Literature Mining and Systems Biology
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Literature Mining and Systems Biology

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Bioinformatics & Gene Discovery, Technical University of Denmark, Lyngby, Denmark, June 8, 2007

Bioinformatics & Gene Discovery, Technical University of Denmark, Lyngby, Denmark, June 8, 2007

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Literature Mining and Systems Biology Literature Mining and Systems Biology Presentation Transcript

  • Literature Mining and Systems Biology Lars Juhl Jensen EMBL
  • Why?
  • Overview
    • Information retrieval: finding the papers
    • Entity recognition: identifying the substance(s)
    • Information extraction: formalizing the facts
    • Text mining: finding nuggets in the literature
    • Integration: combining text and biological data
  • Status
    • IR, ER, and simple IE methods are fairly well established
    • Advanced NLP-based IE systems are rapidly being improved
    • Methods for text mining and text/data integration are still in their infancy
  • Example
    • Mitotic cyclin (Clb2)-bound Cdc28 (Cdk1 homolog) directly phosphorylated Swe1 and this modification served as a priming step to promote subsequent Cdc5-dependent Swe1 hyperphosphorylation and degradation
  • Information retrieval
    • Ad hoc information retrieval
      • The user enters a query/a set of keywords
      • The system attempts to retrieve the relevant texts from a large text corpus (typically Medline)
    • Text categorization
      • A training set of texts is created in which texts are manually assigned to classes (often only yes/no)
      • A machine learning methods is trained to classify texts
      • This method can subsequently be used to classify a much larger text corpus
  • Ad hoc IR
    • These systems are very useful since the user can provide any query
      • The query is typically Boolean ( yeast AND cell cycle )
      • A few systems instead allow the relative weight of each search term to be specified by the user
    • The art is to find the relevant papers even if they do not actually match the query
      • Ideally our example sentence should be extracted by the query yeast cell cycle although none of these words are mentioned
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  • Automatic query expansion
    • In a typical query, the user will not have provided all relevant words and variants thereof
    • By automatically expanding queries with additional search terms, recall can be improved
      • Stemming removes common endings ( yeast / yeasts )
      • Thesauri can be used to expand queries with synonyms and/or abbreviations ( yeast / S. cerevisiae )
      • The next logical step is to use ontologies to make complex inferences ( yeast cell cycle / Cdc28 )
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  • Document similarity
    • The similarity of two documents can be defined based on their word content
      • Each document can be represented by a word vector
      • Words should be weighted based on their frequency and background frequency
      • The most commonly used scheme is tf*idf weighting
    • Document similarity can be used in ad hoc IR
      • Rather than matching the query against each document only, the N most similar documents are also considered
  • Document clustering
    • Unsupervised clustering algorithms can be applied to a document similarity matrix
      • All pairwise document similarities are calculated
      • Clusters of “similar documents” can be constructed using one of numerous standard clustering methods
    • Practical uses of document clustering
      • The “related documents” function in PubMed
      • Logical organization of the documents found by IR
  • Text categorization
    • These systems are a lot less flexible than ad hoc systems but can attain better accuracy
      • Works on a pre-defined set of document classes
      • Each class is defined by manually assigning a number of documents to it
    • Method
      • Rules may be manually crafted based on a very small set of manually classified documents
      • Statistical machine learning methods can be trained on a large number of classified documents
  • Example
    • Mitotic cyclin (Clb2)-bound Cdc28 (Cdk1 homolog) directly phosphorylated Swe1 and this modification served as a priming step to promote subsequent Cdc5-dependent Swe1 hyperphosphorylation and degradation
    • Hints in the text
      • Strong: Cdc28 and Swe1 (“cell cycle” and “yeast”)
      • Weaker: mitotic cyclin , Clb2 , and Cdk1 ( “cell cycle”)
  • Machine learning
    • Input features
      • Word content or bi-/tri-grams
      • Part-of-speech tags
