Sparse integrative clustering of multiple omics data sets

High resolution microarrays and second-generation sequencing platforms are powerful tools to investigate genome-wide alterations in DNA copy number, methylation and gene expression associated with a disease. An integrated genomic profiling approach measures multiple omics data types simultaneously in the same set of biological samples. Such approach renders an integrated data resolution that would not be available with any single data type. In this study, we use penalized latent variable regression methods for joint modeling of multiple omics data types to identify common latent variables that can be used to cluster patient samples into biologically and clinically relevant disease subtypes. We consider lasso [J. Roy. Statist. Soc. Ser. B 58 (1996) 267-288], elastic net [J. R. Stat. Soc. Ser. B Stat. Methodol. 67 (2005) 301-320] and fused lasso [J. R. Stat. Soc. Ser. B Stat. Methodol. 67 (2005) 91-108] methods to induce sparsity in the coefficient vectors, revealing important genomic features that have significant contributions to the latent variables. An iterative ridge regression is used to compute the sparse coefficient vectors. In model selection, a uniform design [Monographs on Statistics and Applied Probability (1994) Chapman & Hall] is used to seek "experimental" points that scattered uniformly across the search domain for efficient sampling of tuning parameter combinations. We compared our method to sparse singular value decomposition (SVD) and penalized Gaussian mixture model (GMM) using both real and simulated data sets. The proposed method is applied to integrate genomic, epigenomic and transcriptomic data for subtype analysis in breast and lung cancer data sets.Comment: Published in at http://dx.doi.org/10.1214/12-AOAS578 the Annals of Applied Statistics (http://www.imstat.org/aoas/) by the Institute of Mathematical Statistics (http://www.imstat.org

Transkingdom Networks: A Systems Biology Approach to Identify Causal Members of Host-Microbiota Interactions

Improvements in sequencing technologies and reduced experimental costs have resulted in a vast number of studies generating high-throughput data. Although the number of methods to analyze these "omics" data has also increased, computational complexity and lack of documentation hinder researchers from analyzing their high-throughput data to its true potential. In this chapter we detail our data-driven, transkingdom network (TransNet) analysis protocol to integrate and interrogate multi-omics data. This systems biology approach has allowed us to successfully identify important causal relationships between different taxonomic kingdoms (e.g. mammals and microbes) using diverse types of data

FAIRness and Usability for Open-access Omics Data Systems

Omics data sharing is crucial to the biological research community, and the last decade or two has seen a huge rise in collaborative analysis systems, databases, and knowledge bases for omics and other systems biology data. We assessed the FAIRness of NASAs GeneLab Data Systems (GLDS) along with four similar kinds of systems in the research omics data domain, using 14 FAIRness metrics. The range of overall FAIRness scores was 6-12 (out of 14), average 10.1, and standard deviation 2.4. The range of Pass ratings for the metrics was 29-79%, Partial Pass 0-21%, and Fail 7-50%. The systems we evaluated performed the best in the areas of data findability and accessibility, and worst in the area of data interoperability. Reusability of metadata, in particular, was frequently not well supported. We relate our experiences implementing semantic integration of omics data from some of the assessed systems for federated querying and retrieval functions, given their shortcomings in data interoperability. Finally, we propose two new principles that Big Data system developers, in particular, should consider for maximizing data accessibility

Identification of the expressome by machine learning on omics data.

Accurate annotation of plant genomes remains complex due to the presence of many pseudogenes arising from whole-genome duplication-generated redundancy or the capture and movement of gene fragments by transposable elements. Machine learning on genome-wide epigenetic marks, informed by transcriptomic and proteomic training data, could be used to improve annotations through classification of all putative protein-coding genes as either constitutively silent or able to be expressed. Expressed genes were subclassified as able to express both mRNAs and proteins or only RNAs, and CG gene body methylation was associated only with the former subclass. More than 60,000 protein-coding genes have been annotated in the reference genome of maize inbred B73. About two-thirds of these genes are transcribed and are designated the filtered gene set (FGS). Classification of genes by our trained random forest algorithm was accurate and relied only on histone modifications or DNA methylation patterns within the gene body; promoter methylation was unimportant. Other inbred lines are known to transcribe significantly different sets of genes, indicating that the FGS is specific to B73. We accurately classified the sets of transcribed genes in additional inbred lines, arising from inbred-specific DNA methylation patterns. This approach highlights the potential of using chromatin information to improve annotations of functional genes

