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Medinfo 2013
Copenhagen, Denmark
Session: Data models and representations - II
August 21, 2013
Exploring pharmacoepidemiologic groupings
of drugs from a clinical perspective
Rainer Winnenburg, Olivier Bodenreider
Lister Hill National Center
for Biomedical Communications
Bethesda, Maryland - USA
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
 To
investigate the extent to which
pharmacoepidemiologic groupings are
homogeneous in terms of clinical properties

Pharmacoepidemiologic groupings



Clinical properties


ATC classification WHO
For comparison: Micromedex
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

Levels 1-4: drug groups (~ pharmacologic classes)


classification
1,255 drug group codes
Level 5: individual drugs

4,464 drug codes
(as of 2012)
Code
C
C01
C01A
C01AA
C01AA05
Label
Cardiovascular system
Cardiac therapy
Cardiac glycosides
Digitalis glycosides
Digoxin
Level
1 - anatomical
2 - therapeutic
3 - pharmacological
4 - pharmaceutic
5 - drug
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National Drug File-Reference
Terminology (NDF-RT)
 Organized


7,162 active moieties (level = ingredient)
Relations to entities from other hierarchies

 We


into several hierarchies
e.g., has_MoA relationships to mechanism of action hierarchy
used NDF-RT API for
Mapping drug names from ATC to NDF-RT
Querying drug properties
Drug
atorvastatin
atorvastatin
atorvastatin
atorvastatin
Property
has_MoA
has_PE
may_treat
may_prevent
Value
Hydroxymethylglutaryl-CoA Reductase Inhibitors
Decreased Cholesterol Synthesis
Hypercholesterolemia
Coronary Artery Disease
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Methods Overview
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
1.
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Step 1
Mapping ATC drugs to clinical properties
ATC
Drugs
5th level
Eligibility
ATC Drugs
(single ingredients
within scope)
Exclude:
Prednisolone (R01AD02) • Multi-ingredient drugs
Prednisolone (R01AD02)
• Radiopharmaceuticals
• Unspecific, collective terms
Lexical mapping
and via RxNorm
Clinical Properties
(any of the
3 categories)
has_MoA 5-Lipoxygenase Inhibitors
has_MoA Glucocorticoid Receptor Agonists
has_MoA Lipoxygenase Inhibitors
Relationships
may_treat
has_MoA
has_PE
NDF-RT
Ingredients
PREDNISOLONE (N0000146334)
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Step 2
Computing homogeneity scores (classes)
Grouping
A10BG
Drugs in
grouping
+
Clinical
Properties
A10BG01
troglitazone
Thiazolidinediones
Peroxisome Proliferatoractivated Receptor alpha
Agonists
Peroxisome Proliferatoractivated Receptor gamma
Agonists
A10BG012
rosiglitazone
A10BG013
pioglitazone
Insulin Receptor Agonists
Insulin Receptor Agonists
3 distinct properties
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?
• 1 property accounts for 2 drugs (66% of the drugs)
• 2 properties account for all 3 drugs (>90% of the drugs)
=> Homogeneity score = 2
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Step 2
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 alpha1Antagonists, Adrenergic alpha2-Antagonists}, and Cholinesterase
Reactivators.
=> homogeneity score =8
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Step 3
Comparison to a clinical reference
 Clinical

reference: drug groupings in Micromedex
Extracted from a drug-drug interaction system
homogeneity scores (“profiles”) in
ATC and Micromedex
 3 profiles
 Distribution of



Therapeutic group
Mechanism of action
Physiologic effect
 Hypothesis:
if ATC is less homogeneous than
Micromedex, it should have greater scores
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Therapeutic group profile

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
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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
Lister Hill National Center for Biomedical Communications
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Medical
Ontology
Research
Contact: [email protected]
Web:
mor.nlm.nih.gov
Olivier Bodenreider
Lister Hill National Center
for Biomedical Communications
Bethesda, Maryland - USA