- Research article
- Open Access
Retrieval with gene queries
© Sehgal and Srinivasan; licensee BioMed Central Ltd. 2006
Received: 12 August 2005
Accepted: 21 April 2006
Published: 21 April 2006
Accuracy of document retrieval from MEDLINE for gene queries is crucially important for many applications in bioinformatics. We explore five information retrieval-based methods to rank documents retrieved by PubMed gene queries for the human genome. The aim is to rank relevant documents higher in the retrieved list. We address the special challenges faced due to ambiguity in gene nomenclature: gene terms that refer to multiple genes, gene terms that are also English words, and gene terms that have other biological meanings.
Our two baseline ranking strategies are quite similar in performance. Two of our three LocusLink-based strategies offer significant improvements. These methods work very well even when there is ambiguity in the gene terms. Our best ranking strategy offers significant improvements on three different kinds of ambiguities over our two baseline strategies (improvements range from 15.9% to 17.7% and 11.7% to 13.3% depending on the baseline). For most genes the best ranking query is one that is built from the LocusLink (now Entrez Gene) summary and product information along with the gene names and aliases. For others, the gene names and aliases suffice. We also present an approach that successfully predicts, for a given gene, which of these two ranking queries is more appropriate.
We explore the effect of different post-retrieval strategies on the ranking of documents returned by PubMed for human gene queries. We have successfully applied some of these strategies to improve the ranking of relevant documents in the retrieved sets. This holds true even when various kinds of ambiguity are encountered. We feel that it would be very useful to apply strategies like ours on PubMed search results as these are not ordered by relevance in any way. This is especially so for queries that retrieve a large number of documents.
This research focuses on the problem of retrieval from MEDLINE for gene queries. The ability to retrieve the correct set of documents about genes is at the foundation of a fast growing variety of text-based solutions in bioinformatics. Whether the end goal is to automatically identify gene disease relationships  or to extract relevant information about drugs and genes related to a specific disease such as cancer , it is important to identify the associated document set accurately. Effective retrieval for gene queries is particularly relevant to the expanding body of research on using MEDLINE to analyze gene clusters generated by DNA microarray and oligonucleotide arrays experiments [3–7]. A single array experiment typically involves thousands of genes, often on a genome-wide scale. This makes the analysis of array expression data quite challenging. Several researchers have proposed techniques using MEDLINE data for each gene. For example Chaussabel and Sher  complement gene expression cluster analysis by clustering genes according to their literature profiles. Kankar et al.  statistically evaluate MeSH terms from the gene literature to identify a gene cluster's topical characteristics at different levels of importance. Wren and Garner  exploit literature co-occurences to evaluate the cohesiveness of gene clusters. Naturally such methods for analyzing several hundred genes at a time crucially depend upon the accuracy of their underlying document retrieval functions.
A significant aspect that makes gene query retrieval challenging, and hence interesting, is the ambiguity associated with gene names . There is a sizable and growing body of research on this gene name ambiguity phenomenon [9–13], with particular emphasis on designing and testing disambiguation strategies. Weeber et al.  studied the various kinds of ambiguities, such as synonymy and homonymy, in LocusLink (LL) gene names. They also use the Schwartz and Hearst expansion algorithm to automatically create a gene disambiguation test collection. Tuason et al.  studied ambiguity in gene names for four organisms (Mouse, Drosophila, Worms and Yeast). They identify ambiguity across all organisms, within each organism and with general English words.
Various disambiguation approaches can be found in the literature. Liu et al.  used a two-phase unsupervised approach to automatically train and build word sense classifiers for ambiguous biomedical terms. Podowski et al.  used a supervised approach to assign to each gene name in a MEDLINE abstract its corresponding LocusLink ID. They created models for each LocusLink ID trained using MEDLINE citations in LocusLink and SWISSPROT records. Koike and Takagi  used heuristically built dictionaries for gene names and for gene family names while Seki and Mostafa  explored probabilistic approaches. Most recently Schijvenaars et al.  used a method involving both a thesaurus and reference descriptions for the different meanings of genes with the latter built from representative documents or from OMIM. Their thesaurus of gene symbols, names etc. was built from five public databases such as OMIM and LocusLink.
