BACKGROUND
in the last years the focus of biological research has shifted from individual genes and proteins towards the study of entire biological systems.
the advent of high-throughput experimentation has led to the generation of large data sets, which is reflected in the constant growth of dedicated repositories such as sequence databases and literature collections.
for instance, medline indexes more than  <dig> million articles in the biomedical sciences , and it's increasing at a rate of more than 10% each year  <cit> .
in this scenario, literature mining tools are becoming essential for biomedical researchers, as they can be used to extract, manage, integrate and exploit the biological knowledge recorded in the literature.
text mining approaches are being applied to predict the function of novel genes, for the functional annotation of molecules, discovering protein-protein interactions, interpreting microarray experiments, association of genes and phenotypes, to only mention some applications .
the basis of any text mining system is the proper identification of the entities mentioned in the text, also known as named entity recognition .
in biology, the entities of interest are genes, proteins, chemical compounds, diseases, tissues, and cellular components, among others.
since naming of biological entities is inconsistent and imprecise, tools that automatically extract the terms that refer to the entities and link them to biological databases are required  <cit> .
ner has been an intense subject of research in the last years, specially for the identification of terms pertaining to genes and proteins  <cit> .
the mapping of a term to a database identifier  is important from a biomedical perspective, because it provides the correct biological context to that term.
for instance, mapping a variation entity with a dbsnp  <cit>  identifier allows its unambiguous identification, and in consequence all the information available for this variation can be gathered .
however, not all ner systems include a normalization step.
the first ner tools developed relied on manually devised rules that reflected typical features of gene and protein names as well as contextual information provided by nearby words such as "gene" or "protein" or "receptor"  <cit> .
as annotated literature collections  in which gene and protein names are manually tagged were available, application of machine learning algorithms became feasible  <cit> .
contrasting, dictionary based methods rely on comprehensive lists of terms that are matched against the documents allowing variations in how the terms are written  <cit> .
the crucial advantage of dictionary based approaches is that they allow the normalization of the entities so far identified.
contrasting to the extensive research carried out in the field of gene and protein identification, few initiatives have been directed to the task of identification of single nucleotide polymorphisms  and other types of sequence variants from the literature.
the first approach on this direction was mutext, which focused on collecting single point mutations for two protein families: nuclear hormone receptors  and g-protein coupled receptors   <cit> .
mutext searched on full text articles looking for protein mutations using regular expressions, achieving a recall of  <dig> % and  <dig> %, and a precision of  <dig> % and  <dig> % .
a related approach has been implemented in mema  <cit> , in which regular expressions were used to extract variation-gene pairs from medline abstracts.
a difference with mutext is that mema takes into account variations of the substitution type both at the nucleotide and the amino acid levels.
nevertheless, the mema system achieved a higher performance  for the identification and extraction of allelic variants from text.
the variation tagger vtag  <cit>  was developed for the identification of several types of sequence variations related to cancer in the literature.
it is based on a probability model called conditional random fields.
the reported performance of this method is quite good as it reaches 79% recall, 85% precision, and 82% f-score.
although the above mentioned approaches represent nice examples of systems for the identification of variations, some of them are specifically focused on specific protein family classes  <cit>  or diseases  <cit> , and more importantly, none of these methods tackle the problem of the normalization of the variation entities so far identified.
these features, however, are incorporated in the osiris information retrieval system .
osirisv <dig>  integrates different sources of information and incorporates ad-hoc tools for terminology generation with the aim of literature retrieval about the allelic variants of a gene using the pubmed search engine  <cit> .
although the use of osirisv <dig>  helps the researchers in the tedious task of searching literature for sequence variants of genes, there was room for improvement.
for instance, the first implementation of osiris uses the pubmed search engine, and does not include a ner system for the identification and tagging of the terms within the text.
the present article describes the development of a new version of osiris .
a key aspect was to develop a ner system for identification and normalization of sequence variants of human genes.
the new implementation of osiris incorporates its own ner module and is built on top of a local mirror of medline collection and hgenetinfodb.
hgenetinfodb is a database that integrates data on human entries from the ncbi gene database  <cit>  and dbsnp  <cit> .
the ner module is based on a corpus of articles automatically annotated with ncbi gene identifiers and the new osirisv <dig>  search algorithm.
the new osirisv <dig>  search algorithm uses a pattern matching based search strategy and a sequence variant nomenclature dictionary for the identification of terms denoting snps and other sequence variants and their mapping to dbsnp identifiers.
the use of osirisv <dig>  on medline abstracts generates a corpus of annotated literature linked to sequence database identifiers .
the performance of osirisv <dig>  was evaluated on a manually annotated corpus, resulting in 99% precision, 82% recall, and an f-score of  <dig> .
as an example, the application of the system for collecting literature for the allelic variants of genes related with two complex diseases  is presented.
RESULTS
development of a ner system for gene sequence variants
our group has previously reported the development of osirisv <dig>   <cit> , a tool for the retrieval of literature associated to the allelic variants of a gene based in the pubmed search engine.
with the aim to improve the recognition of variations from text in terms of recall and precision we developed osirisv <dig> , based on its own ner algorithm and local data sources .
in addition, we paid special attention to the normalization of the genetic variants, as it provides biologically relevant contextual information.
the work flow of osirisv <dig>  is detailed in the methods section and illustrated in figure  <dig>  briefly, osirisv <dig>  scans medline abstracts, identifies texts passages corresponding to variation terms, and disambiguates the terms to dbsnp identifiers.
the results are stored in the textminingdb database, and a web interface for the query and visualization of the results was developed  <cit> .
results for two diseases used as test cases are currently available in the database.
a description of these results can be found in the section "application of osirisv <dig>  for finding sequence variants information on a set of aneurysm-related genes".
in the following section, a brief description of the user interface is presented.