      • Filtering (stop words, part-of-speech)
      • Singular value decomposition
    • Training
      • Support vector machines are best suited
      • Choice of kernel function
      • Separate training and evaluation sets, cross validation
  • Entity recognition
    • An important but boring problem
      • The genes/proteins/drugs mentioned within a given text must be identified
    • Recognition vs. identification
      • Recognition: find the words that are names of entities
      • Identification: figure out which entities they refer to
      • Recognition without identification is of limited use
  • Example
    • Mitotic cyclin ( Clb2 )-bound Cdc28 (Cdk1 homolog) directly phosphorylated Swe1 and this modification served as a priming step to promote subsequent Cdc5 -dependent Swe1 hyperphosphorylation and degradation
    • Entities identified
      • S. cerevisiae proteins: Clb2 (YPR119W), Cdc28 (YBR160W), Swe1 (YJL187C), and Cdc5 (YMR001C)
  • Recognition
    • Features
      • Morphological: mixes letters and digits or ends on -ase
      • Context: followed by “protein” or “gene”
      • Grammar: should occur as a noun
    • Methodologies
      • Manually crafted rule-based systems
      • Machine learning (SVMs)
    • But what can it be used for?
  • Identification
    • A good synonyms list is the key
      • Combine many sources
      • Curate to eliminate stop words
    • Flexible matching to handle orthographic variation
      • Case variation: CDC28 , Cdc28 , and cdc28
      • Prefixes: myc and c-myc
      • Postfixes: Cdc28 and Cdc28p
      • Spaces and hyphens: cdc28 and cdc-28
      • Latin vs. Greek letters: TNF-alpha and TNFA
  • Disambiguation
    • The same word may mean many different things
      • Entity names may also be common English words ( hairy ) or technical terms ( SDS )
      • Protein names may refer to related or unrelated proteins in other species ( cdc2 )
    • The meaning can be resolved from the context
      • ER can distinguish between names and common words
      • Disambiguating non-unique names is a hard problem
      • Ambiguity between orthologs can be safely be ignored
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  • Co-occurrence extraction
    • Relations are extracted for co-occurring entities
      • Relations are always symmetric
      • The type of relation is not given
    • Scoring the relations
      • More co-occurrences  more significant
      • Ubiquitous entities  less significant
      • Same sentence vs. same paragraph
    • Simple, good recall, poor precision
  • Example
    • Mitotic cyclin ( Clb2 )-bound Cdc28 (Cdk1 homolog) directly phosphorylated Swe1 and this modification served as a priming step to promote subsequent Cdc5 -dependent Swe1 hyperphosphorylation and degradation
    • Relations
      • Correct: Clb2–Cdc28 , Clb2–Swe1 , Cdc28–Swe1 , and Cdc5–Swe1
      • Wrong: Clb2–Cdc5 and Cdc28–Cdc5
  • Categorization of relations
    • Extracting specific types of relations
      • Text categorization methods can be used to identify sentences that mention a certain type of relations
      • Filtering can be done before or after relation extraction
    • Well suited for database curation
      • Text categorization can be reused
      • High recall is most important
      • Curators can compensate for the lack of precision
  • Relation extraction by NLP
    • Information is extracted based on parsing and interpreting phrases or full sentences
      • Good at extracting specific types of relations
      • Handles directed relations
    • Complex, good precision, poor recall
  • Example
    • Mitotic cyclin ( Clb2 )-bound Cdc28 (Cdk1 homolog) directly phosphorylated Swe1 and this modification served as a priming step to promote subsequent Cdc5 -dependent Swe1 hyperphosphorylation and degradation
    • Relations:
      • Complex: Clb2–Cdc28
      • Phosphorylation: Clb2  Swe1 , Cdc28  Swe1 , and Cdc5  Swe1
  • An NLP architecture
    • Tokenization
      • Entity recognition with synonyms list
      • Word boundaries (multi words)
      • Sentence boundaries (abbreviations)
    • Part-of-speech tagging
      • TreeTagger trained on G ENIA
    • Semantic labeling
      • Dictionary of regular expressions
    • Entity and relation chunking
      • Rule-based system implemented in CASS
    • Semantic labeling
      • Gene and protein names
      • Cue words for entity recognition
      • Cue words for relation extraction
    • Named entity chunking
      • A CASS grammar recognizes noun chunks related to gene expression: [ nxgene The GAL4 gene ]
    • Relation chunking
      • Our CASS grammar also extracts relations between entities: [ nxexpr T he expression of [ nxgene the cytochrome genes [ nxpg CYC1 and CYC7 ]]] is controlled by [ nxpg HAP1 ]