As indicated before, our approach is to view the problem from a retrieval perspective. Initiatives such as the KDD 2002 challenge cup , BioCreAtIvE challenge  and TREC Genomics  offer related research. However, our research is distinct both in its goals and in the experimental design. In KDD 2002 although one task was to rank and retrieve papers in order of probability of the need for curation, the experimental conditions are significantly different from ours. For example, the collection had less than 1100 "cleaned" full text papers from the FlyBase domain. In sub-task 2.3 for the BioCreAtIvE 2004 workshop, participants were asked to "provide for, ten proteins, the articles which are relevant for annotation," along with information pertaining to GO annotation . Here again the collection was limited to 212 full text articles from the Journal of Biological Chemistry. Moreover, as stated by the organizers, the results of the sub-task were not evaluated due to reasons such as "the limited number of participants".
In the 2003 TREC Genomics Track, one task was retrieval from a collection of 525,938 MEDLINE records for 50 gene topics . The 2004 TREC Genomics track also had a retrieval task again with 50 queries but this time representing a broader variety of bioinformatics queries  as for example queries exploring the relationship between a gene and a disease. Our effort is different from these two TREC efforts. Although we use a dataset of 4.6 million MEDLINE records, built chiefly from the TREC 2004 dataset, we focus on a much larger (close to 9,400 queries) and different query set (focussed on gene queries). We use a similar, but not identical strategy, as that in TREC 2003, to identify gold standard relevant documents. Our method identifies more than double the number of relevant documents. In addition to differences in experimental design, our retrieval goal relates more directly to the needs of bioscientists using MEDLINE based evidence for the analysis of array based expression data involving thousands of genes.
In contrast to the extensive research on gene string ambiguity recognition and resolution, there are few studies where the central emphasis is on assessing the effectiveness of MEDLINE document retrieval with gene queries. Disambiguation focuses on individual occurrences of gene strings in specific documents. However, although a disambiguation strategy may correctly decide that a given ambiguous string represents a gene of interest, the document may still be non relevant. This could happen for example if the gene was mentioned only in a peripheral context. Retrieval on the other hand is, by definition, concerned with relevance. In the long run it may be beneficial to combine the strengths of both retrieval research and disambiguation research when working with genes. Our focus in this paper is on retrieval. For each gene in our sample we begin with the set of documents retrieved via PubMed and aim at improving this set using ranking methods from information retrieval research.
PubMed, the public interface to MEDLINE, offers a sophisticated range of search functions designed within the Boolean framework. However, the main option for sorting a retrieved set of documents is chronological. In other words, a PubMed query divides the MEDLINE collection into 2 sets: one that satisfies the query and one that does not. The former is then shown to the user in chronological order. There are no 'shades of grey' in PubMed retrieved sets. Ranking documents by their relevance potential can be of significant benefit, especially when large sets of documents are retrieved – the case with many gene queries. Thus our objective is to explore strategies for effectively ranking documents retrieved by PubMed. We begin with a baseline ranking strategy that uses only the terms in the original gene query submitted to PubMed. We then explore a variety of other ranking strategies assuming different levels of domain knowledge about the genes. We also study the effect of ambiguity on performance.
In recent research, Chen et al.  conducted the most extensive study to date, on gene names. Exploring 21 species, they studied the distribution of different ambiguities including the ones studied in this research. They found, for example, that although only 0.57% of their gene set consisted of genes with English meanings (in the context of a mouse dataset), these retrieved an additional 233% gene document 'instances' of which the majority were incorrect. We offer logically complementary research albeit one that focuses on the genes of a single genome. We present a systematic study on retrieval effectiveness, for human genes, with all of their inherent nomenclature ambiguities. Specifically we present three main experiments altogether involving 9,390 genes (human genes with known function identified from LocusLink (LL)). Each experiment explores the effectiveness of one or more ranking queries applied to document sets retrieved for gene queries from MEDLINE. Our goal is to rank relevant documents higher than the non relevant ones in the retrieved set.