<dig>  user interface
the user interface offers two possibilities for browsing the results of osirisv <dig>  on the test cases.
the results can be queried by a gene-centred search approach on the basis of the related disease , or by using mesh disease terms .
<dig> .
gene-centred search approach
by using this modality of search, a list of the genes for which results were found are presented.
two possibilities for browsing the results on these genes are available: "see variants" and "see references" .
by clicking the link "see variants", a page comprising two pieces of information is displayed on the browser: dbsnp-related information for the gene and literature-related information .
the first includes the sequence variants described for the gene.
this information is provided by the database hgenetinfodb and is organized in tabular format with several hyperlinks.
the sequence variants are classified according to their mapping to the gene sequence in coding or non-coding regions of the gene.
the table includes the following information for each dbsnp entry: the unique identifier from dbsnp , the type of variant , the position of the variant relative to the gene sequence, the alleles, and specifies the mapping or location of the variant .
in addition, the identifiers of the mrna and protein sequences are provided in the case of snps that map to coding sequences.
in the case of variations located in coding regions, the position and amino acidic residues of the variation in the protein sequence are shown.
the data are provided with hyperlinks to the corresponding data sources .
regarding the literature information, the last column in the table indicates if any reference was found for each dbsnp entry, and provides a link to another page where this information is detailed .
in this page, the data is organized by dbsnp entry, displaying the text passages where a term representing the dbsnp entry was identified by osirisv <dig> .
these terms are highlighted to aid visualization and contain hyperlinks to dbsnp.
three colouring codes are used: the terms corresponding to the current dbsnp entry appear in red, in light blue the terms corresponding to other sequence variants found in the text, and in yellow the terms that are mapped to more than one dbsnp identifier.
in addition, a table showing the terms from the disease category of the mesh hierarchy extracted from the set of abstracts annotated to the variation is provided .
by using this approach, the reader is directly pointed to the text passages where snps, for instance, are mentioned.
in addition, the pmid of the corresponding article is provided with its hyperlink to the abstract, giving the reader the opportunity to review the complete abstract.
another view of the results is displayed by clicking "see references", where text passages from all the abstracts found for the sequence variants of the gene are shown.
again, the terms corresponding to the variants are highlighted and contain hyperlinks to dbsnp.
three colouring codes are used: the variants mapped to the current gene appear in red, and in light blue the variants belonging to other genes, in yellow the variants that are mapped to more than one dbsnp identifier.
<dig> .
mesh term search approach
the results can also be queried using the mesh disease terms .
variations associated to the main disease categories from the mesh hierarchy can be retrieved.
for instance, genetic variants associated with musculoskeletal diseases or cardiovascular diseases, both examples of broad categories of diseases in the mesh hierarchy, can be retrieved using this search modality.
the results are organized in a table showing the variants described in association with the disease in the literature .
alternatively, the mesh disease terms associated to an specific dbsnp entry through the literature can be obtained as well.
this functionality provides a phenotypic description in the disease area for the allelic variations of a gene.
these results are also shown using the gene-centred search modality.
it is worthwhile to mention that not all the terms that refer to variations in the text passages shown in osirisv <dig>  output are highlighted.
this is due to the following reasons:  <dig> – not all the variants mentioned in the text can be mapped to a dbsnp identifier;  <dig> – the variant mentioned in the text is mapped to a gene for which a osirisv <dig>  search has not been performed;  <dig> – the level of recall of the search algorithm .
in summary, the use of osirisv <dig>  provides a way to access to the literature reported for the allelic variants of a gene of interest in a few mouse clicks.
in addition, it identifies and highlights the terms corresponding to the allelic variants aiding in the visualization of the search results, and therefore saving time for the user.
evaluation
an evaluation was carried out to assess the performance of osirisv <dig> .
this kind of evaluation requires a set of reference documents that are judged as relevant or irrelevant for a certain query, i.e.
a corpus or gold standard .
a manually annotated corpus was developed for the purpose of the evaluation of the sequence variant extraction and normalization tasks.
this is a valuable accomplishment since there is high demand of such standards for evaluation purposes  <cit> .
the corpus is available upon request.
the evaluation consisted in assessing of both the identification of the terms that refer to variations and the normalization of these terms.
the result of the evaluation indicated that the algorithm is geared towards high precision  at a recall of 89%, resulting in an f-score of  <dig> , for the recognition of variation terms and disambiguation to dbsnp identifiers.
a comparison of the performance of all the current methodologies is shown in table  <dig>  both versions of osiris were evaluated on the corpus developed in this study.
regarding the other approaches, although the results of the evaluations carried out in each case are not directly comparable , it serves as a rough comparison with the published methods.
osirisv <dig>  and osirisv <dig>  were evaluated on the corpus described in this study.
performance of other methods correspond to published data for each development.
since the use of different benchmarks and the different evaluation criteria make the results not strictly comparable, the results can only be considered for a rough comparison of the state of the art.
