Download - Marc Weeber 1,2 Grietje Molema 2
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Literature-based Discovery in Biomedicine
Five Potentially New Therapeutic Applications for Thalidomide
Marc Weeber1,2
Grietje Molema2
1National Library of Medicine, Bethesda, MD
2Groningen University Institute for Drug Exploration, The Netherlands
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Discovery Research in Groningen
• Rein Vos, Drugs looking for diseases, 1991. Supervisor Theo Kuipers
• Floor Rikken, Drugs in a different context, 1998. Supervisor Rein Vos
• Marc Weeber, Literature-based discovery in biomedicine, 2001. Supervisors Rein Vos and Lolkje de Jong - van den Berg
• Alexander van den Bosch, Rationality in discovery, 2001. Supervisors Theo Kuipers and Rein Vos
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Rationality in discovery• A study of logic, cognition, computation,
and neuropharmacology, by Alexander van den Bosch.1. a study of the concept of discovery, from the
angles of logic, psychology and machine learning
2. a study of kinds of discoveries in the practice of neuropharmacology, distinguising different types of problems: searching for a good explanation, prediction or intervention.
http://www.philos.rug.nl/~vdbosch/thesis-abstract.html for an abstract and a link to a preprint, hardcopies will be available in April.
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Introduction
• Goal:
Finding new biomedical scientific knowledge through the combination of existing knowledge as represented in the medical literature
• Motivation:
Prevention of re-inventing the wheel, re-usage of specific knowledge outside the original domain of discovery
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Swanson (I)
Substance
A
Effects B
Disease C
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Swanson (II)
Fish oil
High blood viscosity Platelet aggregation
Raynaud’s
disease
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Our Interests
• Drugs instead of diet factors• Intermediate (B) terms may be adverse
drug reactions• Drug – Adverse drug reactions –
Disease: The DAD-system• Vos (1991) Drugs looking for diseases• Advanced Natural Language Processing
(NLP) techniques
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Two-step Approach
• Open discovery, generating a hypothesis
A ?c?b
• Closed discovery, testing a hypothesis
A C?b
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Discovery Task
• Replicating Swanson’s two famous literature-based discoveries: Weeber et al. 2001. JASIS 52(8)
• Finding new applications for existing drugs
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Thalidomide• Introduced in early 60’s as a sedative
• Withdrawn from market because of birth defects
• In 1998: registered for use in leprosy patients
• If after 40 years such a controversial drug has a new application, there might be more hidden knowledge for other applications
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Discovery Setting• Two human discoverers
• information scientist• domain expert: immunologist/pharmacologist
• Computer assisted text analysis
• Computer output: biomedical concepts and sentences in which they occur (context)
• Reading of relevant abstracts and full papers
• Continuing reduction of possibilities
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Open Discovery: A B
• 1,366 MEDLINE abstracts and titles
• Selecting all immunologic factors results in 82 concepts. Most frequent ones:• Tumor necrosis factor• IL-2• Cytokines• Antigens, CD4• lymphocyte antigen CD69• IL-12• Antigens, CD5
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Why IL-12?
• Expert vs. non-expert knowledge, IL-12 vs. TNF
• Reasons:• IL-12 has recently been acknowledged an
import immunologic role• IL-12 has not been researched as
intensively as TNF• New knowledge not to be found in
mainstream research
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Output for IL-12
• Inhibition of IL-12 production by thalidomide.
• Thalidomide potentially suppressed the production of IL-12 by PBMC […].
• Thalidomide-induced inhibition of IL-12 production was additive […].
- - - - - - - - - -• Thalidomide stimulates […] IL-12
production in HIV patients.
