marc weeber 1,2 grietje molema 2

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

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

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.

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

Swanson (I)

Substance

A

Effects B

Disease C

Swanson (II)

Fish oil

High blood viscosity Platelet aggregation

Raynaud’s

disease

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

Two-step Approach

• Open discovery, generating a hypothesis

A ?c?b

• Closed discovery, testing a hypothesis

A C?b

Discovery Task

• Replicating Swanson’s two famous literature-based discoveries: Weeber et al. 2001. JASIS 52(8)

• Finding new applications for existing drugs

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• Withdrawn from market because of birth defects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

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

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

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

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.

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

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

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

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

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.

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

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 […].

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.

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

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

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?

Acknowledgments

• Henny Klein (GUIDE)

• Alan Aronson (NLM)

• Jim Mork (NLM)

• Rein Vos (Maastricht University)

• Lolkje de Jong - van den Berg (GUIDE)