*average of evaluation on two protein families reported
the evaluation for osirisv <dig>  shows satisfactory results for both precision and recall.
the low recall of osirisv <dig>  could be explained by the inability of the query expansion approach used by the system to recover all the variation specific terms.
the recall is increased in the new implementation by improvement of both the recognition of gene and variation terms.
regarding the other approaches, published results indicate that the mema system  <cit>  achieved a 75% recall and 98% precision for the recovery of mutations from texts.
mema uses regular expressions for finding mutations-gene pairs, but it does not provide mapping to dbsnp entries.
in this system, the association of a mutation with a gene is done by co-occurrence of both terms in a sentence.
contrasting, osirisv <dig>  uses co-occurrence and a sequence based approach.
the vtag approach  <cit> , based on a probabilistic model to identify mutation terms, achieves a high recall level, but without providing mapping to sequence database entries.
the strategy used by osirisv <dig>  provides a way to achieve recognition and mapping of variation terms to dbsnp identifiers with high precision and recall, which are very important features for database annotation purposes and mining information from text.
in addition, the results of the evaluation indicates that a simple search algorithm performs well in the task of ner and normalization of sequence variants.
the recall could be further improved by recognition of complex expressions representing sequence variants, such as "g/a genotype associated with tumour necrosis factor-alpha promoter positions - <dig> and -244".
future implementations including a broader terminology will probably achieve higher recall levels.
other factor having a negative impact on osirisv <dig>  recall are the lack of agreement between the numbering of variants position in articles and the one found in databases for some variations.
as mentioned above, the approach used by osirisv <dig>  to correctly link a variation with a gene is based on co-occurrence of gene and variation terms in the text and sequence mapping.
nevertheless, in some cases it is not possible to assign a variation to a gene in an unambiguous manner.
this occurs when two genes and their sequence variants are mentioned in the abstract, and, just by chance, the variants share some of the features required for normalization .
in such cases, the term will be annotated with two dbsnp identifiers that are mapped to different genes, leading to an ambiguous annotation.
these cases are highlighted in yellow in the results displayed on the web.
in order to study in what extent this situation leads to ambiguous annotations, we conducted the following evaluation.
we assessed the number of terms referring to a variation that were assigned to more than one dbsnp identifier by osirisv <dig> .
this evaluation was conducted on all the data present in the textminingdb .
we found that  <dig> %  of the variations had been annotated with more than one identifier from dbsnp.
from this set,  <dig> %  resulted from an incorrect identification of a gene term by prominer,  <dig> %  were due to multiple annotations in dbsnp, and  <dig> %  resulted from an incorrect assignment of the variation to the term.
multiple annotations in dbsnp occur when a variation has more than one dbsnp identifier , and are merged in subsequent updates of the database.
this means that  <dig> % of the cases are not really ambiguous: the dbsnp identifiers assigned point to the same variation in the gene sequence.
in summary, only  <dig> % of annotations are ambiguous due to the inability to distinguish between multiple dbsnp identifiers for a single variation, and lead to an incorrect linkage of variation and gene.
the ambiguous annotations are shown in table  <dig>
<dig>  <dig> 15941956
<dig>  <dig> 11096344
17885129
1059350
the table show the cases where an ambiguous assignment of a dbsnp identifier to a variation term was obtained.
the first column depicts the pmid of the abstracts where the term  was found.
the third column shows the dbsnp identifiers assigned to the term by osirisv <dig> .
highlighted in bold are the correct assignment of dbsnp identifier to that term.
in some instances the information from the text does not allow to discern between two snps occurring at the same position in the protein sequence but differing only in one of the alternative residues.
for example, for the "asp86" term, both snps highlighted in bold represent changes at position  <dig> of the protein in which an asp residue is involved.
one is a synonymous change while the other is non-synonymous.
however, the information extracted from the text is not sufficient to distinguish among these two possibilities , and therefore both identifiers are assigned to the term.
application of osirisv <dig>  for finding sequence variant information on a set of aneurysm related genes
two complex diseases were used as test cases for the system: breast cancer and intracranial aneurysm and subarachnoid haemorrhage.
the results can be queried through the web interface  <cit> .
only results for intracranial aneurysm will be discussed as an example.
a summary of the data present in the textminingdb database is shown in table  <dig>
results for the diseases intracranial aneurysm and breast cancer were compiled.
the disease-specific corpora were built using pubmed and the queries described in the methods section.
the genes described in each corpora were extracted using prominer, and a list of genes specific for each disease was obtained.
then, osirisv <dig>  searches were performed for each list of genes on the whole medline collection.
results presented in the table correspond to the medline collection at august  <dig>
subarachnoid haemorrhage as a consequence of intracranial aneurysm is one of the most devastating cerebrovascular diseases due to its high morbidity and mortality.
cerebral aneurysms are extensions of arterial vessels in the brain.
these extensions are balloon-type bulges that form in apparently healthy people with a comparably high frequency   <cit> .
the interaction of genetic as well as environmental risk factors are thought to play an important role in the pathogenesis and prognosis of the disease.
in addition to smoking, hypertension, arteriosclerosis and alcohol intake, haemodynamic stress at arterial bifurcations is believed to contribute to the development of aneurysms  <cit> .
several studies have claimed that the presence of certain allelic variants may increase the individual's susceptibility to develop intracranial aneurysms, and might be used as biomarkers for the risk of aneurysm rupture  <cit> .
in this context, the identification of the sequence variants associated to the disease phenotype in specific populations is of high value for early diagnosis and treatment, and also for providing an understanding of the pathogenesis of the disease.
osirisv <dig>  was utilized for collecting sequence variants data for a set of genes related to the disease, and for the identification of snp terms from medline abstracts, with the aim of collecting the available information on the variants under study in the disease.
a set of aneurysm-related genes was automatically identified on the basis of their occurrence in abstracts pertaining to the disease.
