Inheritance of Drug Information
C.J. Wroe1,W.D. Solomon1, A.L. Rector1, J.E. Rogers1
Medical Informatics Group,
Department of Computer Science, University of Manchester, UK
& OpenGALEN www.opengalen.org
1
The GALEN Drug Ontology has been developed
to provide a reference terminology by which
prescribing guidelines within the PRODIGY
Project and the patient record can be integrated.
Consistency and ease of maintenance are
provided by GALEN classification techniques,
which promise to improve consistency by
classification-based inheritance. This allows
information to be asserted only once in the most
general case. We have found examples where this
promise is realised and cases where more
elaborate inheritance behaviours are needed. In
addition to determining what these behaviours
should be, we have developed a model of drug
information to help identify which behaviour
should be applied to each aspect of a drug
description. Two implementations of these
inheritance behaviours are described detailing
the advantages of each. Authoring the content of
the ontology and development of applications that
use the ontology has gone on in parallel to the
implementation of these inheritance behaviours.
The use of an intermediate representation shield
authors of the ontology content from these lowlevel implementation issues.
Introduction
The GALEN Drug Ontology is aiming to provide
a reference terminology for prescribing
guidelines developed within phase III of the
PRODIGY Project1.
The ontology is built from the bottom up. Firstly,
descriptions about drug terms are authored in an
Intermediate Representation. These descriptions
are based on information present in the British
National Formulary2. The guidelines require drug
terms to be indexed by formulation, ingredients,
action,
pharmacokinetics,
side
effects,
interactions, contraindications, indications and
interactions. Therefore each drug description
consists of a terminological definition of the drug
concept together with a set of properties detailing
the relevant features listed above. These are then
translated into GRAIL, to allow a description
logic classifier to automatically produce a multiaxial classification of these terms3,4. A guideline
can then be authored using general drug terms
such as 'Anti-anginal preparation'. When the
guideline is interpreted, the drug ontology
provides a multi-axial classification, which
relates the general guideline term with the more
specific terms present in the patient record such
as Atenolol.
We have shown in other domains that the
GALEN approach can provide the following
benefits5,6,7:

Logical consistency of the classification.

Descriptions can be authored to arbitrary
levels of detail.

Classification occurs along multiple and
separate axes of classification.

Classification allows information added
about a more general class to be inherited by
its descendants. Information need only be
specified once in the most general case.
The drug ontology differs from previous GALEN
projects in the form of information present in the
ontology. The drug ontology mostly contains
information about the properties of the core drug
concepts in contrast to previous GALEN projects
which concentrate on the terminological
definition of concepts. This shows up differences
in the required degree of inheritance.
Drug inheritance examples
When using a description logic classifier, all
information asserted about a drug class is
automatically inherited by its descendants and
cannot be overridden. This can be seen as a form
of inference. The properties of individual drug
classes are inferred from the properties of parent
drugs classes. The following examples explore
cases where this may or may not be valid and
useful.
1. Pharmacological action of dihydropyridines
Dihydropyridines are a structural class of drugs.
The ontology asserts that dihydropyridines have a
calcium channel blocking action.
Chemical structure and pharmacological action
are closely related and so it is justified to infer
that any drug possessing the dihydropyrindine
structure will posses the calcium channel
blocking action. In terms of classification and
inheritance, it is valid to inherit the calcium
channel blocking action property from a parent
defined in terms of chemical structure. In the
following examples this is described as inheriting
a drug action property along a chemical structure
axis of classification.
valid to infer from the respective single
ingredient drugs?
‘Co-amilofruse’ is a drug preparation containing
both frusemide and amiloride. The amiloride is
added to counteract the increased potassium
excretion produced by frusemide.
Drug
2. Contraindications of betablockers
Betablockers are a class of drug based on
pharmacological action. Contraindications are a
'clinical' property assigned to the drug by
professional clinical authorities based on theory
and observational research. A link may exist
between the action and the contraindication but it
may not be relied upon to infer that all
betablockers have the same contraindications.
For example, all betablockers are absolutely
contraindicated in the presence of a history of
asthma, except for the subset of cardioselective
betablockers, which may be used with extreme
caution. These are the decisions of clinical
authorities, which are based on the action of the
drug but cannot be inferred directly from it.
Inheritance can act as a 'fail soft' mechanism
providing the safest set of contraindications from
the available information. In this case an absolute
contraindication with a history of asthma will be
automatically inherited by all betablockers by
default.
However, if a contraindication is known not to be
true for a specific drug, there must be a
mechanism for overriding the inherited property.
In this case the absolute contraindication should
be overridden with an extreme caution property.
3. Indications of betablockers
Indications are a 'clinical property', as are
contraindications described above. However in
contrast to contraindications, it would not be safe
to inherit an indication property by default. An
example is Betablockers and Sotalol. All
Betablockers are indicated for the treatment of
hypertension, except Sotalol. If the drug ontology
author was not aware of the exception, the
indication would automatically be inherited by
Sotalol leading to the presentation of dangerous
information to an application. In this case the
desired behaviour is to not inherit the indication
property from parent drug classes.
Frusemide
Amiloride
action - increased potassium action - decreased potassium
excretion
excretion
side effect - hypokalaemia
side effect - hyperkalaemia
Co-amilofruse
action - increased potassium excretion
action - decreased potassium excretion
side effect - ?
Figure 1. Example of a ‘Nixon’ Diamond
in the drug domain
As shown in figure 1, in the ontology, a
preparation containing frusemide is asserted to
have a ‘potassium excreting action’ while a
preparation containing amiloride is asserted to
have a ‘potassium conserving action’. ‘Coamilofruse’ contains both active ingredients and
so is a child of both ‘Frusemide preparation’ and
‘Amiloride preparation’. Chemical composition is
closely related to the action of a drug. Therefore,
we have concluded that the compound
preparation should inherit both actions from the
parent, as the resulting preparation will indeed
have both these actions.
As a result of these actions, ‘Frusemide
preparation’ is asserted to have a side effect of
‘hypokalaemia’ and ‘Amiloride preparation’ is
asserted to have the side effect ‘hyperkalaemia’.
This an example of a ‘Nixon diamond’ in which
contradictory properties are inherited from
multiple parents. Research in this area has shown
that the contradiction cannot be resolved based
just on the information within the classification
but requires additional knowledge8. In this case a
specific side effect profile for the combination
drug. In the absence of this information the most
useful behaviour of the ontology would be:
4. Co-amilofruse actions and side effects

