Exploring pharmacoepidemiologic groupingsof drugs from a clinical perspective

Medinfo 2013Copenhagen, DenmarkSession: Data models and representations - IIAugust 21, 2013

Rainer Winnenburg, Olivier BodenreiderLister Hill National Centerfor Biomedical CommunicationsBethesda, Maryland - USA

Lister Hill National Center for Biomedical Communications

Motivation

Anatomical Therapeutic Chemical (ATC) classification Used in pharmacoepidemiologic studies Recently also used in applications from a clinical

perspective Assumes homogeneity of drug groups (in terms of therapeutic use,

mechanism of action, physiologic effect) BUT: “Substances classified in the same ATC fourth level

cannot be considered pharmacotherapeutically equivalent since their mode of action, therapeutic effect, drug interactions and adverse drug reaction profile may differ.” (ATC documentation)

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Objectives

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To investigate the extent to which pharmacoepidemiologic groupings are homogeneous in terms of clinical properties Pharmacoepidemiologic groupings

ATC classification WHO For comparison: Micromedex

Clinical properties National Drug File-Reference Terminology (NDF-RT)

Homogeneity Distribution of clinical properties of drugs within a grouping

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Anatomical Therapeutic Chemical (ATC) drug classification

Hierarchical classification Levels 1-4: drug groups (~ pharmacologic classes)

1,255 drug group codes Level 5: individual drugs

4,464 drug codes

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Code Label LevelC Cardiovascular system 1 - anatomicalC01 Cardiac therapy 2 - therapeuticC01A Cardiac glycosides 3 - pharmacologicalC01AA Digitalis glycosides 4 - pharmaceuticC01AA05 Digoxin 5 - drug

(as of 2012)

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National Drug File-Reference Terminology (NDF-RT)

Organized into several hierarchies 7,162 active moieties (level = ingredient) Relations to entities from other hierarchies

e.g., has_MoA relationships to mechanism of action hierarchy We used NDF-RT API for

Mapping drug names from ATC to NDF-RT Querying drug properties

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Drug Property Valueatorvastatin has_MoA Hydroxymethylglutaryl-CoA Reductase Inhibitorsatorvastatin has_PE Decreased Cholesterol Synthesisatorvastatin may_treat Hypercholesterolemiaatorvastatin may_prevent Coronary Artery Disease

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Methods Overview

1. Mapping ATC drugs to ingredients in NDF-RT and acquiring clinical properties for ingredients

2. Computing homogeneity scores for each drug class based on properties of drugs in class

3. Comparison to the clinical reference Micromedex

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Mapping ATC drugs to clinical properties

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ATCDrugs

5th level

Clinical Properties(any of the

3 categories)

ATC Drugs(single ingredients

within scope)

NDF-RTIngredients

Lexical mapping and via RxNorm

Eligibility

may_treathas_MoAhas_PE

Exclude:• Multi-ingredient drugs • Radiopharmaceuticals• Unspecific, collective terms

Relationships

has_MoA 5-Lipoxygenase Inhibitorshas_MoA Glucocorticoid Receptor Agonistshas_MoA Lipoxygenase Inhibitors

PREDNISOLONE (N0000146334)

Prednisolone (R01AD02) Prednisolone (R01AD02)

Step 1

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Computing homogeneity scores (classes)

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Grouping

Drugs ingrouping

+Clinical

Properties

A10BG01 troglitazone 

Peroxisome Proliferator-activated Receptor alpha Agonists

Peroxisome Proliferator-activated Receptor gamma Agonists

A10BG012rosiglitazone Insulin Receptor Agonists

A10BG013pioglitazone 

Insulin Receptor Agonists

A10BG Thiazolidinediones

Step 2

• 1 property accounts for 2 drugs (66% of the drugs)• 2 properties account for all 3 drugs (>90% of the drugs) => Homogeneity score = 2

HomogeneityScore

How many distinct properties (or sets of properties) are necessary to account for at least 90% of the drugs in a given subgroup?

3 distinct properties

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Homogeneity scores Examples

Example 1: homogeneous group ATC 4th level group Corticosteroids (R01AD)

10 drugs All 10 drugs have the same mechanism of action:

Glucocorticoid Receptor Antagonists One single property accounts for 100% of the drugs in

this group => homogeneity score =1

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Step 2

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Homogeneity scores Examples

Example 2: heterogeneous group ATC 4th level group Antidotes (V03AB)

12 drugs 8 mechanism of action properties are needed to

account for > 90% of the drugs in this groupSiderophore Iron Chelating Activity, Cholinesterase Inhibitors, GABA B Antagonists, Free Radical Scavenging Activity, Alcohol Dehydrogenase Inhibitors, {Noncompetitive Opioid Antagonists, Competitive Opioid Antagonists}, {Adrenergic alpha1-Antagonists, Adrenergic alpha2-Antagonists}, and Cholinesterase Reactivators.

=> homogeneity score =8

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Step 2

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Comparison to a clinical reference

Clinical reference: drug groupings in Micromedex Extracted from a drug-drug interaction system

Distribution of homogeneity scores (“profiles”) in ATC and Micromedex

3 profiles Therapeutic group Mechanism of action Physiologic effect

Hypothesis: if ATC is less homogeneous than Micromedex, it should have greater scores

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Step 3

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53% of 2nd level groups in ATC have homogeneity score of 1 or 2 vs. 75% for Micromedex

ATC therapeutic (2nd level) groups less homogeneous than groups in Micromedex

Therapeutic group profile

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Profiles for mechanism of action (MoA) and physiologic effect (PE)

> 60 % of 4th level groups in ATC have homogeneity score of 1 Homogeneity of ATC groups comparable to that of groups in

Micromedex

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Limitations and future work

Only 50% of single drugs in ATC could be mapped to NDF-RT properties Some drugs are out of scope, not marketed in the U.S. Incompleteness of NDF-RT in terms of drug properties

No statistical methodology used for the comparison of homogeneity distributions

We plan to explore alternative drug information sources for evaluation of ATC Only few reliable and publicly available (e.g., DrugBank) Most are commercial products (e.g., First Databank)

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Summary

Investigated homogeneity of pharmacoepidemiologic groupings in terms of clinical properties

Mapped ATC 5th level drugs to NDF-RT properties Based on these properties we computed homogeneity

scores for all ATC groups and contrasted their distribution against the Micromedex reference

ATC classes are generally homogeneous in terms of clinical properties, especially mechanism of action and physiologic effect, less so for therapeutic use

Incomplete drug description in NDF-RT is a major issue

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MedicalOntologyResearch

Olivier Bodenreider

Lister Hill National Centerfor Biomedical CommunicationsBethesda, Maryland - USA

Contact:Web:

olivier@nlm.nih.govmor.nlm.nih.gov