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- All Subjects: Bioinformatics
- Genre: Academic theses
- Creators: Dinu, Valentin
- Member of: ASU Electronic Theses and Dissertations
- Resource Type: Text
Description
High throughput transcriptome data analysis like Single-cell Ribonucleic Acid sequencing (scRNA-seq) and Circular Ribonucleic Acid (circRNA) data have made significant breakthroughs, especially in cancer genomics. Analysis of transcriptome time series data is core in identifying time point(s) where drastic changes in gene transcription are associated with homeostatic to non-homeostatic cellular transition (tipping points). In Chapter 2 of this dissertation, I present a novel cell-type specific and co-expression-based tipping point detection method to identify target gene (TG) versus transcription factor (TF) pairs whose differential co-expression across time points drive biological changes in different cell types and the time point when these changes are observed. This method was applied to scRNA-seq data sets from a SARS-CoV-2 study (18 time points), a human cerebellum development study (9 time points), and a lung injury study (18 time points). Similarly, leveraging transcriptome data across treatment time points, I developed methodologies to identify treatment-induced and cell-type specific differentially co-expressed pairs (DCEPs). In part one of Chapter 3, I presented a pipeline that used a series of statistical tests to detect DCEPs. This method was applied to scRNA-seq data of patients with non-small cell lung cancer (NSCLC) sequenced across cancer treatment times. However, this pipeline does not account for correlations among multiple single cells from the same sample and correlations among multiple samples from the same patient. In Part 2 of Chapter 3, I presented a solution to this problem using a mixed-effect model. In Chapter 4, I present a summary of my work that focused on the cross-species analysis of circRNA transcriptome time series data. I compared circRNA profiles in neonatal pig and mouse hearts, identified orthologous circRNAs, and discussed regulation mechanisms of cardiomyocyte proliferation and myocardial regeneration conserved between mouse and pig at different time points.
ContributorsNyarige, Verah Mocheche (Author) / Liu, Li (Thesis advisor) / Wang, Junwen (Thesis advisor) / Dinu, Valentin (Committee member) / Arizona State University (Publisher)
Created2022
Description
Study of canine cancer’s molecular underpinnings holds great potential for informing veterinary and human oncology. Sporadic canine cancers are highly abundant (~4 million diagnoses/year in the United States) and the dog’s unique genomic architecture due to selective inbreeding, alongside the high similarity between dog and human genomes both confer power for improving understanding of cancer genes. However, characterization of canine cancer genome landscapes has been limited. It is hindered by lack of canine-specific tools and resources. To enable robust and reproducible comparative genomic analysis of canine cancers, I have developed a workflow for somatic and germline variant calling in canine cancer genomic data. I have first adapted a human cancer genomics pipeline to create a semi-automated canine pipeline used to map genomic landscapes of canine melanoma, lung adenocarcinoma, osteosarcoma and lymphoma. This pipeline also forms the backbone of my novel comparative genomics workflow.
Practical impediments to comparative genomic analysis of dog and human include challenges identifying similarities in mutation type and function across species. For example, canine genes could have evolved different functions and their human orthologs may perform different functions. Hence, I undertook a systematic statistical evaluation of dog and human cancer genes and assessed functional similarities and differences between orthologs to improve understanding of the roles of these genes in cancer across species. I tested this pipeline canine and human Diffuse Large B-Cell Lymphoma (DLBCL), given that canine DLBCL is the most comprehensively genomically characterized canine cancer. Logistic regression with genes bearing somatic coding mutations in each cancer was used to determine if conservation metrics (sequence identity, network placement, etc.) could explain co-mutation of genes in both species. Using this model, I identified 25 co-mutated and evolutionarily similar genes that may be compelling cross-species cancer genes. For example, PCLO was identified as a co-mutated conserved gene with PCLO having been previously identified as recurrently mutated in human DLBCL, but with an unclear role in oncogenesis. Further investigation of these genes might shed new light on the biology of lymphoma in dogs and human and this approach may more broadly serve to prioritize new genes for comparative cancer biology studies.