  • [ expression_repression_active Btk regulates the IL-2 gene ] [ dephosphorylation_nominal Dephosphorylation of Syk and Btk mediated by SHP-1 ] [ phosphorylation_nominal phosphorylation of Shc by the hematopoietic cell-specific tyrosine kinase Syk ] [ phosphorylation_nominal the phosphorylation of the adapter protein SHC by the Src-related kinase Lyn ] [ phosphorylation_active Lyn also participates in [ phosphorylation the tyrosine phosphorylation and activation of syk ]] [ phosphorylation_active Lyn , [ negation but not Jak2 ] phosphorylated CrkL ] [ phosphorylation_active Lyn , [ negation but not Jak2 ] phosphorylated CrkL ] [ phosphorylation_active Lyn also participates in [ phosphorylation the tyrosine phosphorylation and activation of syk ]] [ phosphorylation_nominal the phosphorylation of the adapter protein SHC by the Src-related kinase Lyn ] [ phosphorylation_nominal phosphorylation of Shc by the hematopoietic cell-specific tyrosine kinase Syk ] [ dephosphorylation_nominal Dephosphorylation of Syk and Btk mediated by SHP-1 ] [ expression_repression_active IL-10 also decreased [ expression mRNA expression of IL-2 and IL18 cytokine receptors] [ expression_repression_active IL-10 also decreased [ expression mRNA expression of IL-2 and IL18 cytokine receptors ] [ expression_activation_passive [ expression IL-13 expression] induced by IL-2 + IL-18 ] [ expression_activation_passive [ expression IL-13 expression ] induced by IL-2 + IL-18 ] [ expression_repression_active Btk regulates the IL-2 gene ]
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  • Mining text for nuggets
    • New relations can be inferred from published ones
      • This can lead to actual discoveries if no person knows all the facts required for making the inference
      • Combining facts from disconnected literatures
    • Swanson’s pioneering work
      • Fish oil and Reynaud's disease
      • Magnesium and migraine
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  • Trends
    • Most similar to existing data mining approaches
      • Although all the detailed data is in the text, people may have missed the big picture
    • Temporal trends
      • Historical summaries
      • Forecasting
    • Correlations
      • “ Customers who bought this item also bought …”
  • Time
  • Buzzwords
  • Correlations
    • “ Customers who bought this item also bought …”
    • Protein networks
      • “ Proteins that regulate expression …”
      • “ Proteins that control phosphorylation …”
      • “ Proteins that are phosphorylated …”
    • Co-author networks
  • Transcriptional networks 32 79 83 3592 Regulates Regulated P < 9  10 -9
  • Signaling pathways 11 27 44 3704 Phosphorylates Phosphorylated P < 2  10 -7
  • Integration
    • Automatic annotation of high-throughput data
      • Loads of fairly trivial methods
    • Protein interaction networks
      • Can unify many types of interactions
      • Powerful as exploratory visualization tools
    • More creative strategies
      • Identification of candidate genes for genetic diseases
      • Linking genes to traits based on species distributions
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  • RCCs
  • Disease candidate genes
    • Rank the genes within a chromosomal region to which a disease has been mapped
    • Methods
      • G2D
        • Gene  Function  Chemical  Phenotype  Disease
        • Uses M EDLINE but not the text
      • B ITOLA
        • Gene  Words  Disease (similar to A RROWSMITH )
      • Hide and co-workers
        • Gene  Tissue  Disease
  • G2D
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  • Genotype–phenotype
    • Genes can be linked to traits by comparing the species distributions of both
      • Mainly works for prokaryotes
      • Traits are represented by keywords
    • Finding the species profiles
      • Gene profiles are found by sequence similarity
      • Keyword profiles are based co-occurrence with the species name in M EDLINE
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  • Annotation
    • Many experiment result in groups of related genes
      • ER is used to find the associated abstracts
      • The frequency of each word is counted in the abstracts
      • Background frequencies of all words are pre-calculated
      • A statistical test is used to rank the words
    • The same strategy can be applied to find MeSH terms associated with a gene cluster
    • Most people prefer using GO annotation instead
  • Outlook
    • Literature mining will not be made obsolete by <insert your favorite new technology here>
      • Repositories are always made too late
      • There will always be new types of relations
      • Semantically tagged XML may replace ER (hopefully!)
