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Association based prioritization of genes

Description

Genes have widely different pertinences to the etiology and pathology of diseases. Thus, they can be ranked according to their disease-significance on a genomic scale, which is the subject of gene prioritization. Given a set of genes known to be

Genes have widely different pertinences to the etiology and pathology of diseases. Thus, they can be ranked according to their disease-significance on a genomic scale, which is the subject of gene prioritization. Given a set of genes known to be related to a disease, it is reasonable to use them as a basis to determine the significance of other candidate genes, which will then be ranked based on the association they exhibit with respect to the given set of known genes. Experimental and computational data of various kinds have different reliability and relevance to a disease under study. This work presents a gene prioritization method based on integrated biological networks that incorporates and models the various levels of relevance and reliability of diverse sources. The method is shown to achieve significantly higher performance as compared to two well-known gene prioritization algorithms. Essentially, no bias in the performance was seen as it was applied to diseases of diverse ethnology, e.g., monogenic, polygenic and cancer. The method was highly stable and robust against significant levels of noise in the data. Biological networks are often sparse, which can impede the operation of associationbased gene prioritization algorithms such as the one presented here from a computational perspective. As a potential approach to overcome this limitation, we explore the value that transcription factor binding sites can have in elucidating suitable targets. Transcription factors are needed for the expression of most genes, especially in higher organisms and hence genes can be associated via their genetic regulatory properties. While each transcription factor recognizes specific DNA sequence patterns, such patterns are mostly unknown for many transcription factors. Even those that are known are inconsistently reported in the literature, implying a potentially high level of inaccuracy. We developed computational methods for prediction and improvement of transcription factor binding patterns. Tests performed on the improvement method by employing synthetic patterns under various conditions showed that the method is very robust and the patterns produced invariably converge to nearly identical series of patterns. Preliminary tests were conducted to incorporate knowledge from transcription factor binding sites into our networkbased model for prioritization, with encouraging results. Genes have widely different pertinences to the etiology and pathology of diseases. Thus, they can be ranked according to their disease-significance on a genomic scale, which is the subject of gene prioritization. Given a set of genes known to be related to a disease, it is reasonable to use them as a basis to determine the significance of other candidate genes, which will then be ranked based on the association they exhibit with respect to the given set of known genes. Experimental and computational data of various kinds have different reliability and relevance to a disease under study. This work presents a gene prioritization method based on integrated biological networks that incorporates and models the various levels of relevance and reliability of diverse sources. The method is shown to achieve significantly higher performance as compared to two well-known gene prioritization algorithms. Essentially, no bias in the performance was seen as it was applied to diseases of diverse ethnology, e.g., monogenic, polygenic and cancer. The method was highly stable and robust against significant levels of noise in the data. Biological networks are often sparse, which can impede the operation of associationbased gene prioritization algorithms such as the one presented here from a computational perspective. As a potential approach to overcome this limitation, we explore the value that transcription factor binding sites can have in elucidating suitable targets. Transcription factors are needed for the expression of most genes, especially in higher organisms and hence genes can be associated via their genetic regulatory properties. While each transcription factor recognizes specific DNA sequence patterns, such patterns are mostly unknown for many transcription factors. Even those that are known are inconsistently reported in the literature, implying a potentially high level of inaccuracy. We developed computational methods for prediction and improvement of transcription factor binding patterns. Tests performed on the improvement method by employing synthetic patterns under various conditions showed that the method is very robust and the patterns produced invariably converge to nearly identical series of patterns. Preliminary tests were conducted to incorporate knowledge from transcription factor binding sites into our networkbased model for prioritization, with encouraging results. To validate these approaches in a disease-specific context, we built a schizophreniaspecific network based on the inferred associations and performed a comprehensive prioritization of human genes with respect to the disease. These results are expected to be validated empirically, but computational validation using known targets are very positive.