The British National Formulary (BNF) has been
used as the source of information in the ontology.
In most cases, it does not state the properties of
combination preparations such as side effects. In
the absence of specific information, what is it
Present an application with the set of
candidate side effects based on respective
single ingredient parents

Identify contradictions if possible.

Allow authors to override inheritance from
single ingredient parents if additional
knowledge
about
the
combination
preparation becomes available.
Inheritance behaviours needed
The above examples demonstrate the need for at
least three different inheritance behaviours.

Logical inheritance - all properties inherited
automatically.

Modified inheritance - properties inherited
by default but they can be overridden in
specific cases.

No inheritance
Application of inheritance behaviours
In the above examples we have described some
features as 'clinical'. That is they can be
influenced by the intrinsic structure and
pharmacological actions of the drug, but are
assigned by professional clinical authorities. In
developing the ontology we have formed a model
of how the different properties can be arranged in
a spectrum from 'intrinsic' to 'clinical'.
Indication
Side Effect
Interaction
Action
(Pharmacodynamics)
Pharmacokinetics
Key:
Formulation
Intrinsic
Can influence
It is justified to inherit an intrinsic property
down a more intrinsic axis of classification
(e.g. example 1- action along structure)

Modified inheritance should occur when
inheriting clinical properties down an
intrinsic axis of classification if safe to do so.
(e.g. example 2 – contraindication along
structure)

No inheritance should occur when inheriting
clinical properties down an intrinsic axis of
classification if unsafe to do so. (e.g.
example 3 – indication along structure)

It is never justified to inherit an intrinsic
property down a clinical axis of
classification. In fact, an intrinsic property
should not be attached to an abstract drug
class defined in terms of a clinical property.
(e.g. structure along contraindication)
Inheritance without exception
Logical inheritance is implemented within the
description logic classifier and needs no
additional mechanisms. Any property asserted to
be true of one concept is also true of all
descendants of that concept.
Contraindication
Chemical
structure

Implementation
Clinical
Low confidence that properties
should be inherited.
Licensed
Indication
Figure 2 demonstrates that 'Chemical structure' is
an intrinsic property of a drug and can indirectly
influence a clinical property such as 'Indication'.
However the converse is not true: 'Indication'
properties cannot influence 'Chemical structure'
properties. Using this model we have formulated
a small number of rules to decide which
inheritance strategy to apply to each situation.
High confidence that properties
should be inherited.
Figure 2. Proposed model of how drug
properties can influence each other and where
they lie in the spectrum from intrinsic to
clinical.
No inheritance and modified inheritance
To prevent inheritance of a property it must not
be presented to the description logic classifier.
There are two possibilities.
1) Properties can be excluded from abstract
drug classes, either by authors or authoring
tools. Although properties are presented to
the classifier, they are attached to classes
with no descendants and so inheritance
cannot occur.
2) The properties can remain but are tagged to
prevent them being presented to the classifier.
These have been termed 'GRAIL extrinsic
properties'. Applying an extrinsic property to a
GRAIL concept has no effect on its logical
structure: as far as the classifier is concerned, it
may as well not exist. An extrinsic property is a
‘decoration’, or ‘annotation’ of a GRAIL concept.
It’s utility comes from the fact that these
decorations remain associated with a GRAIL
concept as that concept’s position moves around
in the automatically-generated and maintained
hierarchy. The classification acts as a semantic
index to aid access to a concept’s extrinsic
properties9,10.