Results and discussion
For each gene we retrieve documents from MEDLINE by searching the disjunction of its aliases taken from the OFFICIAL_GENE_NAME, OFFICIAL_SYMBOL and ALIAS_SYMBOL fields of LL. Retrieved documents are restricted to a subset of MEDLINE (close to 4.6 million records) consisting chiefly of the 2004 TREC Genomics dataset . 44% of the gene queries retrieve 100 or more documents while almost 25% retrieve 500 or more documents. Relevant documents (our gold standard) are extracted from the PMID' and 'GRIF' fields in each gene's LL record. In TREC 2003, gold standard documents were identified for the 50 gene topics using only the GRIF field of LL. This pool of relevance information has been noted to be incomplete . For our collection of 9,390 queries, our strategy extracting from both PMID and GRIF fields identified more than twice the number of gold standard judgments (47,639) as compared to using the GRIF field alone (21,517). We observe that 76% of our topics have five or less relevant documents identified through LL. This suggests that ensuring accuracy in retrieval for gene queries is a challenge and users are likely to benefit from retrieved sets ranked by relevance potential. For a given gene we compute a set of term vectors using a basic tf*idf strategy for term weighting. Term vectors are computed for each retrieved MEDLINE record and for each ranking query. Cosine similarity scores in [0,1] are calculated for each ranking query vector – retrieved document vector pair. Given a ranking query retrieved documents are ranked by cosine similarity to the query. The ranked sets are limited to the top ranked 10,000 documents. We believe it is unlikely that a user would want a larger retrieved set. We measure the quality of ranking using average precision (AP) . AP is the average of the precision scores calculated at the position of each relevant document in a ranked document list. E.g., given a ranked list where the 3 gold standard documents are at rank 2, 5 and 7, AP is the average of precision scores (0.5, 0.4, 0.43) which equals 0.44. Since AP is sensitive to the rank of each relevant document we also compute (normalized) precision of the top 5 ranked documents (NTop5P = Top5P/max_Top5P). Top5P is the number of relevant documents in the top 5 ranks divided by 5. The normalization factor is included as some queries have less than 5 relevant documents. E.g., if a gene has only 3 gold standard documents then the max_Top5P is 0.6. If for such a query, all 3 relevant documents are within the top 5 positions, NTop5P = 0.6/0.6 = 1. If instead only 2 are in the top 5, then NTop5P = 0.4/0.6 = 0.63. For queries with at least 5 relevant documents, NTop5P is the same as Top5P.
Baseline 1 (B1): This ranking query is the same as the PubMed query (gene name and aliases) without the disjunction operator.
Baseline 2 (B2): We add to the B1 ranking query the terms 'gene', 'genetics', 'genome' and 'oncogene'. Here we hope to steer the ranking in favor of documents in the overall genetics domain. This query is motivated in part by the notion of a "query zone" .
Summary (S): We add to B1 the SUMMARY field of the gene's LL record. This field, when available, describes for example, the gene's function, its structure and associated phenotype information. It is generated using data from various sources .
Product (P): We add to the B1 query the PRODUCT, PREFERRED_PRODUCT, ALIAS_PROT fields in LL.
Summary+Product (SP): Both LL summary and product information are added to the B1 ranking query.
Unfortunately not all 9,390 genes in our pool have both the summary and product fields in LL. A subset of 4,647 genes have both summary and product (used in expt. 1); a different subset of 4,195 has no summary (used in expt. 2), while the full set is used in expt. 3.
Ranking results (Expt. 1)
In general, our best strategies, SP and S, do significantly better than B2. For SP, the percentage improvements start at 11.6% for AP (from bin 4) and 7.9% for NTop5P (from bin 5). Thus our gene specific strategies perform better than the generic ranking strategy. Not surprisingly, we observe that it is difficult to make improvements when B1 performance is already quite reasonable. The question we now face is, given a gene query, can we predict whether its B1 performance is going to be sufficient? In other words, can we identify genes for which our SP ranking will generate improvements? We return to this question later in the paper.
