Computational Methods for Data Integration and Imputation of Missing Values in Omics Datasets

Molecular profiling of different omic-modalities (e.g., DNA methylomics, transcriptomics, proteomics) in biological systems represents the basis for research and clinical decision-making. Measurement-specific biases, so-called batch effects, often hinder the integration of independently acquired datasets, and missing values further hamper the applicability of typical data processing algorithms. In addition to careful experimental design, well-defined standards in data acquisition and data exchange, the alleviation of these phenomena particularly requires a dedicated data integration and preprocessing pipeline. This review aims to give a comprehensive overview of computational methods for data integration and missing value imputation for omic data analyses. We provide formal definitions for missing value mechanisms and propose a novel statistical taxonomy for batch effects, especially in the presence of missing data. Based on an automated document search and systematic literature review, we describe 32 distinct data integration methods from five main methodological categories, as well as 37 algorithms for missing value imputation from five separate categories. Additionally, this review highlights multiple quantitative evaluation methods to aid researchers in selecting a suitable set of methods for their work. Finally, this work provides an integrated discussion of the relevance of batch effects and missing values in omics with corresponding method recommendations. We then propose a comprehensive three-step workflow from the study conception to final data analysis and deduce perspectives for future research. Eventually, we present a comprehensive flow chart as well as exemplary decision trees to aid practitioners in the selection of specific approaches for imputation and data integration in their studies.