Practical impediments to comparative genomic analysis of dog and human include challenges identifying similarities in mutation type and function across species. For example, canine genes could have evolved different functions and their human orthologs may perform different functions. Hence, I undertook a systematic statistical evaluation of dog and human cancer genes and assessed functional similarities and differences between orthologs to improve understanding of the roles of these genes in cancer across species. I tested this pipeline canine and human Diffuse Large B-Cell Lymphoma (DLBCL), given that canine DLBCL is the most comprehensively genomically characterized canine cancer. Logistic regression with genes bearing somatic coding mutations in each cancer was used to determine if conservation metrics (sequence identity, network placement, etc.) could explain co-mutation of genes in both species. Using this model, I identified 25 co-mutated and evolutionarily similar genes that may be compelling cross-species cancer genes. For example, PCLO was identified as a co-mutated conserved gene with PCLO having been previously identified as recurrently mutated in human DLBCL, but with an unclear role in oncogenesis. Further investigation of these genes might shed new light on the biology of lymphoma in dogs and human and this approach may more broadly serve to prioritize new genes for comparative cancer biology studies.
ContributorsSivaprakasam, Karthigayini (Author) / Dinu, Valentin (Thesis advisor) / Trent, Jeffrey (Thesis advisor) / Hendricks, William (Committee member) / Runger, George C. (Committee member) / Arizona State University (Publisher)
Created2018
Description
Understanding intratumor heterogeneity and their driver genes is critical to
designing personalized treatments and improving clinical outcomes of cancers. Such
investigations require accurate delineation of the subclonal composition of a tumor, which
to date can only be reliably inferred from deep-sequencing data (>300x depth). The
resulting algorithm from the work presented here, incorporates an adaptive error model
into statistical decomposition of mixed populations, which corrects the mean-variance
dependency of sequencing data at the subclonal level and enables accurate subclonal
discovery in tumors sequenced at standard depths (30-50x). Tested on extensive computer
simulations and real-world data, this new method, named model-based adaptive grouping
of subclones (MAGOS), consistently outperforms existing methods on minimum
sequencing depth, decomposition accuracy and computation efficiency. MAGOS supports
subclone analysis using single nucleotide variants and copy number variants from one or
more samples of an individual tumor. GUST algorithm, on the other hand is a novel method
in detecting the cancer type specific driver genes. Combination of MAGOS and GUST
results can provide insights into cancer progression. Applications of MAGOS and GUST
to whole-exome sequencing data of 33 different cancer types’ samples discovered a
significant association between subclonal diversity and their drivers and patient overall
survival.
designing personalized treatments and improving clinical outcomes of cancers. Such
investigations require accurate delineation of the subclonal composition of a tumor, which
to date can only be reliably inferred from deep-sequencing data (>300x depth). The
resulting algorithm from the work presented here, incorporates an adaptive error model
into statistical decomposition of mixed populations, which corrects the mean-variance
dependency of sequencing data at the subclonal level and enables accurate subclonal
discovery in tumors sequenced at standard depths (30-50x). Tested on extensive computer
simulations and real-world data, this new method, named model-based adaptive grouping
of subclones (MAGOS), consistently outperforms existing methods on minimum
sequencing depth, decomposition accuracy and computation efficiency. MAGOS supports
subclone analysis using single nucleotide variants and copy number variants from one or
more samples of an individual tumor. GUST algorithm, on the other hand is a novel method
in detecting the cancer type specific driver genes. Combination of MAGOS and GUST
results can provide insights into cancer progression. Applications of MAGOS and GUST
to whole-exome sequencing data of 33 different cancer types’ samples discovered a
significant association between subclonal diversity and their drivers and patient overall
survival.
