate on new data. A common additional obstacle in computational biology is scarce data with many more features than samples. To address these problems, we propose a method for unsupervised domain adaptation that is based on a weighted elastic net. The key idea of our approach is to compare dependencies between inputs in training and test data and to increase the cost of differently behaving features in the elastic net regularization term. In doing so, we encourage the model to assign a higher importance to features that are robust and behave similarly across domains. Results We evaluate our method both on simulated data with varying degrees of distribution mismatch and on real data, considering the problem of age prediction based on DNA methylation data across multiple tissues. Compared with a non-adaptive standard model, our approach substantially reduces errors on samples with a mismatched distribution. On real data, we achieve far lower errors on cerebellum samples, a tissue which is not part of the training data and poorly predicted by standard models. Our results demonstrate that unsupervised domain adaptation is possible for applications in computational biology, even with many more features than samples. Availability and implementation Source code is available at https://github.com/PfeiferLabTue/wenda. Supplementary information Supplementary data are available at Bioinformatics online.

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