the abstracts related to the disease were retrieved using pubmed search engine with the queries described in methods and scanned with prominer  <cit> .
this resulted in a set of  <dig> genes, to which  <dig> variations are mapped according to dbsnp.
then, osirisv <dig>  was used to search literature citations for the dbsnp entries mapped to the  <dig> aneurysm-related genes.
since the searches performed on the abstracts belonging to the aneurysm-related corpora resulted in a small number of osirisv <dig>  annotations , the searches were then conducted in the entire medline collection.
results were obtained for  <dig> genes and  <dig> variants, which were found to be linked to  <dig> citations .
these results represent a collection of the citations that refer to sequence variants on these genes, and are available at  <cit> .
to illustrate the kind of insights that can be obtained using osirisv <dig> , the gene for the endothelial nitric oxide synthase or enos,  will be used as an example.
nos <dig> is one of the candidates for the pathogenesis of intracranial aneurysm, and its association with the disease has been addressed by several studies  <cit> .
moreover, it might be involved in the observed sex differences in the outcome of subarachnoidal haemorrhage as a consequence of intracranial aneurysms  <cit> .
endothelial nitric oxide synthase is one of the three isoforms of the enzyme nitric oxide synthase.
nitric oxide  is important in the regulation of vasomotor tone and blood flow by inhibiting smooth muscle contraction and platelet aggregation.
mice lacking nos <dig> gene are hypertensive and the combined deletion of nos <dig> and apolipoprotein e confers an increased susceptibility to arteriosclerosis.
the production of no is regulated at the level of nos <dig> gene expression and activity of the enzyme.
the promoter of the gene contains transcription factor binding sites that mediate regulation by shear stress and oestrogens  <cit> .
several citations were found to refer to variations in the nos <dig> gene by osirisv <dig> .
the analysis that follows is based on the literature citations found by osirisv <dig>  for one of the most studied variants of the gene .
regarding the association with aneurysm, the rs <dig> variant has been described as one of the genetic factors related to the risk of aneurysm rupture in a population from usa .
although this finding could not be replicated in a japanese population , the rs <dig> variant was found to be a mild predisposing factor for abdominal aortic aneurysm, a chronic degenerative condition associated with arteriosclerosis .
the putative association of this variant with diseases other than aneurysms has been extensively investigated, as shown by the mesh disease terms extracted from the set of articles annotated to this variant: hypertension, pre-eclampsia, myocardial infarction, alzheimer disease.
deregulation of vascular homeostasis is a common factor among the above mentioned diseases, appearing as a symptom or as a risk factor.
the association of the rs <dig> variant with these phenotypes might be reflecting a common mechanism in the disease pathogenesis.
the rs <dig> variant, although leads to a conservative change in the protein sequence , would have functional consequences, as suggested by studies showing that the asp residue is subjected to selective proteolytic cleavage in endothelial cells and vascular tissues  that impairs no production .
however, recent findings have challenged these observations .
thus, it is likely that any relationship between the variant and the disease phenotype is due to this being an indirect marker of the genetic association rather than a direct functional effect.
alternatively, a different functional effect of the variant  might explain the observed clinical features under pathological conditions.
further work is required to clarify the kind of relationship  of the rs <dig> variant with the disease phenotypes.
CONCLUSIONS
in this report we present osirisv <dig> , a system for collecting the current knowledge about gene sequence variants from the literature.
the evaluation of osirisv <dig>  on a manually annotated corpus showed that it achieves high precision  and recall  in named entity recognition and disambiguation of terms.
the ner system that is the basis of osirisv <dig>  was combined with a ner system for genes and proteins  that in turn will form the basis of a disease centric information system by integrating ner with disease specific biomedical literature search.
this integrated system will allow the extraction of information related to genotype-phenotype relationships in human diseases.
the architecture of the system allows incorporation of additional modules, such as ner modules for drugs and diseases, and modules for mining relationships between the entities so far identified.
in addition, automatic systems for updating the text mining results allow to keep up to date the extracted information.
to demonstrate the usefulness of the approach, osirisv <dig>  was applied for the development of a database of literature references associated with allelic variants of genes related with two complex diseases: intracranial aneurysm and subarachnoid haemorrhage, and breast cancer.
as illustrated with the example on one of the snps of the nos <dig> gene, several interesting pieces of information regarding related phenotypes and functional effects of a variation can be easily obtained using osirisv <dig> .
the approach also illustrates the strategy for linking genetic variants of genes present in sequence databases  with disease terms of a controlled vocabulary  through the literature.
moreover, this approach could be used for developing similar databases focused in other diseases.
although the system has been implemented for human genes, the general approach is easily applicable to other organisms with variation data available .
osirisv <dig>  is focused in identifying the terms from text that represent variations from reference sequence repositories such as dbsnp.
the combined use of osirisv <dig>   and any other ner that search for variation entities in general without normalization  would provide with two sets of snp data that could be of interest to dbsnp curators.
in this regard, we anticipate that a suitable application of osirisv <dig>  would be for supporting the functional annotation of dbsnp entries.
this is a relevant issue since the unravelling of the biological consequences of sequence variants remains a challenging task.
in addition, elucidation of the functional impact of predisposing snp alleles identified by genome wide association studies has important implications in terms of understanding the underlying biology of complex diseases and identifying putative therapeutic targets.

