Post on 05-Jan-2016
Exploring pharmacoepidemiologic groupingsof drugs from a clinical perspective
Medinfo 2013Copenhagen, DenmarkSession: Data models and representations - IIAugust 21, 2013
Rainer Winnenburg, Olivier Bodenreider
Lister 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