GeneNarrator: Mining the Literaturome for Relations Among Genes

The rapid development of microarray and other genomic technologies now enables biologists to monitor the expression of hundreds, even thousands of genes in a single experiment. Interpreting the biological meaning of the expression patterns still relies largely on biologist\u27s domain knowledge, as well as on information collected from the literature and various public databases. Yet individual experts’ domain knowledge is insufficient for large data sets, and collecting and analyzing this information manually from the literature and/or public databases is tedious and time-consuming. Computer-aided functional analysis tools are therefore highly desirable. We describe the architecture of GeneNarrator, a text mining system for functional analysis of microarray data. This system’s primary purpose is to test the feasibility of a more general system architecture based on a two-stage clustering strategy that is explained in detail. Given a list of genes, GeneNarrator collects abstracts about them from PubMed, then clusters the abstracts into functional topics in a first clustering stage. In the second clustering stage, the genes are clustered into groups based on similarities in their distributions of occurrence across topics. This novel two-stage architecture, the primary contribution of this project, has benefits not easily provided by onestage clustering

Computational approaches for single-cell omics and multi-omics data

Single-cell omics and multi-omics technologies have enabled the study of cellular heterogeneity with unprecedented resolution and the discovery of new cell types. The core of identifying heterogeneous cell types, both existing and novel ones, relies on efficient computational approaches, including especially cluster analysis. Additionally, gene regulatory network analysis and various integrative approaches are needed to combine data across studies and different multi-omics layers. This thesis comprehensively compared Bayesian clustering models for single-cell RNAsequencing (scRNA-seq) data and selected integrative approaches were used to study the cell-type specific gene regulation of uterus. Additionally, single-cell multi-omics data integration approaches for cell heterogeneity analysis were investigated. Article I investigated analytical approaches for cluster analysis in scRNA-seq data, particularly, latent Dirichlet allocation (LDA) and hierarchical Dirichlet process (HDP) models. The comparison of LDA and HDP together with the existing state-of-art methods revealed that topic modeling-based models can be useful in scRNA-seq cluster analysis. Evaluation of the cluster qualities for LDA and HDP with intrinsic and extrinsic cluster quality metrics indicated that the clustering performance of these methods is dataset dependent. Article II and Article III focused on cell-type specific integrative analysis of uterine or decidual stromal (dS) and natural killer (dNK) cells that are important for successful pregnancy. Article II integrated the existing preeclampsia RNA-seq studies of the decidua together with recent scRNA-seq datasets in order to investigate cell-type-specific contributions of early onset preeclampsia (EOP) and late onset preeclampsia (LOP). It was discovered that the dS marker genes were enriched for LOP downregulated genes and the dNK marker genes were enriched for upregulated EOP genes. Article III presented a gene regulatory network analysis for the subpopulations of dS and dNK cells. This study identified novel subpopulation specific transcription factors that promote decidualization of stromal cells and dNK mediated maternal immunotolerance. In Article IV, different strategies and methodological frameworks for data integration in single-cell multi-omics data analysis were reviewed in detail. Data integration methods were grouped into early, late and intermediate data integration strategies. The specific stage and order of data integration can have substantial effect on the results of the integrative analysis. The central details of the approaches were presented, and potential future directions were discussed.  Laskennallisia menetelmiä yksisolusekvensointi- ja multiomiikkatulosten analyyseihin Yksisolusekvensointitekniikat mahdollistavat solujen heterogeenisyyden tutkimuksen ennennäkemättömällä resoluutiolla ja uusien solutyyppien löytämisen. Solutyyppien tunnistamisessa keskeisessä roolissa on ryhmittely eli klusterointianalyysi. Myös geenien säätelyverkostojen sekä eri molekyylidatatasojen yhdistäminen on keskeistä analyysissä. Väitöskirjassa verrataan bayesilaisia klusterointimenetelmiä ja yhdistetään eri menetelmillä kerättyjä tietoja kohdun solutyyppispesifisessä geeninsäätelyanalyysissä. Lisäksi yksisolutiedon integraatiomenetelmiä selvitetään kattavasti. Julkaisu I keskittyy analyyttisten menetelmien, erityisesti latenttiin Dirichletallokaatioon (LDA) ja hierarkkiseen Dirichlet-prosessiin (HDP) perustuvien mallien tutkimiseen yksisoludatan klusterianalyysissä. Kattava vertailu näiden kahden mallin sekä olemassa olevien menetelmien kanssa paljasti, että aihemallinnuspohjaiset menetelmät voivat olla hyödyllisiä yksisoludatan klusterianalyysissä. Menetelmien suorituskyky riippui myös kunkin analysoitavan datasetin ominaisuuksista. Julkaisuissa II ja III keskitytään naisen lisääntymisterveydelle tärkeiden kohdun stroomasolujen ja NK-immuunisolujen solutyyppispesifiseen analyysiin. Artikkelissa II yhdistettiin olemassa olevia tuloksia pre-eklampsiasta viimeisimpiin yksisolusekvensointituloksiin ja löydettiin varhain alkavan pre-eklampsian (EOP) ja myöhään alkavan pre-eklampsian (LOP) solutyyppispesifisiä vaikutuksia. Havaittiin, että erilaistuneen strooman markkerigeenien ilmentyminen vähentyi LOP:ssa ja NK-markkerigeenien ilmentyminen lisääntyi EOP:ssa. Julkaisu III analysoi strooman ja NK-solujen alapopulaatiospesifisiä geeninsäätelyverkostoja ja niiden transkriptiofaktoreita. Tutkimus tunnisti uusia alapopulaatiospesifisiä säätelijöitä, jotka edistävät strooman erilaistumista ja NK-soluvälitteistä immunotoleranssia Julkaisu IV tarkastelee yksityiskohtaisesti strategioita ja menetelmiä erilaisten yksisoludatatasojen (multi-omiikka) integroimiseksi. Integrointimenetelmät ryhmiteltiin varhaisen, myöhäisen ja välivaiheen strategioihin ja kunkin lähestymistavan menetelmiä esiteltiin tarkemmin. Lisäksi keskusteltiin mahdollisista tulevaisuuden suunnista