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Th1/Th2 Differentation
IL-2IFN
Lymphotoxin
IL-4IL-5IL-10IL-13
Allergic diseases
B cell activation
T-cell mediatedautoimmune
diseases
IFN
IL-4, IL-10
IL-4, IL-6IL-12
Th0
Th1 Th2
inhibitionactivation
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Thalidomide and Th1/Th2
IL-2IFN
Lymphotoxin
IL-4IL-5IL-10IL-13
Allergic diseases
B cell activation
T-cell mediatedautoimmune
diseases
Thalidomide
Thalidomide
IFN
IL-4, IL-10
IL-4, IL-6IL-12
Th0
Th1 Th2
inhibitionactivation
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Open Discovery: B C
• 3,846 MEDLINE abstracts + titles on IL-12
• Selecting all diseases results in 420 concepts. 12 are selected:• Chronic hepatitis C• Sialadenitis• Myasthenia gravis• H. pylori-induced gastritis• Acute pancreatitis• Sjogren’s syndrome
•Atherosclerosis•Pulmonary fibrosis•Brucellosis•Graves’ disease•Purpura•Chickenpox
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Selection Criteria
• Already a small overlap between disease and thalidomide literature
• NLP errors, e.g., number pi mapped to concept Pulmonary valve insufficiency
• Some concepts are too broad, e.g., Critical illness
• Some concepts are too specific, e.g., Salmonella infections
• Some diseases benefit from increased IL-12
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Output Sentences: Diseases• IL-12 and […] expression in mononuclear cells
in response to acetylcholine receptor is augmented in myasthenia gravis.
• Possible involvement of IL-12 expression by Epstein-Barr virus in Sjogren syndrome.
• Acute pancreatitis patients had serum concentrations of total IL-12, IL-12p40, and IL-6 significantly higher (p < 0.05) than those of the healthy subjects.
• Expression of B7-1, B7-2, and IL-12 in anti-Fas antibody-induced pulmonary fibrosis in mice.
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Closed Discovery: A B C
• 70,000 titles and abstracts are analyzed• Focus on immunologic aspects• Several hundreds of sentences as final
result• Final list of diseases:
• Myasthenia gravis• Sialadenitis• Acute pancreatitis• Chronic hepatitis C• H. pyliory-induced gastritis
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Output Sialadenitis• These data argue for a major role of the
proinflammatory cytokines […], IL- 12, IFN-gamma initiation and perpetuation of autoimmune sialoadenitis in MRL/lpr mice […] in conjunction with an insufficiency of the anti-inflammatory cytokines TGF-beta and IL-10.
• Cells expressing tumour necrosis factor-alpha, […] and IL-12 mRNA were strongly up-regulated at about the time of onset of sialoadenitis […].
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Output, Chronic Hepatitis C• IL-12 production in chronic hepatitis C
infection.
• Induction of IL-12 production in chronic hepatitis C virus infection correlates with the hepatocellular damage.
• In the current study, increased interferon-gamma, IL-10, and IL-12 p40 serum levels were observed in patients with chronic hepatitis C compared to controls.
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Use of Expert’s Knowledge
• Anecdotal examples
• Selecting IL-12 from the list
• Potentially conflicting information concerning Myasthenia Gravis (Thalidomide in Lewis rats)
• Different database: clinical experiment with thalidomide for Sjogren’s syndrome
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Discovery Support tool• Full automatic process not possible:
• how to encode expert knowledge• principle: traversing all biomedical
knowledge, unknown what expert knowledge is needed
• NLP essential in filtering, but a complete formal representation of knowledge is not feasible
• Full automatic process not desirable:• Guided search, not automatic mining (KDD)• Generation of hypotheses: not laws• Clinical relevance
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Future Perspectives
• Better linguistic analysis
• Different sources (e.g., annotated genetic databases)
• Better user interface: Reduce work load for domain expert while minimizing role of information scientist
• Far future: indirect or second order literature searching?
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Acknowledgments
• Henny Klein (GUIDE)
• Alan Aronson (NLM)
• Jim Mork (NLM)
• Rein Vos (Maastricht University)
• Lolkje de Jong - van den Berg (GUIDE)