A systematic assessment of cell type deconvolution algorithms for DNA methylation data

We performed systematic assessment of computational deconvolution methods that play an important role in the estimation of cell type proportions from bulk methylation data. The proposed framework methylDeConv (available as an R package) integrates several deconvolution methods for methylation profiles (Illumina HumanMethylation450 and MethylationEPIC arrays) and offers different cell-type-specific CpG selection to construct the extended reference library which incorporates the main immune cell subsets, epithelial cells and cell-free DNAs. We compared the performance of different deconvolution algorithms via simulations and benchmark datasets and further investigated the associations of the estimated cell type proportions to cancer therapy in breast cancer and subtypes in melanoma methylation case studies. Our results indicated that the deconvolution based on the extended reference library is critical to obtain accurate estimates of cell proportions in non-blood tissues.U01 OH011478/OH/NIOSH CDC HHS/United StatesU01 OH012257/OH/NIOSH CDC HHS/United StatesU01OH011478/ACL HHS/United StatesU01 OH011478/OH/NIOSH CDC HHS/United State

Brief Bioinform

We performed systematic assessment of computational deconvolution methods that play an important role in the estimation of cell type proportions from bulk methylation data. The proposed framework methylDeConv (available as an R package) integrates several deconvolution methods for methylation profiles (Illumina HumanMethylation450 and MethylationEPIC arrays) and offers different cell-type-specific CpG selection to construct the extended reference library which incorporates the main immune cell subsets, epithelial cells and cell-free DNAs. We compared the performance of different deconvolution algorithms via simulations and benchmark datasets and further investigated the associations of the estimated cell type proportions to cancer therapy in breast cancer and subtypes in melanoma methylation case studies. Our results indicated that the deconvolution based on the extended reference library is critical to obtain accurate estimates of cell proportions in non-blood tissues.U01 OH011478/OH/NIOSH CDC HHSUnited States/U01 OH012257/OH/NIOSH CDC HHSUnited States/U01OH011478/ACL HHSUnited States

A profile of differential DNA methylation in sporadic human prion disease blood: precedent, implications and clinical promise

Sporadic Creutzfeldt-Jakob Disease (sCJD) is a rare but devastating neurodegenerative disorder characterised by misfolding, propagation and deposition of the prion protein in the brain, leading to neuronal death and rapid cognitive and functional decline. As there is no obvious genetic cause of sCJD, the epigenetic status of sCJD patients may clarify spontaneous prion disease aetiology or reveal biomarkers of the disease. Blood from patients was profiled to document genome-wide differential DNA methylation. // 38 loci were identified as being differentially methylated in sCJD blood, including two which associated with disease severity as measured by the MRC Scale score. Of 7 loci considered for replication, 5 showed similar effects in a second cohort of patients, but not in patients of Alzheimer’s disease, iatrogenic CJD, or inherited prion disease, suggesting these effects are specific to the sporadic form of CJD. Notably hypomethylation at a site in the promoter of AIM2, an inflammasome component, retained its association with disease severity. // Hypomethylation of FKBP5, a gene known to regulate the cellular response to cortisol, prompted further investigation which revealed that circulating cortisol is indeed elevated in sCJD patients. Profiling of frontal cortex-derived DNA showed that differential methylation observed in blood is absent from the brain methylome. // Machine learning classification of sCJD based on genome-wide methylation data was able to classify sCJD and healthy control status with an accuracy of 87.04%. This is an appreciable level of accuracy but importantly sets precedence for further classification of prion patients in more complex clinical and research settings, as well as assisting differential diagnosis of less conventional rapid dementias

Health privacy : methods for privacy-preserving data sharing of methylation, microbiome and eye tracking data

This thesis studies the privacy risks of biomedical data and develops mechanisms for privacy-preserving data sharing. The contribution of this work is two-fold: First, we demonstrate privacy risks of a variety of biomedical data types such as DNA methylation data, microbiome data and eye tracking data. Despite being less stable than well-studied genome data and more prone to environmental changes, well-known privacy attacks can be adopted and threaten the privacy of data donors. Nevertheless, data sharing is crucial to advance biomedical research given that collection the data of a sufficiently large population is complex and costly. Therefore, we develop as a second step privacy- preserving tools that enable researchers to share such biomedical data. and second, we equip researchers with tools to enable privacy-preserving data sharing. These tools are mostly based on differential privacy, machine learning techniques and adversarial examples and carefully tuned to the concrete use case to maintain data utility while preserving privacy.Diese Dissertation beleuchtet Risiken für die Privatsphäre von biomedizinischen Daten und entwickelt Mechanismen für privatsphäre-erthaltendes Teilen von Daten. Dies zerfällt in zwei Teile: Zunächst zeigen wir die Risiken für die Privatsphäre auf, die von biomedizinischen Daten wie DNA Methylierung, Mikrobiomdaten und bei der Aufnahme von Augenbewegungen vorkommen. Obwohl diese Daten weniger stabil sind als Genomdaten, deren Risiken der Forschung gut bekannt sind, und sich mehr unter Umwelteinflüssen ändern, können bekannte Angriffe angepasst werden und bedrohen die Privatsphäre der Datenspender. Dennoch ist das Teilen von Daten essentiell um biomedizinische Forschung voranzutreiben, denn Daten von einer ausreichend großen Studienpopulation zu sammeln ist aufwändig und teuer. Deshalb entwickeln wir als zweiten Schritt privatsphäre-erhaltende Techniken, die es Wissenschaftlern erlauben, solche biomedizinischen Daten zu teilen. Diese Techniken basieren im Wesentlichen auf differentieller Privatsphäre und feindlichen Beispielen und sind sorgfältig auf den konkreten Einsatzzweck angepasst um den Nutzen der Daten zu erhalten und gleichzeitig die Privatsphäre zu schützen