 in the last years the focus of biological research has shifted from individual genes and proteins towards the study of entire biological systems. the advent of high-throughput experimentation has led to the generation of large data sets, which is reflected in the constant growth of dedicated repositories such as sequence databases and literature collections. for instance, medline indexes more than million articles in the biomedical sciences, and it's increasing at a rate of more than 10% each year. in this scenario, literature mining tools are becoming essential for biomedical researchers, as they can be used to extract, manage, integrate and exploit the biological knowledge recorded in the literature. text mining approaches are being applied to predict the function of novel genes, for the functional annotation of molecules, discovering protein-protein interactions, interpreting microarray experiments, association of genes and phenotypes, to only mention some applications. the basis of any text mining system is the proper identification of the entities mentioned in the text, also known as named entity recognition. in biology, the entities of interest are genes, proteins, chemical compounds, diseases, tissues, and cellular components, among others. since naming of biological entities is inconsistent and imprecise, tools that automatically extract the terms that refer to the entities and link them to biological databases are required. ner has been an intense subject of research in the last years, specially for the identification of terms pertaining to genes and proteins. the mapping of a term to a database identifier is important from a biomedical perspective, because it provides the correct biological context to that term. for instance, mapping a variation entity with a dbsnp identifier allows its unambiguous identification, and in consequence all the information available for this variation can be gathered. however, not all ner systems include a normalization step. the first ner tools developed relied on manually devised rules that reflected typical features of gene and protein names as well as contextual information provided by nearby words such as "gene" or "protein" or "receptor". as annotated literature collections in which gene and protein names are manually tagged were available, application of machine learning algorithms became feasible. contrasting, dictionary based methods rely on comprehensive lists of terms that are matched against the documents allowing variations in how the terms are written. the crucial advantage of dictionary based approaches is that they allow the normalization of the entities so far identified. contrasting to the extensive research carried out in the field of gene and protein identification, few initiatives have been directed to the task of identification of single nucleotide polymorphisms and other types of sequence variants from the literature. the first approach on this direction was mutext, which focused on collecting single point mutations for two protein families: nuclear hormone receptors and g-protein coupled receptors. mutext searched on full text articles looking for protein mutations using regular expressions, achieving a recall of % and %, and a precision of % and %. a related approach has been implemented in mema, in which regular expressions were used to extract variation-gene pairs from medline abstracts. a difference with mutext is that mema takes into account variations of the substitution type both at the nucleotide and the amino acid levels. nevertheless, the mema system achieved a higher performance for the identification and extraction of allelic variants from text. the variation tagger vtag was developed for the identification of several types of sequence variations related to cancer in the literature. it is based on a probability model called conditional random fields. the reported performance of this method is quite good as it reaches 79% recall, 85% precision, and 82% f-score. although the above mentioned approaches represent nice examples of systems for the identification of variations, some of them are specifically focused on specific protein family classes or diseases, and more importantly, none of these methods tackle the problem of the normalization of the variation entities so far identified. these features, however, are incorporated in the osiris information retrieval system. osirisv integrates different sources of information and incorporates ad-hoc tools for terminology generation with the aim of literature retrieval about the allelic variants of a gene using the pubmed search engine. although the use of osirisv helps the researchers in the tedious task of searching literature for sequence variants of genes, there was room for improvement. for instance, the first implementation of osiris uses the pubmed search engine, and does not include a ner system for the identification and tagging of the terms within the text. the present article describes the development of a new version of osiris. a key aspect was to develop a ner system for identification and normalization of sequence variants of human genes. the new implementation of osiris incorporates its own ner module and is built on top of a local mirror of medline collection and hgenetinfodb. hgenetinfodb is a database that integrates data on human entries from the ncbi gene database and dbsnp. the ner module is based on a corpus of articles automatically annotated with ncbi gene identifiers and the new osirisv search algorithm. the new osirisv search algorithm uses a pattern matching based search strategy and a sequence variant nomenclature dictionary for the identification of terms denoting snps and other sequence variants and their mapping to dbsnp identifiers. the use of osirisv on medline abstracts generates a corpus of annotated literature linked to sequence database identifiers. the performance of osirisv was evaluated on a manually annotated corpus, resulting in 99% precision, 82% recall, and an f-score of. as an example, the application of the system for collecting literature for the allelic variants of genes related with two complex diseases is presented.  development of a ner system for gene sequence variants our group has previously reported the development of osirisv, a tool for the retrieval of literature associated to the allelic variants of a gene based in the pubmed search engine. with the aim to improve the recognition of variations from text in terms of recall and precision we developed osirisv, based on its own ner algorithm and local data sources. in addition, we paid special attention to the normalization of the genetic variants, as it provides biologically relevant contextual information. the work flow of osirisv is detailed in the methods section and illustrated in figure briefly, osirisv scans medline abstracts, identifies texts passages corresponding to variation terms, and disambiguates the terms to dbsnp identifiers. the results are stored in the textminingdb database, and a web interface for the query and visualization of the results was developed. results for two diseases used as test cases are currently available in the database. a description of these results can be found in the section "application of osirisv for finding sequence variants information on a set of aneurysm-related genes". in the following section, a brief description of the user interface is presented. user interface the user interface offers two possibilities for browsing the results of osirisv on the test cases. the results can be queried by a gene-centred search approach on the basis of the related disease, or by using mesh disease terms.. gene-centred search approach by