      • Semantically tagged XML will never tag everything
    • Specific IE problems will become obsolete
      • Protein function
      • Physical protein interactions
  • Permission denied
    • Open access
      • Literature mining methods cannot retrieve, extract, or correlate information from text unless it is accessible
      • Restricted access is already now the primary problem
    • Standard formats
      • Getting the text out of a PDF file is not trivial
      • Many journals now store papers in XML format
    • Where do I get all the patent text?!
  • Innovation
    • The basic tools are now in place for IR, ER, and IE
      • Development was driven by computational linguists
    • Text- and data-mining
      • Biologists are needed
      • Collaboration with linguists
    • Lack of innovation
      • Very few new ideas
      • Text should be combined with other data
  • Acknowledgments
    • EML Research
      • Jasmin Saric
      • Isabel Rojas
    • EMBL Heidelberg
      • Peer Bork
      • Miguel Andrade
      • Michael Kuhn
      • Rossitza Ouzounova
      • Jan Korbel
      • Tobias Doerks
  • Exercises Lars Juhl Jensen EMBL
  • Entity recognition
    • iHOP
      • http://www.pdg.cnb.uam.es/UniPub/iHOP/
    • Ideas
      • Compare iHOP vs. PubMed for finding papers related to a particular gene
      • Use iHOP to construct a small literature-based network
  • Information extraction
    • Relation extraction
      • iProLINK ( http://pir.georgetown.edu/iprolink/ )
      • PreBIND ( http://prebind.bind.ca )
      • PubGene ( http://www.pubgene.org )
    • Ideas
      • Check how complex sentences iProLINK can handle
      • Check how well PreBIND can discriminate between physcial and other interactions (other interactions can be found with PubGene, ProLinks, or STRING)
  • Text mining
    • A RROWSMITH
      • http://arrowsmith.psych.uic.edu
    • Ideas
      • Fish oil and Reynaud's disease
      • Magnesium and migraine
      • Arginine and somatomedin C
      • Estrogen and Alzheimer's disease
  • Integration 1
    • Protein networks
      • S TRING ( http://string.embl.de )
      • ProLinks ( http://dip.doe-mbi.ucla.edu/pronav/ )
    • Ideas
      • Use both tools to find functions for proteins of known and unknown function
      • Use S TRING to construct a network for a set of proteins
      • Try to reproduce the Ssn3–Msn2–Hsp104 link
  • Integration 2
    • Finding candidate disease genes
      • G2D ( http://www.ogic.ca/projects/g2d_2/ )
      • B ITOLA ( http://www.mf.uni-lj.si/bitola/ )
    • Ideas
      • Take a look at the G2D results for some diseases where you know which types of genes would be sensible to suggest
      • Compare the results with B ITOLA (if you have the patience to figure out there interface!)