Results for ambiguous genes
A significant emphasis in recent research is on exploring and understanding the extent and variety of ambiguity in gene terms. Thus we examine the merits of our ranking strategies within particular genes that are referenced by ambiguous terms. We explore three varieties of ambiguity. These are not mutually exclusive, since a given gene search term may be ambiguous in more than one way. We remind the reader of the distinction between a gene and its component gene terms (search terms). Ambiguities are determined at the search term level. A gene is considered ambiguous if at least one of its search terms is ambiguous.
Different genes – same gene terms
Gene terms with English language meanings
The second variety of ambiguity is one where the gene term (typically gene symbols such as GAB, ACT and BAR)also has a general English language meaning. We identify such terms by a simple lookup of WordNet . We eliminate instances where the meanings contain words such as gene, genome, enzyme, amino acid, which point back to a genetics related meaning. 446 of the 4,647 (9.6%) genes in our pool have at least one gene term with a general English meaning. The results for this subset are shown in figures 5 &6 under 'English Genes'. Here the S strategy takes the lead, especially in NTop5P. It gives 13.6% (19%) improvement in MAP and 13.7% (24.5%) improvement in NTop5P over B2 (B1). Except for MAP w.r.t. B2, all improvements are statistically significant at 0.05. SP also performs very well. However, the differences in MAP and mean NTop5P are in general not statistically significant at the 0.05 level.
Gene terms with other meanings in MEDLINE
There are also gene terms with other biological meanings . For example, the gene term ACR has many different biomedical meanings including albumin/creatinine ratios, acquired cellular resistance and acute to chronic ratio .Meanings such as anomalous cosmic rays also appear in MEDLINE. The correct gene meaning we seek is acrosin .Other researchers have explored this aspect, especially in the context of expanding abbreviations [28, 29]. In particular Schwartz and Hearst  published an algorithm that allows one to recognize short form-long form pairs appearing as A (B) in text where A is a short form and B is its corresponding long form. We choose this algorithm over the others [28, 29] because of its simplicity and speed. It is also equivalent in effectiveness to most of the other approaches .
We process the retrieved documents for each gene through the Schwartz and Hearst algorithm looking for possible expansions for each term in that gene's search. 2,277/4,647 genes (47.8%) have at least 1 component gene term with more than 1 long form identified. These are considered ambiguous. This approach is not without limitations, since the algorithm relies on the presence of A (B) structures in the texts with A representing the gene term and B recognized correctly as a possible expansion. Results for this subset of 2,277 genes are shown under 'Bio Genes' in figures 5 &6. The SP strategy, (with S being equivalent) gives a 11.7% (17.5%) improvement in MAP and 9.7% (17.2%) improvement in mean NTop5P over B2 (B1). The figures also indicate that the improvements are significant at the 0.05 significance level. We also estimate the extent of ambiguity at the gene level, which we call Ambiguity Bio . For a gene G it is defined as follows:
Ambiguity Bio (G) = 0, if |Expansions(g i )| = 1,∀i ∈ n
Ambiguity Bio (G) = ∑i∈n|Expansions(g i )| otherwise
where |Expansion(g i )| is the number of long forms for gene term g i found by the algorithm and g i ,i n are the search terms in the PubMed query for gene G.
Summary of ambiguity analysis
With two of the three varieties of ambiguity, SP is significantly better than B1 and B2 in MAP and NTop5P. The scores for ENG seem to lag behind both in MAP and NTop5P. When we consider MAP, DG seems easier to accommodate. We note that the gene sets overlap across these ambiguities. There are 411 genes that are in ENG and BIO, 361 in Eng and DG, 1,948 in DG and BIO. Thus for example, 92.2% and 80.9% of the ENG genes also fall into the BIO and DG categories respectively; 18.1% and 70.3% of the BIO genes are also in ENG and DG respectively.