ContributorsAhmadinejad, Navid (Author) / Liu, Li (Thesis advisor) / Maley, Carlo (Committee member) / Dinu, Valentin (Committee member) / Arizona State University (Publisher)
Created2019
Description
All biological processes like cell growth, cell differentiation, development, and aging requires a series of steps which are characterized by gene regulation. Studies have shown that gene regulation is the key to various traits and diseases. Various factors affect the gene regulation which includes genetic signals, epigenetic tracks, genetic variants, etc. Deciphering and cataloging these functional genetic elements in the non-coding regions of the genome is one of the biggest challenges in precision medicine and genetic research. This thesis presents two different approaches to identifying these elements: TreeMap and DeepCORE. The first approach involves identifying putative causal genetic variants in cis-eQTL accounting for multisite effects and genetic linkage at a locus. TreeMap performs an organized search for individual and multiple causal variants using a tree guided nested machine learning method. DeepCORE on the other hand explores novel deep learning techniques that models the relationship between genetic, epigenetic and transcriptional patterns across tissues and cell lines and identifies co-operative regulatory elements that affect gene regulation. These two methods are believed to be the link for genotype-phenotype association and a necessary step to explaining various complex diseases and missing heritability.
ContributorsChandrashekar, Pramod Bharadwaj (Author) / Liu, Li (Thesis advisor) / Runger, George C. (Committee member) / Dinu, Valentin (Committee member) / Arizona State University (Publisher)
Created2020
Description
This dissertation presents three novel algorithms with real-world applications to genomic oncology. While the methodologies presented here were all developed to overcome various challenges associated with the adoption of high throughput genomic data in clinical oncology, they can be used in other domains as well. First, a network informed feature ranking algorithm is presented, which shows a significant increase in ability to select true predictive features from simulated data sets when compared to other state of the art graphical feature ranking methods. The methodology also shows an increased ability to predict pathological complete response to preoperative chemotherapy from genomic sequencing data of breast cancer patients utilizing domain knowledge from protein-protein interaction networks.
Second, an algorithm that overcomes population biases inherent in the use of a human reference genome developed primarily from European populations is presented to classify microsatellite instability (MSI) status from next-generation-sequencing (NGS) data. The methodology significantly increases the accuracy of MSI status prediction in African and African American ancestries.
Finally, a single variable model is presented to capture the bimodality inherent in genomic data stemming from heterogeneous diseases. This model shows improvements over other parametric models in the measurements of receiver-operator characteristic (ROC) curves for bimodal data. The model is used to estimate ROC curves for heterogeneous biomarkers in a dataset containing breast cancer and cancer-free specimen.
ContributorsSaul, Michelle (Author) / Dinu, Valentin (Thesis advisor) / Liu, Li (Committee member) / Wang, Junwen (Committee member) / Arizona State University (Publisher)
Created2021
Description
Advancements in high-throughput biotechnologies have generated large-scale multi-omics datasets encompassing diverse dimensions such as genomics, epigenomics, transcriptomics, proteomics, metabolomics, metagenomics, and phenomics. Traditionally, statistical and machine learning-based approaches utilize single-omics data sources to uncover molecular signatures, dissect complicated cellular mechanisms, and predict clinical results. However, to capture the multifaceted pathological mechanisms, integrative multi-omics analysis is needed that can provide a comprehensive picture of the disease. Here, I present three novel approaches to multi-omics integrative analysis. I introduce a single-cell integrative clustering method, which leverages multi-omics to enhance the resolution of cell subpopulations. Applied to a Cellular Indexing of Transcriptomes and Epitopes (CITE-Seq) dataset from human Acute Myeloid Lymphoma (AML) and control samples, this approach unveiled nuanced cell populations that otherwise remain elusive. I then shift the focus to a computational framework to discover transcriptional regulatory trios in which a transcription factor binds to a regulatory element harboring a genetic variant and subsequently differentially regulates the transcription level of a target gene. Applied to whole-exome, whole-genome, and transcriptome data of multiple myeloma samples, this approach discovered synergetic cis-acting and trans-acting regulatory elements associated with tumorigenesis. The next part of this work introduces a novel methodology that leverages the transcriptome and surface protein data at the single-cell level produced by CITE-Seq to model the intracellular protein trafficking process. Applied to COVID-19 samples, this approach revealed dysregulated protein trafficking associated with the severity of the infection.
ContributorsMudappathi, Rekha (Author) / Liu, Li (Thesis advisor) / Dinu, Valentin (Committee member) / Sun, Zhifu (Committee member) / Arizona State University (Publisher)
Created2023