Prevent drug properties being attached to
abstract drug classes
The first method, which is used at present, is only
to allow clinical properties such as indications to
be attached to the lowest level drug classes. For
example 'hypertension indication' is attached not
to the betablocker drug class but separately to its
children such as 'Atenolol'. Anti-anginal
indication' is not attached to calcium channel
blockers but separately to its children such as
Nifedipine.
This requires the author or author time tools to
augment the classifier and infer the leaf node
properties from the properties attached to parents
and the desired inheritance behaviour. Properties
presented to the classifier are then only attached
to the 'bottom-most' concepts and so prevent any
logic inheritance occurring. For example the
author may assert all betablockers are 'absolutely
contraindicated in history of asthma' except for
cardioselective betablockers (which can be used
with extreme caution with a history of asthma).
Post-authoring tools resolve this expression by
removing the absolute contraindication from
‘Betablockers’ and adding it to all children except
cardioselective betablockers.
If after this process, all descendants do indeed
posses a common property this can be promoted
up to the parent in a process of abduction.
Advantages
Properties are still presented to the classifier,
which allows it to answer queries such as ‘ What
are the betablockers that have an absolute
contraindication for asthma’.
Disadvantages
The additional inheritance mechanisms are
implemented following authoring of the drug
descriptions but before classification. In this
above example, if a new betablocker was entered
in the ontology the procedure would have to be
repeated and the ontology reclassified to ensure it
inherited the correct properties.

Prevent drug properties
presented to the classifier
from
being
The second method is to allow all properties
attached to abstract classes to remain in the
GRAIL ontology. Those that are not inherited in
all cases are tagged as extrinsic and not presented
to the classifier.
When a query is passed to the terminology server,
the server infers the properties of a class by
examining the properties of itself and its parents
and noting the relevant inheritance behaviour. In
the betablocker example, the betablocker class
would have 'absolutely contraindicated with
history of asthma' attached as an extrinsic
property. Cardioselective betablockers would
posses a 'suppressExtrinsic' property to notify the
query system it does not inherit the 'absolutely
contraindicated with history of asthma' property.
“Does this drug have contraindication y” is
answered by a server call that checks all parents
of the drug in question, until either a
suppressExtrinsic property is found (in which
case the answer is no), or an appropriate property
is found (in which case the answer is yes), or the
top of the concept tree is reached (in which case
the answer is no).
Advantages
Inheritance issues are resolved at query time and
so adding new information into the ontology does
not need additional resources at author time.
Disadvantages
Modified inheritance is now implemented within
the query system and so additional mechanisms
are needed when answering a query.
Implementation and the user
These two possible implementations may alter
the efficiency with which the ontology operates.
The behaviour apparent to authors and
application developers should be the same
irrespective of implementation. GALEN makes
this possible by using an intermediate
representation, and high-level terminology server
calls.
The use of an Intermediate Representation not
only shields the authors but also allows the low
level implementation of inheritance to be changed
without need for re-authoring drug descriptions.
Summary
We now have a large corpus of drug information
available in the ontology and have an
understanding of the different mechanisms that
may be needed to implement inheritance in a
useful way. The next step is to investigate which
of the two implementation strategies involves the
best set of comprises for operation of the drug
ontology.
The separation between authoring in Intermediate
Representation (IR)3 and automatic classification
based on GRAIL, allows the inheritance
behaviour as seen by authors and users to remain
stable even if the low-level implementation is
changed, enabling us to test these hypotheses.
The inheritance behaviours are tailored to
providing the safest set of inferred drug
properties based on the properties of parent drug
classes. However this does not remove the need
for extensive manual validation of the ontology
before use. One aspect of this validation should
be a check on the set of inherited properties for
each class to ensure it is valid. Further work is
needed to explore how we can best support the
validation of the ontology given the information
is in a highly structured form.
Acknowledgements
With thanks to the BNF and the PRODIGY team
at SCHIN.
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