# Presentation: 573124

## 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.
- a study of the concept of discovery, from the angles of logic, psychology and machine learning
- 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- Withdrawn from market because of birth defects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-2
- IFN
- Lymphotoxin

- IL-4
- IL-5
- IL-10
- IL-13

- Allergic diseases
- B cell activation

- T-cell mediated
- autoimmune
- diseases

- IFN

- IL-4, IL-10

- IL-4, IL-6

- IL-12

- Th0

- Th1

- Th2

## Thalidomide and Th1/Th2

- IL-2
- IFN
- Lymphotoxin

- IL-4
- IL-5
- IL-10
- IL-13

- Allergic diseases
- B cell activation

- T-cell mediated
- autoimmune
- diseases

**Thalidomide**

**Thalidomide**

- IFN

- IL-4, IL-10

- IL-4, IL-6

- IL-12

- Th0

- Th1

- Th2

## 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

- 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)