using this modality of search, a list of the genes for which results were found are presented. two possibilities for browsing the results on these genes are available: "see variants" and "see references". by clicking the link "see variants", a page comprising two pieces of information is displayed on the browser: dbsnp-related information for the gene and literature-related information. the first includes the sequence variants described for the gene. this information is provided by the database hgenetinfodb and is organized in tabular format with several hyperlinks. the sequence variants are classified according to their mapping to the gene sequence in coding or non-coding regions of the gene. the table includes the following information for each dbsnp entry: the unique identifier from dbsnp, the type of variant, the position of the variant relative to the gene sequence, the alleles, and specifies the mapping or location of the variant. in addition, the identifiers of the mrna and protein sequences are provided in the case of snps that map to coding sequences. in the case of variations located in coding regions, the position and amino acidic residues of the variation in the protein sequence are shown. the data are provided with hyperlinks to the corresponding data sources. regarding the literature information, the last column in the table indicates if any reference was found for each dbsnp entry, and provides a link to another page where this information is detailed. in this page, the data is organized by dbsnp entry, displaying the text passages where a term representing the dbsnp entry was identified by osirisv. these terms are highlighted to aid visualization and contain hyperlinks to dbsnp. three colouring codes are used: the terms corresponding to the current dbsnp entry appear in red, in light blue the terms corresponding to other sequence variants found in the text, and in yellow the terms that are mapped to more than one dbsnp identifier. in addition, a table showing the terms from the disease category of the mesh hierarchy extracted from the set of abstracts annotated to the variation is provided. by using this approach, the reader is directly pointed to the text passages where snps, for instance, are mentioned. in addition, the pmid of the corresponding article is provided with its hyperlink to the abstract, giving the reader the opportunity to review the complete abstract. another view of the results is displayed by clicking "see references", where text passages from all the abstracts found for the sequence variants of the gene are shown. again, the terms corresponding to the variants are highlighted and contain hyperlinks to dbsnp. three colouring codes are used: the variants mapped to the current gene appear in red, and in light blue the variants belonging to other genes, in yellow the variants that are mapped to more than one dbsnp identifier.. mesh term search approach the results can also be queried using the mesh disease terms. variations associated to the main disease categories from the mesh hierarchy can be retrieved. for instance, genetic variants associated with musculoskeletal diseases or cardiovascular diseases, both examples of broad categories of diseases in the mesh hierarchy, can be retrieved using this search modality. the results are organized in a table showing the variants described in association with the disease in the literature. alternatively, the mesh disease terms associated to an specific dbsnp entry through the literature can be obtained as well. this functionality provides a phenotypic description in the disease area for the allelic variations of a gene. these results are also shown using the gene-centred search modality. it is worthwhile to mention that not all the terms that refer to variations in the text passages shown in osirisv output are highlighted. this is due to the following reasons: – not all the variants mentioned in the text can be mapped to a dbsnp identifier; – the variant mentioned in the text is mapped to a gene for which a osirisv search has not been performed; – the level of recall of the search algorithm. in summary, the use of osirisv provides a way to access to the literature reported for the allelic variants of a gene of interest in a few mouse clicks. in addition, it identifies and highlights the terms corresponding to the allelic variants aiding in the visualization of the search results, and therefore saving time for the user. evaluation an evaluation was carried out to assess the performance of osirisv. this kind of evaluation requires a set of reference documents that are judged as relevant or irrelevant for a certain query, i.e. a corpus or gold standard. a manually annotated corpus was developed for the purpose of the evaluation of the sequence variant extraction and normalization tasks. this is a valuable accomplishment since there is high demand of such standards for evaluation purposes. the corpus is available upon request. the evaluation consisted in assessing of both the identification of the terms that refer to variations and the normalization of these terms. the result of the evaluation indicated that the algorithm is geared towards high precision at a recall of 89%, resulting in an f-score of, for the recognition of variation terms and disambiguation to dbsnp identifiers. a comparison of the performance of all the current methodologies is shown in table both versions of osiris were evaluated on the corpus developed in this study. regarding the other approaches, although the results of the evaluations carried out in each case are not directly comparable, it serves as a rough comparison with the published methods. osirisv and osirisv were evaluated on the corpus described in this study. performance of other methods correspond to published data for each development. since the use of different benchmarks and the different evaluation criteria make the results not strictly comparable, the results can only be considered for a rough comparison of the state of the art. *average of evaluation on two protein families reported the evaluation for osirisv shows satisfactory results for both precision and recall. the low recall of osirisv could be explained by the inability of the query expansion approach used by the system to recover all the variation specific terms. the recall is increased in the new implementation by improvement of both the recognition of gene and variation terms. regarding the other approaches, published results indicate that the mema system achieved a 75% recall and 98% precision for the recovery of mutations from texts. mema uses regular expressions for finding mutations-gene pairs, but it does not provide mapping to dbsnp entries. in this system, the association of a mutation with a gene is done by co-occurrence of both terms in a sentence. contrasting, osirisv uses co-occurrence and a sequence based approach. the vtag approach, based on a probabilistic model to identify mutation terms, achieves a high recall level, but without providing mapping to sequence database entries. the strategy used by osirisv provides a way to achieve recognition and mapping of variation terms to dbsnp identifiers with high precision and recall, which are very important features for database annotation purposes and mining information from text. in addition, the results of the evaluation indicates that a simple search algorithm performs well in the task of ner and normalization of sequence variants. the recall could be further improved by recognition of complex expressions representing sequence variants, such as "g/a genotype associated with tumour necrosis factor-alpha promoter positions - and -244". future implementations