Generating Hypotheses by Generating Hypotheses by Discovering Implicit Associations in Discovering Implicit Associations in the Literature: A Case Report of a the Literature: A Case Report of a Search for New Potential Search for New Potential Therapeutic Uses for Thalidomide Therapeutic Uses for Thalidomide By Marc Weeber By Marc Weeber, , Henny Henny Klein, Klein, Lolkje Lolkje T. W. T. W. deJong deJong – – van den van den Berg, Alan Aronson, Grietje Berg, Alan Aronson, Grietje Molema Molema From J Am Med Inform Assoc, 2003 From J Am Med Inform Assoc, 2003 Presented by Nancy Baker INLS 279 March 22, 2005
DAD Overview DAD Overview � Automation on Swanson’s A Automation on Swanson’s A- - B B- - C C � paradigm paradigm � Uses Uses PubMed PubMed citations citations – – title and title and � abstract (not just titles) abstract (not just titles) � Role of user vital in initial question, Role of user vital in initial question, � filtering filtering � User decides interestingness User decides interestingness � � Strengthen or reject the hypothesis Strengthen or reject the hypothesis � by looking at mechanisms/ pathways by looking at mechanisms/ pathways
Key Innovation Key Innovation � Units of analysis are UMLS Units of analysis are UMLS metathesaurus metathesaurus � concepts, not terms concepts, not terms � Why? Why? � – Only interested in biomedical concepts Only interested in biomedical concepts – – Won’t need stop words and words not relevant Won’t need stop words and words not relevant – to medicine to medicine – Want to Want to indentify indentify and include compound terms and include compound terms – (e.g. Blood Pressure) (e.g. Blood Pressure) – UMLS concepts have semantic types UMLS concepts have semantic types – – for for – abstraction and filtering abstraction and filtering – Multiple words collapse to one concept Multiple words collapse to one concept –
UMLS examples UMLS examples � IL IL- - 12, IL12, interleukin 12, CLMF, 12, IL12, interleukin 12, CLMF, � cytotoxic lymphocyte lymphocyte maturatin maturatin cytotoxic factor, natural killer cell stimulatory factor, natural killer cell stimulatory factor all refer to Interleukin- - 12 12 factor all refer to Interleukin � Concepts have 134 categories: Concepts have 134 categories: � Disease or Syndrome, Gene or Disease or Syndrome, Gene or Genome, Amino Acid, Peptide, or Genome, Amino Acid, Peptide, or Protein Protein
Next steps (from earlier paper) Next steps (from earlier paper) � Swanson’s first discovery has been Swanson’s first discovery has been � successfully simulated, so … successfully simulated, so … � Adverse drug reactions Adverse drug reactions � – ADRs ADRs may benefit other conditions may benefit other conditions – Lots of examples ( finasteride finasteride- - alopecia) alopecia) � Lots of examples ( � DAD : drug- - ADR ADR- - disease or disease disease or disease- - ADR ADR- - � DAD : drug � drug drug Investigating retrospectively case of � Investigating retrospectively case of � finasteride finasteride
Future Perspectives (from earlier Future Perspectives (from earlier paper) paper) � For some applications other routes For some applications other routes � are better than PubMed PubMed are better than – Genetic databases, for instance Genetic databases, for instance – – Combine text and database information Combine text and database information –
Case Report - - Thalidomide Thalidomide Case Report � Why thalidomide? Why thalidomide? � – Known to have Known to have immunomodulatory immunomodulatory and and – antiinflammatory properties properties antiinflammatory – Anti Anti- - wasting (HIV) wasting (HIV) – Immunologic Factor B C A Thalidomide Disease or Syndrome The ABC discovery model.
