exploring pharmacoepidemiologic groupings of drugs from a … · 2013-08-25 · lister hill...

Exploring pharmacoepidemiologic groupings of drugs from a clinical perspective

Medinfo 2013 Copenhagen, Denmark Session: Data models and representations - II August 21, 2013

Rainer Winnenburg, Olivier Bodenreider

Lister Hill National Center for Biomedical Communications Bethesda, 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


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 Level C Cardiovascular system 1 - anatomical C01 Cardiac therapy 2 - therapeutic C01A Cardiac glycosides 3 - pharmacological C01AA Digitalis glycosides 4 - pharmaceutic C01AA05 Digoxin 5 - drug

(as of 2012)


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 Value atorvastatin has_MoA Hydroxymethylglutaryl-CoA Reductase Inhibitors atorvastatin has_PE Decreased Cholesterol Synthesis atorvastatin may_treat Hypercholesterolemia atorvastatin may_prevent Coronary Artery Disease


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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ATC Drugs

5th level

Clinical Properties (any of the

3 categories)

ATC Drugs (single ingredients

within scope)

NDF-RT Ingredients

Lexical mapping and via RxNorm

Eligibility

may_treat has_MoA has_PE

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

Relationships

has_MoA 5-Lipoxygenase Inhibitors has_MoA Glucocorticoid Receptor Agonists has_MoA Lipoxygenase Inhibitors

PREDNISOLONE (N0000146334)

Prednisolone (R01AD02) Prednisolone (R01AD02)

Step 1


Computing homogeneity scores (classes)

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Grouping

Drugs in grouping

+ Clinical

Properties

A10BG01 troglitazone

Peroxisome Proliferator-‐ac0vated Receptor alpha Agonists

Peroxisome Proliferator-‐ac0vated Receptor gamma Agonists

A10BG012 rosiglitazone Insulin Receptor Agonists

A10BG013 pioglitazone 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

Homogeneity Score

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


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


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 group Siderophore 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


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

Lister Hill National Center for Biomedical Communications 12

  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


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


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)


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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Medical Ontology Research

Olivier Bodenreider

Lister Hill National Center for Biomedical Communications Bethesda, Maryland - USA

Contact: Web:

[email protected] mor.nlm.nih.gov

exploring pharmacoepidemiologic groupings of drugs from a … · 2013-08-25 · lister hill...

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