Synergistic Effects of Different Levels of Genomic Data for the Staging of Lung Adenocarcinoma: An Illustrative Study

Lung adenocarcinoma (LUAD) is a common and very lethal cancer. Accurate staging is a prerequisite for its effective diagnosis and treatment. Therefore, improving the accuracy of the stage prediction of LUAD patients is of great clinical relevance. Previous works have mainly focused on single genomic data information or a small number of different omics data types concurrently for generating predictive models. A few of them have considered multi-omics data from genome to proteome. We used a publicly available dataset to illustrate the potential of multi-omics data for stage prediction in LUAD. In particular, we investigated the roles of the specific omics data types in the prediction process. We used a self-developed method, Omics-MKL, for stage prediction that combines an existing feature ranking technique Minimum Redundancy and Maximum Relevance (mRMR), which avoids redundancy among the selected features, and multiple kernel learning (MKL), applying different kernels for different omics data types. Each of the considered omics data types individually provided useful prediction results. Moreover, using multi-omics data delivered notably better results than using single-omics data. Gene expression and methylation information seem to play vital roles in the staging of LUAD. The Omics-MKL method retained 70 features after the selection process. Of these, 21 (30%) were methylation features and 34 (48.57%) were gene expression features. Moreover, 18 (25.71%) of the selected features are known to be related to LUAD, and 29 (41.43%) to lung cancer in general. Using multi-omics data from genome to proteome for predicting the stage of LUAD seems promising because each omics data type may improve the accuracy of the predictions. Here, methylation and gene expression data may play particularly important roles

Inferring gene ontologies from pairwise similarity data.

MotivationWhile the manually curated Gene Ontology (GO) is widely used, inferring a GO directly from -omics data is a compelling new problem. Recognizing that ontologies are a directed acyclic graph (DAG) of terms and hierarchical relations, algorithms are needed that: analyze a full matrix of gene-gene pairwise similarities from -omics data; infer true hierarchical structure in these data rather than enforcing hierarchy as a computational artifact; and respect biological pleiotropy, by which a term in the hierarchy can relate to multiple higher level terms. Methods addressing these requirements are just beginning to emerge-none has been evaluated for GO inference.MethodsWe consider two algorithms [Clique Extracted Ontology (CliXO), LocalFitness] that uniquely satisfy these requirements, compared with methods including standard clustering. CliXO is a new approach that finds maximal cliques in a network induced by progressive thresholding of a similarity matrix. We evaluate each method's ability to reconstruct the GO biological process ontology from a similarity matrix based on (a) semantic similarities for GO itself or (b) three -omics datasets for yeast.ResultsFor task (a) using semantic similarity, CliXO accurately reconstructs GO (>99% precision, recall) and outperforms other approaches (<20% precision, <20% recall). For task (b) using -omics data, CliXO outperforms other methods using two -omics datasets and achieves ∼30% precision and recall using YeastNet v3, similar to an earlier approach (Network Extracted Ontology) and better than LocalFitness or standard clustering (20-25% precision, recall).ConclusionThis study provides algorithmic foundation for building gene ontologies by capturing hierarchical and pleiotropic structure embedded in biomolecular data

On the combination of omics data for prediction of binary outcomes

Enrichment of predictive models with new biomolecular markers is an important task in high-dimensional omic applications. Increasingly, clinical studies include several sets of such omics markers available for each patient, measuring different levels of biological variation. As a result, one of the main challenges in predictive research is the integration of different sources of omic biomarkers for the prediction of health traits. We review several approaches for the combination of omic markers in the context of binary outcome prediction, all based on double cross-validation and regularized regression models. We evaluate their performance in terms of calibration and discrimination and we compare their performance with respect to single-omic source predictions. We illustrate the methods through the analysis of two real datasets. On the one hand, we consider the combination of two fractions of proteomic mass spectrometry for the calibration of a diagnostic rule for the detection of early-stage breast cancer. On the other hand, we consider transcriptomics and metabolomics as predictors of obesity using data from the Dietary, Lifestyle, and Genetic determinants of Obesity and Metabolic syndrome (DILGOM) study, a population-based cohort, from Finland