The Discovery Process The Discovery Process � Experimental Setting: The people Experimental Setting: The people � – Information Scientist ( Information Scientist ( Weeber Weeber) ) – – Pharmacologist/ immunologist Pharmacologist/ immunologist – – Worked in collaboration Worked in collaboration –
Generating Hypotheses Generating Hypotheses � Start with thalidomide Start with thalidomide � – Pubmed Pubmed search (titles and search (titles and abstracts)using abstracts)using – terms thalidomide, sedoval sedoval, , synovir,kevadon synovir,kevadon terms thalidomide, – Downloaded results Downloaded results – – Mapped results to UMLS concepts Mapped results to UMLS concepts – – Applied semantic filter Applied semantic filter – � Selected only concepts classified as Immunologic Selected only concepts classified as Immunologic � Factor from sentences which also mentioned Factor from sentences which also mentioned thalidomide. thalidomide. � “The increase of “The increase of Interleukin Interleukin- - 2 2 levels after application levels after application � of thalidomide of thalidomide … … ” ”
Generating Hypotheses (cont.) Generating Hypotheses (cont.) � In sentences with thalidomide, 3,860 In sentences with thalidomide, 3,860 � concepts occurred, 82 with symantic symantic concepts occurred, 82 with type “Immunologic factor” type “Immunologic factor” � Removed concepts considered too Removed concepts considered too � general general � Tool allows viewing of A Tool allows viewing of A- - B B � � Promising B concepts selected Promising B concepts selected � – Frequency Frequency – – Expert knowledge Expert knowledge –
Results : Results : immunologic immunologic factors factors
Results Results � Domain expert selected Interleukin Domain expert selected Interleukin- - � 12 and Interleukin- - 10. 10. 12 and Interleukin � Thalidomide inhibits IL Thalidomide inhibits IL- - 12 and 12 and � stimulates IL- - 10. 10. stimulates IL � Further research focuses on IL Further research focuses on IL- - 12. 12. �
Generating Hypotheses (cont.) Generating Hypotheses (cont.) � The selected B concepts were used The selected B concepts were used � as PubMed PubMed search criteria search criteria as � Diseases selected using semantic Diseases selected using semantic � filtering filtering
Interleukin- -12 12 Interleukin � 3,846 MEDLINE citations had concept 3,846 MEDLINE citations had concept � Interleukin- - 12 12 Interleukin � 420 Disease or Syndrome concepts 420 Disease or Syndrome concepts � co- - occurred with interleukin occurred with interleukin- - 12 12 co � Filtered Filtered � – Threw out too general, too few Threw out too general, too few – occurrances, already known connections , already known connections occurrances – Subjective Subjective –
List of diseases List of diseases
Evaluating Hypotheses Evaluating Hypotheses � Download and analyze citations Download and analyze citations � � Looked at A Looked at A- - B concepts juxtaposed B concepts juxtaposed � with B- - C C with B
Results: Results: � Chronic Hepatitis C Chronic Hepatitis C � – Inflammatory disease of the liver Inflammatory disease of the liver – – Th1/ Th2 cytokine balance involved Th1/ Th2 cytokine balance involved – � Myasthenia Gravis Myasthenia Gravis � – Organ specific autoimmune disease Organ specific autoimmune disease – affecting neuromuscular junctions affecting neuromuscular junctions – Aberrant production of cytokines Aberrant production of cytokines –
Results: Results: � H. pylori H. pylori induced gastritis induced gastritis � – Th1 medicated chronic inflammation Th1 medicated chronic inflammation – � Acute Acute Pancreatis Pancreatis � – Again, Th1 mediated response. Again, Th1 mediated response. –
Thalidomide Th1/Th2 Thalidomide Th1/Th2
Other databases Other databases � Queries other databases Queries other databases � – Biological Abstracts Biological Abstracts – – CINAHL CINAHL – – Nursing and Allied Health Nursing and Allied Health – – EMBASE EMBASE – – Current Contents Current Contents – – Altavista Altavista and Google and Google – � Some discussion of thalidomide and Some discussion of thalidomide and � diseases – – nothing definitive nothing definitive diseases
Conclusion Conclusion � These four diseases represent novel These four diseases represent novel � potential targets for thalidomide potential targets for thalidomide � Clinical investigation needed Clinical investigation needed � � Although the computer system is Although the computer system is � valuable, discovery is an valuable, discovery is an intellectually intensive process intellectually intensive process
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