Analysis, Visualization, and Machine Learning of Epigenomic Data

The goal of the Encyclopedia of DNA Elements (ENCODE) project has been to characterize all the functional elements of the human genome. These elements include expressed transcripts and genomic regions bound by transcription factors (TFs), occupied by nucleosomes, occupied by nucleosomes with modified histones, or hypersensitive to DNase I cleavage, etc. Chromatin Immunoprecipitation (ChIP-seq) is an experimental technique for detecting TF binding in living cells, and the genomic regions bound by TFs are called ChIP-seq peaks. ENCODE has performed and compiled results from tens of thousands of experiments, including ChIP-seq, DNase, RNA-seq and Hi-C. These efforts have culminated in two web-based resources from our lab—Factorbook and SCREEN—for the exploration of epigenomic data for both human and mouse. Factorbook is a peak-centric resource presenting data such as motif enrichment and histone modification profiles for transcription factor binding sites computed from ENCODE ChIP-seq data. SCREEN provides an encyclopedia of ~2 million regulatory elements, including promoters and enhancers, identified using ENCODE ChIP-seq and DNase data, with an extensive UI for searching and visualization. While we have successfully utilized the thousands of available ENCODE ChIP-seq experiments to build the Encyclopedia and visualizers, we have also struggled with the practical and theoretical inability to assay every possible experiment on every possible biosample under every conceivable biological scenario. We have used machine learning techniques to predict TF binding sites and enhancers location, and demonstrate machine learning is critical to help decipher functional regions of the genome

Systems Analytics and Integration of Big Omics Data

A “genotype"" is essentially an organism's full hereditary information which is obtained from its parents. A ""phenotype"" is an organism's actual observed physical and behavioral properties. These may include traits such as morphology, size, height, eye color, metabolism, etc. One of the pressing challenges in computational and systems biology is genotype-to-phenotype prediction. This is challenging given the amount of data generated by modern Omics technologies. This “Big Data” is so large and complex that traditional data processing applications are not up to the task. Challenges arise in collection, analysis, mining, sharing, transfer, visualization, archiving, and integration of these data. In this Special Issue, there is a focus on the systems-level analysis of Omics data, recent developments in gene ontology annotation, and advances in biological pathways and network biology. The integration of Omics data with clinical and biomedical data using machine learning is explored. This Special Issue covers new methodologies in the context of gene–environment interactions, tissue-specific gene expression, and how external factors or host genetics impact the microbiome

Computational Methods for the Analysis of Genomic Data and Biological Processes

In recent decades, new technologies have made remarkable progress in helping to understand biological systems. Rapid advances in genomic profiling techniques such as microarrays or high-performance sequencing have brought new opportunities and challenges in the fields of computational biology and bioinformatics. Such genetic sequencing techniques allow large amounts of data to be produced, whose analysis and cross-integration could provide a complete view of organisms. As a result, it is necessary to develop new techniques and algorithms that carry out an analysis of these data with reliability and efficiency. This Special Issue collected the latest advances in the field of computational methods for the analysis of gene expression data, and, in particular, the modeling of biological processes. Here we present eleven works selected to be published in this Special Issue due to their interest, quality, and originality

Bioinformatics applied to human genomics and proteomics: development of algorithms and methods for the discovery of molecular signatures derived from omic data and for the construction of co-expression and interaction networks

[EN] The present PhD dissertation develops and applies Bioinformatic methods and tools to address key current problems in the analysis of human omic data. This PhD has been organised by main objectives into four different chapters focused on: (i) development of an algorithm for the analysis of changes and heterogeneity in large-scale omic data; (ii) development of a method for non-parametric feature selection; (iii) integration and analysis of human protein-protein interaction networks and (iv) integration and analysis of human co-expression networks derived from tissue expression data and evolutionary profiles of proteins. In the first chapter, we developed and tested a new robust algorithm in R, called DECO, for the discovery of subgroups of features and samples within large-scale omic datasets, exploring all feature differences possible heterogeneity, through the integration of both data dispersion and predictor-response information in a new statistic parameter called h (heterogeneity score). In the second chapter, we present a simple non-parametric statistic to measure the cohesiveness of categorical variables along any quantitative variable, applicable to feature selection in all types of big data sets. In the third chapter, we describe an analysis of the human interactome integrating two global datasets from high-quality proteomics technologies: HuRI (a human protein-protein interaction network generated by a systematic experimental screening based on Yeast-Two-Hybrid technology) and Cell-Atlas (a comprehensive map of subcellular localization of human proteins generated by antibody imaging). This analysis aims to create a framework for the subcellular localization characterization supported by the human protein-protein interactome. In the fourth chapter, we developed a full integration of three high-quality proteome-wide resources (Human Protein Atlas, OMA and TimeTree) to generate a robust human co-expression network across tissues assigning each human protein along the evolutionary timeline. In this way, we investigate how old in evolution and how correlated are the different human proteins, and we place all them in a common interaction network. As main general comment, all the work presented in this PhD uses and develops a wide variety of bioinformatic and statistical tools for the analysis, integration and enlighten of molecular signatures and biological networks using human omic data. Most of this data corresponds to sample cohorts generated in recent biomedical studies on specific human diseases