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Date Created
2011

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A timeline extraction approach to derive drug usage patterns in pregnant women using social media

Description

Proliferation of social media websites and discussion forums in the last decade has resulted in social media mining emerging as an effective mechanism to extract consumer patterns. Most research on social media and pharmacovigilance have concentrated on

Adverse Drug Reaction (ADR)

Proliferation of social media websites and discussion forums in the last decade has resulted in social media mining emerging as an effective mechanism to extract consumer patterns. Most research on social media and pharmacovigilance have concentrated on

Adverse Drug Reaction (ADR) identification. Such methods employ a step of drug search followed by classification of the associated text as consisting an ADR or not. Although this method works efficiently for ADR classifications, if ADR evidence is present in users posts over time, drug mentions fail to capture such ADRs. It also fails to record additional user information which may provide an opportunity to perform an in-depth analysis for lifestyle habits and possible reasons for any medical problems.

Pre-market clinical trials for drugs generally do not include pregnant women, and so their effects on pregnancy outcomes are not discovered early. This thesis presents a thorough, alternative strategy for assessing the safety profiles of drugs during pregnancy by utilizing user timelines from social media. I explore the use of a variety of state-of-the-art social media mining techniques, including rule-based and machine learning techniques, to identify pregnant women, monitor their drug usage patterns, categorize their birth outcomes, and attempt to discover associations between drugs and bad birth outcomes.

The technique used models user timelines as longitudinal patient networks, which provide us with a variety of key information about pregnancy, drug usage, and post-

birth reactions. I evaluate the distinct parts of the pipeline separately, validating the usefulness of each step. The approach to use user timelines in this fashion has produced very encouraging results, and can be employed for a range of other important tasks where users/patients are required to be followed over time to derive population-based measures.

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Created

Date Created
2016

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Knowledge-driven methods for geographic information extraction in the biomedical domain

Description

Accounting for over a third of all emerging and re-emerging infections, viruses represent a major public health threat, which researchers and epidemiologists across the world have been attempting to contain for decades. Recently, genomics-based surveillance of viruses through methods such

Accounting for over a third of all emerging and re-emerging infections, viruses represent a major public health threat, which researchers and epidemiologists across the world have been attempting to contain for decades. Recently, genomics-based surveillance of viruses through methods such as virus phylogeography has grown into a popular tool for infectious disease monitoring. When conducting such surveillance studies, researchers need to manually retrieve geographic metadata denoting the location of infected host (LOIH) of viruses from public sequence databases such as GenBank and any publication related to their study. The large volume of semi-structured and unstructured information that must be reviewed for this task, along with the ambiguity of geographic locations, make it especially challenging. Prior work has demonstrated that the majority of GenBank records lack sufficient geographic granularity concerning the LOIH of viruses. As a result, reviewing full-text publications is often necessary for conducting in-depth analysis of virus migration, which can be a very time-consuming process. Moreover, integrating geographic metadata pertaining to the LOIH of viruses from different sources, including different fields in GenBank records as well as full-text publications, and normalizing the integrated metadata to unique identifiers for subsequent analysis, are also challenging tasks, often requiring expert domain knowledge. Therefore, automated information extraction (IE) methods could help significantly accelerate this process, positively impacting public health research. However, very few research studies have attempted the use of IE methods in this domain.

This work explores the use of novel knowledge-driven geographic IE heuristics for extracting, integrating, and normalizing the LOIH of viruses based on information available in GenBank and related publications; when evaluated on manually annotated test sets, the methods were found to have a high accuracy and shown to be adequate for addressing this challenging problem. It also presents GeoBoost, a pioneering software system for georeferencing GenBank records, as well as a large-scale database containing over two million virus GenBank records georeferenced using the algorithms introduced here. The methods, database and software developed here could help support diverse public health domains focusing on sequence-informed virus surveillance, thereby enhancing existing platforms for controlling and containing disease outbreaks.