Undisclosed, unmet and neglected challenges in multi-omics studies

[EN] Multi-omics approaches have become a reality in both large genomics projects and small laboratories. However, the multi-omics research community still faces a number of issues that have either not been sufficiently discussed or for which current solutions are still limited. In this Perspective, we elaborate on these limitations and suggest points of attention for future research. We finally discuss new opportunities and challenges brought to the field by the rapid development of single-cell high-throughput molecular technologies.This work has been funded by the Spanish Ministry of Science and Innovation with grant number BES-2016-076994 to A.A.-L.Tarazona, S.; Arzalluz-Luque, Á.; Conesa, A. (2021). Undisclosed, unmet and neglected challenges in multi-omics studies. Nature Computational Science. 1(6):395-402. https://doi.org/10.1038/s43588-021-00086-z3954021

Discovering semantic features in the literature: a foundation for building functional associations

BACKGROUND: Experimental techniques such as DNA microarray, serial analysis of gene expression (SAGE) and mass spectrometry proteomics, among others, are generating large amounts of data related to genes and proteins at different levels. As in any other experimental approach, it is necessary to analyze these data in the context of previously known information about the biological entities under study. The literature is a particularly valuable source of information for experiment validation and interpretation. Therefore, the development of automated text mining tools to assist in such interpretation is one of the main challenges in current bioinformatics research. RESULTS: We present a method to create literature profiles for large sets of genes or proteins based on common semantic features extracted from a corpus of relevant documents. These profiles can be used to establish pair-wise similarities among genes, utilized in gene/protein classification or can be even combined with experimental measurements. Semantic features can be used by researchers to facilitate the understanding of the commonalities indicated by experimental results. Our approach is based on non-negative matrix factorization (NMF), a machine-learning algorithm for data analysis, capable of identifying local patterns that characterize a subset of the data. The literature is thus used to establish putative relationships among subsets of genes or proteins and to provide coherent justification for this clustering into subsets. We demonstrate the utility of the method by applying it to two independent and vastly different sets of genes. CONCLUSION: The presented method can create literature profiles from documents relevant to sets of genes. The representation of genes as additive linear combinations of semantic features allows for the exploration of functional associations as well as for clustering, suggesting a valuable methodology for the validation and interpretation of high-throughput experimental data

Mining semantics for culturomics: towards a knowledge-based approach

The massive amounts of text data made available through the Google Books digitization project have inspired a new field of big-data textual research. Named culturomics, this field has attracted the attention of a growing number of scholars over recent years. However, initial studies based on these data have been criticized for not referring to relevant work in linguistics and language technology. This paper provides some ideas, thoughts and first steps towards a new culturomics initiative, based this time on Swedish data, which pursues a more knowledge-based approach than previous work in this emerging field. The amount of new Swedish text produced daily and older texts being digitized in cultural heritage projects grows at an accelerating rate. These volumes of text being available in digital form have grown far beyond the capacity of human readers, leaving automated semantic processing of the texts as the only realistic option for accessing and using the information contained in them. The aim of our recently initiated research program is to advance the state of the art in language technology resources and methods for semantic processing of Big Swedish text and focus on the theoretical and methodological advancement of the state of the art in extracting and correlating information from large volumes of Swedish text using a combination of knowledge-based and statistical methods

Functional Cohesion of Gene Sets Determined by Latent Semantic Indexing of PubMed Abstracts

