Stromectol is indicated for the treatment of Strongyloidiasis of the intestinal tract and Onchocerciasis due to nematode parasite. This indication is based on randomized double blind, placebo controlled and comparative studies.

Ketorolac tromethamine tablets are indicated for short term management of moderate to severe pain that requires analgesia at the opioid level.

ACULAR ophthalmic solution is indicated for the temporary relief of ocular itching due to seasonal allergic conjunctivitis. It is also indicated for the treatment of postoperative inflammation in patients who have undergone cataract surgery.

LabeledIn: Cataloging Labeled Indications for Human Drugs Ritu Khare1, Jiao Li1,2, Zhiyong Lu1

1National Center for Biotechnology Information, National Library of Medicine, NIH 2Institute of Medical Information, Chinese Academy of Medical Sciences

Background Semi-Automated Annotation Pipeline

Results: LabeledIn

Drug Label Selection Manual Indication Annotation (Experts A1 and A2 - Two Rounds)

Drug Indication Resource

(LabeledIn)

#Drugs #Drug-Indication Pairs

IN (249) 1,318

IN+DF (611) 2,997

IN+DF+ST (1,513)

7,805

Fig 3 The Annotation Framework with Three Components

LabeledIn Highlights

Computable Structured and Normalized

Human-Validated

Kappa agreement:

Round-1 77.48%

Round-2 88.35%

Source Linked Offsets in drug labels

Source Coverage ~50% Human Rx Drug Labels

Drug Coverage >65% drug searches on PubMed Health

Data Availability Multiple Formats

Related Publications

Khare R, Wei C-H, Lu Z, Annotating FDA Drug Labels for Drug Indications, AMIA Summits on Translational Sciences, 2014

Khare R, Li J, Lu Z, Toward Creating a Gold Standard of Drug Indications, IEEE International Conference on Health Informatics, 2013

Future Directions

Increase drug coverage: machine learning & crowdsourcing

Integrate with other resources (e.g. EMRs)

Most existing “gold standard” repositories on drugs and their indications are unstructured and do not support computer processing or semantic interoperability. Text mining efforts to automatically extract structured indications from free text are limited due to NLP challenges.

Fig 2 Using Existing Disease NER Tools for Indication Recognition

We propose a semi-automatic annotation framework and present a unique resource – LabeledIn – which contains information about drugs and their marketed indications and has the following key properties:

DailyMed (XML/HTML) (FDA Drug Labels)

Motivation

Disease 1

Disease 2

Disease 3

Disease

Drug Indications e.g. What are the indicated usages of

Fluoxetine

Disease Treatments e.g. What drugs may be prescribed for

hypertension

Fig 1 Applications of Drug-Disease Treatment Relationships

Question and Answering e.g. Google Knowledge Graph

Enrich Hyperlinks in Online Resources

Computational Drug Repurposing EMR Decision Support and

Error Control

1. Computable Structured Normalized (UMLS, RxNorm)

2. Accurate Source Linked Precise “Azithromycin 250 mg oral tablet” instead of

“Azithromycin” “Respiratory Tract Infections” instead of “Infections”

Our Contributions

Human Judgment

Automatic Disease Recognition

IN = ingredient DF = dose form ST = strength

Clonazepam(Klonopin) Azithromycin(Zithromax)

16,621

8,151 500

All Human Rx

250 most searched ingredients

Representative labels for annotation

DailyMed Current Medication Information

Round-1: Accept/Reject Pre-annotations

Round-2: Improve Previous Judgments

Fig 4 Applying the Annotation Framework on DailyMed August 2012 Version

Acknowledgments

This research was supported by the Intramural Research Program of the National Institutes of Health, National Library of Medicine. The investigators would like to thank the three human annotators for their efforts.

Rejected Accepted Additionally Suggested

Using Disease Recognition for Indication Extraction

Precision Recall F1-measure

0.55 0.94 0.69

ACULAR ophthalmic solution is indicated for the temporary relief of ocular itching due to seasonal allergic conjunctivitis. It is also indicated for the treatment of postoperative inflammation in patients who have undergone cataract surgery.

Ketorolac tromethamine tablets are indicated for short term management of moderate to severe pain that requires analgesia at the opioid level.

Diltiazem hydrochloride extended release capsules USP are indicated for the treatment of hypertension. Diltiazem hydrochloride extended release capsules is indicated for the management of chronic stable angina and angina due to coronary artery spasm.

Diltiazem hydrochloride extended release capsules USP are indicated for the treatment of hypertension. Diltiazem hydrochloride extended release capsules is indicated for the management of chronic stable angina and angina due to coronary artery spasm.

Diltiazem hydrochloride extended release capsules USP are indicated for the treatment of hypertension. Diltiazem hydrochloride extended release capsules is indicated for the management of chronic stable angina and angina due to coronary artery spasm.

Legend: Current Selected Not Selected

Legend: Previously Selected by A1 only Previously Selected by A2 only

1618 1332 97

LabeledIn Pre-annotations

Fig 5 Computer pre-annotations Vs. Human Annotations

Fig 6 Comparison of LabeledIn and SIDER 2 (50 drug labels)

LabeledIn SIDER 2

92 431 384 56%

9%

14%

21%

Unique Pairs in LabeledIn

23%

49%

12%

10% 3% 3%

Unique Pairs in SIDER

● More Specific ● CUI Different ● Disjoint Mention ● Missed by SIDER

● Other Context ● Generic Overlapping ● Less Specific ● Non-Disease ● CUI Different ● Side Effect /Contraindication

x

x

#DrugLabel-Disease Pairs

#DrugLabel-Disease Pairs

LabeledIn vs. Computer Pre-annotations LabeledIn vs. SIDER 2 Indications