including a broader terminology will probably achieve higher recall levels. other factor having a negative impact on osirisv recall are the lack of agreement between the numbering of variants position in articles and the one found in databases for some variations. as mentioned above, the approach used by osirisv to correctly link a variation with a gene is based on co-occurrence of gene and variation terms in the text and sequence mapping. nevertheless, in some cases it is not possible to assign a variation to a gene in an unambiguous manner. this occurs when two genes and their sequence variants are mentioned in the abstract, and, just by chance, the variants share some of the features required for normalization. in such cases, the term will be annotated with two dbsnp identifiers that are mapped to different genes, leading to an ambiguous annotation. these cases are highlighted in yellow in the results displayed on the web. in order to study in what extent this situation leads to ambiguous annotations, we conducted the following evaluation. we assessed the number of terms referring to a variation that were assigned to more than one dbsnp identifier by osirisv. this evaluation was conducted on all the data present in the textminingdb. we found that % of the variations had been annotated with more than one identifier from dbsnp. from this set, % resulted from an incorrect identification of a gene term by prominer, % were due to multiple annotations in dbsnp, and % resulted from an incorrect assignment of the variation to the term. multiple annotations in dbsnp occur when a variation has more than one dbsnp identifier, and are merged in subsequent updates of the database. this means that % of the cases are not really ambiguous: the dbsnp identifiers assigned point to the same variation in the gene sequence. in summary, only % of annotations are ambiguous due to the inability to distinguish between multiple dbsnp identifiers for a single variation, and lead to an incorrect linkage of variation and gene. the ambiguous annotations are shown in table 15941956 11096344 17885129 1059350 the table show the cases where an ambiguous assignment of a dbsnp identifier to a variation term was obtained. the first column depicts the pmid of the abstracts where the term was found. the third column shows the dbsnp identifiers assigned to the term by osirisv. highlighted in bold are the correct assignment of dbsnp identifier to that term. in some instances the information from the text does not allow to discern between two snps occurring at the same position in the protein sequence but differing only in one of the alternative residues. for example, for the "asp86" term, both snps highlighted in bold represent changes at position of the protein in which an asp residue is involved. one is a synonymous change while the other is non-synonymous. however, the information extracted from the text is not sufficient to distinguish among these two possibilities, and therefore both identifiers are assigned to the term. application of osirisv for finding sequence variant information on a set of aneurysm related genes two complex diseases were used as test cases for the system: breast cancer and intracranial aneurysm and subarachnoid haemorrhage. the results can be queried through the web interface. only results for intracranial aneurysm will be discussed as an example. a summary of the data present in the textminingdb database is shown in table results for the diseases intracranial aneurysm and breast cancer were compiled. the disease-specific corpora were built using pubmed and the queries described in the methods section. the genes described in each corpora were extracted using prominer, and a list of genes specific for each disease was obtained. then, osirisv searches were performed for each list of genes on the whole medline collection. results presented in the table correspond to the medline collection at august subarachnoid haemorrhage as a consequence of intracranial aneurysm is one of the most devastating cerebrovascular diseases due to its high morbidity and mortality. cerebral aneurysms are extensions of arterial vessels in the brain. these extensions are balloon-type bulges that form in apparently healthy people with a comparably high frequency. the interaction of genetic as well as environmental risk factors are thought to play an important role in the pathogenesis and prognosis of the disease. in addition to smoking, hypertension, arteriosclerosis and alcohol intake, haemodynamic stress at arterial bifurcations is believed to contribute to the development of aneurysms. several studies have claimed that the presence of certain allelic variants may increase the individual's susceptibility to develop intracranial aneurysms, and might be used as biomarkers for the risk of aneurysm rupture. in this context, the identification of the sequence variants associated to the disease phenotype in specific populations is of high value for early diagnosis and treatment, and also for providing an understanding of the pathogenesis of the disease. osirisv was utilized for collecting sequence variants data for a set of genes related to the disease, and for the identification of snp terms from medline abstracts, with the aim of collecting the available information on the variants under study in the disease. a set of aneurysm-related genes was automatically identified on the basis of their occurrence in abstracts pertaining to the disease. the abstracts related to the disease were retrieved using pubmed search engine with the queries described in methods and scanned with prominer. this resulted in a set of genes, to which variations are mapped according to dbsnp. then, osirisv was used to search literature citations for the dbsnp entries mapped to the aneurysm-related genes. since the searches performed on the abstracts belonging to the aneurysm-related corpora resulted in a small number of osirisv annotations, the searches were then conducted in the entire medline collection. results were obtained for genes and variants, which were found to be linked to citations. these results represent a collection of the citations that refer to sequence variants on these genes, and are available at. to illustrate the kind of insights that can be obtained using osirisv, the gene for the endothelial nitric oxide synthase or enos, will be used as an example. nos is one of the candidates for the pathogenesis of intracranial aneurysm, and its association with the disease has been addressed by several studies. moreover, it might be involved in the observed sex differences in the outcome of subarachnoidal haemorrhage as a consequence of intracranial aneurysms. endothelial nitric oxide synthase is one of the three isoforms of the enzyme nitric oxide synthase. nitric oxide is important in the regulation of vasomotor tone and blood flow by inhibiting smooth muscle contraction and platelet aggregation. mice lacking nos gene are hypertensive and the combined deletion of nos and apolipoprotein e confers an increased susceptibility to arteriosclerosis. the production of no is regulated at the level of nos gene expression and activity of the enzyme. the promoter of the gene contains transcription factor binding sites that mediate regulation by shear stress and oestrogens. several citations were found to refer to variations in the nos gene by osirisv. the analysis that follows is based on the literature citations found by osirisv for one of the most studied variants of the gene. regarding the association with aneurysm, the rs variant has been described as one of the genetic factors related to the risk of aneurysm rupture in a population from usa. although this