High-throughput genomic technologies enable researchers to identify genes that are co-regulated with respect to specific experimental conditions. Numerous statistical approaches have been developed to identify differentially expressed genes. Because each approach can produce distinct gene sets, it is difficult for biologists to determine which statistical approach yields biologically relevant gene sets and is appropriate for their study. To address this issue, we implemented Latent Semantic Indexing (LSI) to determine the functional coherence of gene sets. An LSI model was built using over 1 million Medline abstracts for over 20,000 mouse and human genes annotated in Entrez Gene. The gene-to-gene LSI-derived similarities were used to calculate a literature cohesion p-value (LPv) for a given gene set using a Fisher's exact test. We tested this method against genes in more than 6,000 functional pathways annotated in Gene Ontology (GO) and found that approximately 75% of gene sets in GO biological process category and 90% of the gene sets in GO molecular function and cellular component categories were functionally cohesive (LPv<0.05). These results indicate that the LPv methodology is both robust and accurate. Application of this method to previously published microarray datasets demonstrated that LPv can be helpful in selecting the appropriate feature extraction methods. To enable real-time calculation of LPv for mouse or human gene sets, we developed a web tool called Gene-set Cohesion Analysis Tool (GCAT). GCAT can complement other gene set enrichment approaches by determining the overall functional cohesion of data sets, taking into account both explicit and implicit gene interactions reported in the biomedical literature

Unsupervised Bayesian explorations of mass spectrometry data

In recent years, the large-scale, untargeted studies of the compounds that serve as workers in the cell (proteins) and the small molecules involved in essential life-sustaining chemical processes (metabolites) have provided insights into a wide array of fields, such as medical diagnostics, drug discovery, personalised medicine and many others. Measurements in such studies are routinely performed using liquid chromatography mass spectrometry (LC-MS) instruments. From these measurements, we obtain a set of peaks having mass-to-charge, retention time (RT) and intensity values. Before further analysis is possible, the raw LC-MS data has to be processed in a data pre-preprocessing pipeline. In the alignment step of the pipeline, peaks from multiple LC-MS measurements have to be matched. In the identification step, the identity of unknown compounds in the sample that generate the observed peaks have to be assigned. Using tandem mass spectrometry, fragmentation peaks characteristic to a compound can be obtained and used to help establish the identity of the compound. Alignment and identification are challenging because the true identities of the entire set of compounds in the sample are unknown, and a single compound can produce many observed peaks, each with a potential drift in its retention time value. These observed peaks are not independent as they can be explained as being generated by the same compound. The aim of this thesis is to introduce methods to group these related peaks and to use these groupings to improve alignment and assist in identification during data pre-processing. Firstly, we introduce a generative model to group related peaks by their retention time. This information is used to influence direct-matching alignment, bringing related peak groups closer during matching. Investigations using benchmark datasets reveal that improved alignment performance is obtained from this approach. Next, we also consider mass information in the grouping process, resulting in PrecursorCluster, a model that performs the grouping of related peaks in metabolomics by their explainable mass relationships, RT and intensity values. Through a second-stage process that matches these related peak groups, peak alignment is produced. Experiments on benchmark datasets show that an improved alignment performance is obtained, while uncertainties in matched peaksets can also be extracted from the method. In the next section, we expand upon this two-stage method and introduce HDPAlign, a model that performs the clustering of related peaks within and across multiple LC-MS runs at once. This allows for matched peaksets and their respective uncertainties to be naturally extracted from the model. Finally, we look at fragmentation peaks used for identification and introduce MS2LDA, a topic model to group related fragmentation features. These groups of related fragmentation features potentially correspond to substructures shared by metabolites and can be used to assist data interpretation during identification. This final section corresponds to a work in progress and points to many interesting avenues for future research

A Computational Framework for Host-Pathogen Protein-Protein Interactions

Infectious diseases cause millions of illnesses and deaths every year, and raise great health concerns world widely. How to monitor and cure the infectious diseases has become a prevalent and intractable problem. Since the host-pathogen interactions are considered as the key infection processes at the molecular level for infectious diseases, there have been a large amount of researches focusing on the host-pathogen interactions towards the understanding of infection mechanisms and the development of novel therapeutic solutions. For years, the continuously development of technologies in biology has benefitted the wet lab-based experiments, such as small-scale biochemical, biophysical and genetic experiments and large-scale methods (for example yeast-two-hybrid analysis and cryogenic electron microscopy approach). As a result of past decades of efforts, there has been an exploded accumulation of biological data, which includes multi omics data, for example, the genomics data and proteomics data. Thus, an initiative review of omics data has been conducted in Chapter 2, which has exclusively demonstrated the recent update of ‘omics’ study, particularly focusing on proteomics and genomics. With the high-throughput technologies, the increasing amount of ‘omics’ data, including genomics and proteomics, has even further boosted. An upsurge of interest for data analytics in bioinformatics comes as no surprise to the researchers from a variety of disciplines. Specifically, the astonishing rate at which genomics and proteomics data are generated leads the researchers into the realm of ‘Big Data’ research. Chapter 2 is thus developed to providing an update of the omics background and the state-of-the-art developments in the omics area, with a focus on genomics data, from the perspective of big data analytics..