Using surveys of Affymetrix GeneChips to study antisense expression.

We have used large surveys of Affymetrix GeneChip data in the public domain to conduct a study of antisense expression across diverse conditions. We derive correlations between groups of probes which map uniquely to the same exon in the antisense direction. When there are no probes assigned to an exon in the sense direction we find that many of the antisense groups fail to detect a coherent block of transcription. We find that only a minority of these groups contain coherent blocks of antisense expression suggesting transcription. We also derive correlations between groups of probes which map uniquely to the same exon in both sense and antisense direction. In some of these cases the locations of sense probes overlap with the antisense probes, and the sense and antisense probe intensities are correlated with each other. This configuration suggests the existence of a Natural Antisense Transcript (NAT) pair. We find the majority of such NAT pairs detected by GeneChips are formed by a transcript of an established gene and either an EST or an mRNA. In order to determine the exact antisense regulatory mechanism indicated by the correlation of sense probes with antisense probes, a further investigation is necessary for every particular case of interest. However, the analysis of microarray data has proved to be a good method to reconfirm known NATs, discover new ones, as well as to notice possible problems in the annotation of antisense transcripts

Identifying the impact of G-quadruplexes on Affymetrix 3' arrays using cloud computing.

A tetramer quadruplex structure is formed by four parallel strands of DNA/ RNA containing runs of guanine. These quadruplexes are able to form because guanine can Hoogsteen hydrogen bond to other guanines, and a tetrad of guanines can form a stable arrangement. Recently we have discovered that probes on Affymetrix GeneChips that contain runs of guanine do not measure gene expression reliably. We associate this finding with the likelihood that quadruplexes are forming on the surface of GeneChips. In order to cope with the rapidly expanding size of GeneChip array datasets in the public domain, we are exploring the use of cloud computing to replicate our experiments on 3' arrays to look at the effect of the location of G-spots (runs of guanines). Cloud computing is a recently introduced high-performance solution that takes advantage of the computational infrastructure of large organisations such as Amazon and Google. We expect that cloud computing will become widely adopted because it enables bioinformaticians to avoid capital expenditure on expensive computing resources and to only pay a cloud computing provider for what is used. Moreover, as well as financial efficiency, cloud computing is an ecologically-friendly technology, it enables efficient data-sharing and we expect it to be faster for development purposes. Here we propose the advantageous use of cloud computing to perform a large data-mining analysis of public domain 3' arrays

Extracting causal relations on HIV drug resistance from literature

<p>Abstract</p> <p>Background</p> <p>In HIV treatment it is critical to have up-to-date resistance data of applicable drugs since HIV has a very high rate of mutation. These data are made available through scientific publications and must be extracted manually by experts in order to be used by virologists and medical doctors. Therefore there is an urgent need for a tool that partially automates this process and is able to retrieve relations between drugs and virus mutations from literature.</p> <p>Results</p> <p>In this work we present a novel method to extract and combine relationships between HIV drugs and mutations in viral genomes. Our extraction method is based on natural language processing (NLP) which produces grammatical relations and applies a set of rules to these relations. We applied our method to a relevant set of PubMed abstracts and obtained 2,434 extracted relations with an estimated performance of 84% for F-score. We then combined the extracted relations using logistic regression to generate resistance values for each <drug, mutation> pair. The results of this relation combination show more than 85% agreement with the Stanford HIVDB for the ten most frequently occurring mutations. The system is used in 5 hospitals from the Virolab project <url>http://www.virolab.org</url> to preselect the most relevant novel resistance data from literature and present those to virologists and medical doctors for further evaluation.</p> <p>Conclusions</p> <p>The proposed relation extraction and combination method has a good performance on extracting HIV drug resistance data. It can be used in large-scale relation extraction experiments. The developed methods can also be applied to extract other type of relations such as gene-protein, gene-disease, and disease-mutation.</p