Performance versus retrieval set size
Ranking results without LL summaries (Expt. 2)
Predicting B1 performance
Correlation Coefficients. The table shows the strength of the correlations among the different kinds of ambiguities and the number of retrieved documents and their correlation with the B1 AP Score.
B1 AP Score
score = β0 + β1. N'+ ∈
Regression Results. The results of the regression to predict the B1 AP score using the size of the retrieved set as the predictive variable.
To test this calibrated model we exploit the natural split in our collection of genes. The regression model was developed on the set of 4,647 genes of experiment 1. We use the non-overlapping, naturally held out set of 4,195 genes (those without summary and product information) as our test set. We are specifically interested in predicting if the B1 score for each test gene is likely to be higher than 0.7 or not. From figure 3 observe that if B1 AP score is approximately 0.7 or higher, it is best not to do any other kind of ranking. In the test set there are 1,498/4,195 (35.7%) genes with B1 score > 0.7. The default (majority) decision that all genes will have scores ≤ 0.7, gives an accuracy of 0.643. In contrast the regression results applied to the test data gives an accuracy of 0.716, an improvement of 11.4%. These encouraging results indicate that it may be possible to predict the level of B1 performance given just the size of the retrieved set. These conclusions will be tested further in future research.
Results with an overall strategy (Expt. 3)
We explored the relative effectiveness of five different post PubMed retrieval ranking strategies for human gene queries. We conclude that the combination of LocusLink summary and product information (or just summary) along with the gene name and aliases may be used to effectively rank retrieved documents. This conclusion is consistent with other research where some form of curated knowledge has been used to improve performance as for example the work of Koike and Takagi . A ranked list of documents for each gene is provided on our web site .
Interestingly, using product names without summary is ineffective. This could be because the product names are more prone to being ambiguous. We find that in the absence of summary information, our manually designed generic query targeting the genetics domain combined with the gene names is the best. We were not able to automatically build a more effective 'generic' query.
Our LocusLink strategies are significantly more effective than baselines even when faced with ambiguity. The English ambiguity problem is the most challenging and is also fortunately the least prevalent. Finally, retrieved set size may give us a way to predict which genes are best handled by the B2 strategy. This could also be the basis of gene query clarity scores akin to research in . We observe the presence of genes with very low B1 AP scores (< 0.2) that are not identified as having any ambiguity using our methods. Either our ambiguity detection methods are inadequate or there are other facets impeding retrieval. We plan to explore other detection approaches as seen for example in .
An analysis of the probable causes of error raises some interesting observations. We observe three probable causes of failure with our SP strategy. Firstly, there are relevant documents without abstracts. SP favors documents with abstracts (as more words are then likely to be shared with the summary from LocusLink). E.g., the gene A2M (LLID 2) has a gold standard document (PMID 1707161) which has no abstract. This is ranked at position 5 by B2 and 180 by SP. In our dataset 25% of the gold standard instances that have abstracts are in the top 5 ranked documents (for SP) while the corresponding percentage for gold standard instances without abstracts is only 15% (also for SP). Another probable cause of error is the varying themes in the documents. Since the SP strategy is dominated by the LocusLink summary, this strategy favors documents that reflect a similar theme. For an example of an error where themes do not match, the gold standard document with PMID 9116026 for the gene CENPB (LLID 1059) talks about isolating a novel human homolog to the gene whereas the LL summary is primarily a description of the gene's function. This document is ranked 17th by SP and 2nd by B2. A third probable cause of error is the high rank given to some documents that mention the correct gene but in the context of another organism. E.g., for the gastrin gene (LLID 2520), 6 of the top 10 ranked documents (including the top ranked document) are not about humans. These are not in the gold standard set for the gene. One way of dealing with this problem may be to consider only those documents that have the MeSH term 'Human' (under the 'Organisms' semantic category), assigned to them. Although far from conclusive, these observations give us directions for more rigorous error analysis in the future.