finding could not be replicated in a japanese population, the rs variant was found to be a mild predisposing factor for abdominal aortic aneurysm, a chronic degenerative condition associated with arteriosclerosis. the putative association of this variant with diseases other than aneurysms has been extensively investigated, as shown by the mesh disease terms extracted from the set of articles annotated to this variant: hypertension, pre-eclampsia, myocardial infarction, alzheimer disease. deregulation of vascular homeostasis is a common factor among the above mentioned diseases, appearing as a symptom or as a risk factor. the association of the rs variant with these phenotypes might be reflecting a common mechanism in the disease pathogenesis. the rs variant, although leads to a conservative change in the protein sequence, would have functional consequences, as suggested by studies showing that the asp residue is subjected to selective proteolytic cleavage in endothelial cells and vascular tissues that impairs no production. however, recent findings have challenged these observations. thus, it is likely that any relationship between the variant and the disease phenotype is due to this being an indirect marker of the genetic association rather than a direct functional effect. alternatively, a different functional effect of the variant might explain the observed clinical features under pathological conditions. further work is required to clarify the kind of relationship of the rs variant with the disease phenotypes.  in this report we present osirisv, a system for collecting the current knowledge about gene sequence variants from the literature. the evaluation of osirisv on a manually annotated corpus showed that it achieves high precision and recall in named entity recognition and disambiguation of terms. the ner system that is the basis of osirisv was combined with a ner system for genes and proteins that in turn will form the basis of a disease centric information system by integrating ner with disease specific biomedical literature search. this integrated system will allow the extraction of information related to genotype-phenotype relationships in human diseases. the architecture of the system allows incorporation of additional modules, such as ner modules for drugs and diseases, and modules for mining relationships between the entities so far identified. in addition, automatic systems for updating the text mining results allow to keep up to date the extracted information. to demonstrate the usefulness of the approach, osirisv was applied for the development of a database of literature references associated with allelic variants of genes related with two complex diseases: intracranial aneurysm and subarachnoid haemorrhage, and breast cancer. as illustrated with the example on one of the snps of the nos gene, several interesting pieces of information regarding related phenotypes and functional effects of a variation can be easily obtained using osirisv. the approach also illustrates the strategy for linking genetic variants of genes present in sequence databases with disease terms of a controlled vocabulary through the literature. moreover, this approach could be used for developing similar databases focused in other diseases. although the system has been implemented for human genes, the general approach is easily applicable to other organisms with variation data available. osirisv is focused in identifying the terms from text that represent variations from reference sequence repositories such as dbsnp. the combined use of osirisv and any other ner that search for variation entities in general without normalization would provide with two sets of snp data that could be of interest to dbsnp curators. in this regard, we anticipate that a suitable application of osirisv would be for supporting the functional annotation of dbsnp entries. this is a relevant issue since the unravelling of the biological consequences of sequence variants remains a challenging task. in addition, elucidation of the functional impact of predisposing snp alleles identified by genome wide association studies has important implications in terms of understanding the underlying biology of complex diseases and identifying putative therapeutic targets. 
thus, automatic systems for the identification of citations of allelic variants of genes in biomedical texts are required. our group has previously reported the development of osiris, a system aimed at the retrieval of literature about allelic variants of genes. as an example, the application of the system for collecting literature citations for the allelic variants of genes related to the diseases intracranial aneurysm and breast cancer is presented. here we describe the development of a new version of osiris which incorporates a new entity recognition module and is built on top of a local mirror of the medline collection and hgenetinfodb: a database that collects data on human gene sequence variations. the new entity recognition module is based on a pattern-based search algorithm for the identification of variation terms in the texts and their mapping to dbsnp identifiers. the performance of osirisv was evaluated on a manually annotated corpus, resulting in 99% precision, 82% recall, and an f-score of. single nucleotide polymorphisms, among other type of sequence variants, constitute key elements in genetic epidemiology and pharmacogenomics. osirisv can be used to link literature references to dbsnp database entries with high accuracy, and therefore is suitable for collecting current knowledge on gene sequence variations and supporting the functional annotation of variation databases.
 single nucleotide polymorphisms, among other type of sequence variants, constitute key elements in genetic epidemiology and pharmacogenomics. while sequence data about genetic variation is found at databases such as dbsnp, clues about the functional and phenotypic consequences of the variations are generally found in biomedical literature. the identification of the relevant documents and the extraction of the information from them are hampered by the large size of literature databases and the lack of widely accepted standard notation for biomedical entities. thus, automatic systems for the identification of citations of allelic variants of genes in biomedical texts are required.  our group has previously reported the development of osiris, a system aimed at the retrieval of literature about allelic variants of genes. here we describe the development of a new version of osiris which incorporates a new entity recognition module and is built on top of a local mirror of the medline collection and hgenetinfodb: a database that collects data on human gene sequence variations. the new entity recognition module is based on a pattern-based search algorithm for the identification of variation terms in the texts and their mapping to dbsnp identifiers. the performance of osirisv was evaluated on a manually annotated corpus, resulting in 99% precision, 82% recall, and an f-score of. as an example, the application of the system for collecting literature citations for the allelic variants of genes related to the diseases intracranial aneurysm and breast cancer is presented.  osirisv can be used to link literature references to dbsnp database entries with high accuracy, and therefore is suitable for collecting current knowledge on gene sequence variations and supporting the functional annotation of variation databases. the application of osirisv in combination with controlled vocabularies like mesh provides a way to identify associations of biomedical interest, such as those that relate snps with diseases. 