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Created

Date Created
2019

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Health information extraction from social media

Description

Social media is becoming increasingly popular as a platform for sharing personal health-related information. This information can be utilized for public health monitoring tasks such as pharmacovigilance via the use of Natural Language Processing (NLP) techniques. One of the

Social media is becoming increasingly popular as a platform for sharing personal health-related information. This information can be utilized for public health monitoring tasks such as pharmacovigilance via the use of Natural Language Processing (NLP) techniques. One of the critical steps in information extraction pipelines is Named Entity Recognition (NER), where the mentions of entities such as diseases are located in text and their entity type are identified. However, the language in social media is highly informal, and user-expressed health-related concepts are often non-technical, descriptive, and challenging to extract. There has been limited progress in addressing these challenges, and advanced machine learning-based NLP techniques have been underutilized. This work explores the effectiveness of different machine learning techniques, and particularly deep learning, to address the challenges associated with extraction of health-related concepts from social media. Deep learning has recently attracted a lot of attention in machine learning research and has shown remarkable success in several applications particularly imaging and speech recognition. However, thus far, deep learning techniques are relatively unexplored for biomedical text mining and, in particular, this is the first attempt in applying deep learning for health information extraction from social media.

This work presents ADRMine that uses a Conditional Random Field (CRF) sequence tagger for extraction of complex health-related concepts. It utilizes a large volume of unlabeled user posts for automatic learning of embedding cluster features, a novel application of deep learning in modeling the similarity between the tokens. ADRMine significantly improved the medical NER performance compared to the baseline systems.

This work also presents DeepHealthMiner, a deep learning pipeline for health-related concept extraction. Most of the machine learning methods require sophisticated task-specific manual feature design which is a challenging step in processing the informal and noisy content of social media. DeepHealthMiner automatically learns classification features using neural networks and utilizing a large volume of unlabeled user posts. Using a relatively small labeled training set, DeepHealthMiner could accurately identify most of the concepts, including the consumer expressions that were not observed in the training data or in the standard medical lexicons outperforming the state-of-the-art baseline techniques.

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Created

Date Created
2016

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Comparative genomics and novel bioinformatics methodology applied to the green anole reveal unique sex chromosome evolution

Description

In species with highly heteromorphic sex chromosomes, the degradation of one of the sex chromosomes can result in unequal gene expression between the sexes (e.g., between XX females and XY males) and between the sex chromosomes and the autosomes. Dosage

In species with highly heteromorphic sex chromosomes, the degradation of one of the sex chromosomes can result in unequal gene expression between the sexes (e.g., between XX females and XY males) and between the sex chromosomes and the autosomes. Dosage compensation is a process whereby genes on the sex chromosomes achieve equal gene expression which prevents deleterious side effects from having too much or too little expression of genes on sex chromsomes. The green anole is part of a group of species that recently underwent an adaptive radiation. The green anole has XX/XY sex determination, but the content of the X chromosome and its evolution have not been described. Given its status as a model species, better understanding the green anole genome could reveal insights into other species. Genomic analyses are crucial for a comprehensive picture of sex chromosome differentiation and dosage compensation, in addition to understanding speciation.

In order to address this, multiple comparative genomics and bioinformatics analyses were conducted to elucidate patterns of evolution in the green anole and across multiple anole species. Comparative genomics analyses were used to infer additional X-linked loci in the green anole, RNAseq data from male and female samples were anayzed to quantify patterns of sex-biased gene expression across the genome, and the extent of dosage compensation on the anole X chromosome was characterized, providing evidence that the sex chromosomes in the green anole are dosage compensated.

In addition, X-linked genes have a lower ratio of nonsynonymous to synonymous substitution rates than the autosomes when compared to other Anolis species, and pairwise rates of evolution in genes across the anole genome were analyzed. To conduct this analysis a new pipeline was created for filtering alignments and performing batch calculations for whole genome coding sequences. This pipeline has been made publicly available.

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Created

Date Created
2016