We deliberately kept the ranking model simple using only traditional tf*idf vectors and cosine similarity. This allowed us to focus on other dimensions in this research. Clearly retrieval models such as language models with or without feedback may be tried. Having obtained encouraging results with the TREC dataset, we will now consider the full MEDLINE database. We also plan to work with genes from other genomes. We will also explore other sources for gene descriptions such as OMIM. These may offer interesting avenues for genes without LL/Entrez Gene summaries.
Gene queries and documents
We start with 12,385 human genes with known function identified from LocusLink (LL)1. LL is a manually curated database with a variety of information on genes such as names, symbols and pointers to relevant documents. For each gene we search MEDLINE using the ESearch utility available from the NCBI website . Our search strategy is the disjunction of the aliases for the gene, taken from the OFFICIAL_GENE_NAME, OFFICIAL_SYMBOL and ALIAS_SYMBOL fields of LL. For example the search for the gene with official name alpha- 1-B glycoprotein is "A1BG OR A1B OR ABG OR GAB OR alpha-1-B glycoprotein". Relevant documents (our gold standard) are identified by extracting the documents identified in each gene's LL record (PMID and GRIF fields). Documents listed in these fields are typically identified by human curators and indexers (with subject expertise).
In order to minimize the load on the NCBI server, given our large number of queries, we constrain our experiments to the 2004 3TREC Genomics dataset , which contains close to 4.6 million MEDLINE records. This subset is a recent one-third (approximately 1994 to 2003) of the full MEDLINE database. When limited to this dataset, 9,390 of the 12,385 original gene topics have at least 1 retrieved relevant document. These retrieve a total of 45,216,725 records from this dataset (average = 4,815). The one modification made to the TREC dataset was to add relevant documents retrieved but not already present (5,516 relevant documents). 4,111,272 unique records (of the 4.6 million) in the modified TREC dataset were retrieved for at least 1 gene query. The 9,390 genes and their associated data form the basis of our experiments.
Distribution of Retrieved and Relevant Documents (9,390 genes) A topic is defined as a gene query. Thus, in the table, 5270 gene queries retrieve between 0–100 documents and 7101 gene queries have between 1–5 relevant documents identified in LocusLink.
# Retrieved Documents
# Relevant Documents
We use Lemur version 3.1  installed on a system with 2 GB RAM, running Redhat Linux 9.0. Lemur is a toolkit developed by researchers at Carnegie Mellon University and the University of Massachusetts for language modeling and IR-related tasks. For a given gene its retrieved documents and its ranking query(ies) are first represented by term vectors where term weighting is done using a basic tf*idf (term frequency * inverse document frequency) strategy. These vectors are built using Lemur. A stoplist of 571 commonly used English words (such as 'a', 'are', 'the') is used and words are stemmed. Cosine similarity scores in [0,1] are calculated between query vectors and document vectors. Given a ranking query and a retrieved set of documents for a gene, the documents are ranked by their cosine similarity score with the query vector. The ranked sets are limited to the top ranked 10,000 documents. We believe it is unlikely that a user would want a larger retrieved set. To index the documents we use the title, abstract, MeSH (Medical Subject Headings) and RN (chemical names) fields.
A web-based system offering access to retrieved and ranked document sets for gene queries is freely available at (http://sulu.info-science.uiowa.edu/genedocs).
1 Download date October 2, 2003. We note that LocusLink is now a part of NCBI's Entrez Gene. Importantly, the LocusLink fields used in this study are still available through Entrez Gene.
We would like to thank our colleague Xin Ying Qiu for her helpful comments. We are grateful to Dr. Babru Samal, Cheryl Malone, and Bryan Allen for providing expert judgments in our user evaluation study. We would also like to thank the anonymous reviewers for the suggestions they made during the review process, to improve the paper. This material is based upon work supported by the National Science Foundation under Grant No. 0312356 awarded to Padmini Srinivasan. Any opinions, findings, and conclusions or recommendations expressed in this material are those of the author(s) and do not necessarily reflect the views of the National Science Foundation.
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