Enriching a biomedical event corpus with meta-knowledge annotation

Background: Biomedical papers contain rich information about entities, facts and events of biological relevance. To discover these automatically, we use text mining techniques, which rely on annotated corpora for training. In order to extract protein-protein interactions, genotype-phenotype/gene-disease associations, etc., we rely on event corpora that are annotated with classified, structured representations of important facts and findings contained within text. These provide an important resource for the training of domain-specific information extraction (IE) systems, to facilitate semantic-based searching of documents. Correct interpretation of these events is not possible without additional information, e.g., does an event describe a fact, a hypothesis, an experimental result or an analysis of results? How confident is the author about the validity of her analyses? These and other types of information, which we collectively term meta-knowledge, can be derived from the context of the event.Results: We have designed an annotation scheme for meta-knowledge enrichment of biomedical event corpora. The scheme is multi-dimensional, in that each event is annotated for 5 different aspects of meta-knowledge that can be derived from the textual context of the event. Textual clues used to determine the values are also annotated. The scheme is intended to be general enough to allow integration with different types of bio-event annotation, whilst being detailed enough to capture important subtleties in the nature of the meta-knowledge expressed in the text. We report here on both the main features of the annotation scheme, as well as its application to the GENIA event corpus (1000 abstracts with 36,858 events). High levels of inter-annotator agreement have been achieved, falling in the range of 0.84-0.93 Kappa.Conclusion: By augmenting event annotations with meta-knowledge, more sophisticated IE systems can be trained, which allow interpretative information to be specified as part of the search criteria. This can assist in a number of important tasks, e.g., finding new experimental knowledge to facilitate database curation, enabling textual inference to detect entailments and contradictions, etc. To our knowledge, our scheme is unique within the field with regards to the diversity of meta-knowledge aspects annotated for each event. © 2011 Thompson et al; licensee BioMed Central Ltd

Negated bio-events: Analysis and identification

Background: Negation occurs frequently in scientific literature, especially in biomedical literature. It has previously been reported that around 13% of sentences found in biomedical research articles contain negation. Historically, the main motivation for identifying negated events has been to ensure their exclusion from lists of extracted interactions. However, recently, there has been a growing interest in negative results, which has resulted in negation detection being identified as a key challenge in biomedical relation extraction. In this article, we focus on the problem of identifying negated bio-events, given gold standard event annotations.Results: We have conducted a detailed analysis of three open access bio-event corpora containing negation information (i.e., GENIA Event, BioInfer and BioNLP'09 ST), and have identified the main types of negated bio-events. We have analysed the key aspects of a machine learning solution to the problem of detecting negated events, including selection of negation cues, feature engineering and the choice of learning algorithm. Combining the best solutions for each aspect of the problem, we propose a novel framework for the identification of negated bio-events. We have evaluated our system on each of the three open access corpora mentioned above. The performance of the system significantly surpasses the best results previously reported on the BioNLP'09 ST corpus, and achieves even better results on the GENIA Event and BioInfer corpora, both of which contain more varied and complex events.Conclusions: Recently, in the field of biomedical text mining, the development and enhancement of event-based systems has received significant interest. The ability to identify negated events is a key performance element for these systems. We have conducted the first detailed study on the analysis and identification of negated bio-events. Our proposed framework can be integrated with state-of-the-art event extraction systems. The resulting systems will be able to extract bio-events with attached polarities from textual documents, which can serve as the foundation for more elaborate systems that are able to detect mutually contradicting bio-events. © 2013 Nawaz et al.; licensee BioMed Central Ltd

Negation modeling for German polarity classification

We present an approach for modeling German negation in open-domain fine grained sentiment analysis. Unlike most previous work in sentiment analysis, we assume that negation can be conveyed by many lexical units (and not only common negation words) and that different negation words have different scopes. Our approach is examined on a new dataset comprising sentences with mentions of polar expressions and various negation words. We identify different types of negation words that have the same scopes. We show that already negation modeling based on these types largely outperforms traditional negation models which assume the same scope for all negation words and which employ a window-based scope detection rather than a scope detection based on syntactic information

Widespread existence of uncorrelated probe intensities from within the same probeset on Affymetrix GeneChips.

We have developed a computational pipeline to analyse large surveys of Affymetrix GeneChips, for example NCBI's Gene Expression Omnibus. GEO samples data for many organisms, tissues and phenotypes. Because of this experimental diversity, any observed correlations between probe intensities can be associated either with biology that is robust, such as common co-expression, or with systematic biases associated with the GeneChip technology. Our bioinformatics pipeline integrates the mapping of probes to exons, quality control checks on each GeneChip which identifies flaws in hybridization quality, and the mining of correlations in intensities between groups of probes. The output from our pipeline has enabled us to identify systematic biases in GeneChip data. We are also able to use the pipeline as a discovery tool for biology. We have discovered that in the majority of cases, Affymetrix probesets on Human GeneChips do not measure one unique block of transcription. Instead we see numerous examples of outlier probes. Our study has also identified that in a number of probesets the mismatch probes are an informative diagnostic of expression, rather than providing a measure of background contamination. We report evidence for systematic biases in GeneChip technology associated with probe-probe interactions. We also see signatures associated with post-transcriptional processing of RNA, such as alternative polyadenylation

On the causes of outliers in Affymetrix GeneChip data

We describe various types of outliers seen in Affymetrix GeneChip data. We have been able to utilise the data in the Gene Expression Omnibus to screen GeneChips across a range of scales, from single probes, to spatially adjacent fractions of arrays, to whole arrays, to whole experiments. In this review we describe a number of causes for why some reported intensities might be misleading on GeneChips. © The Author 2009. Published by Oxford University Press