1. 1
Toward a Biomedical Ethics
Ontology
David Koepsell, Delft University of Technology, NL
Robert Arp, NCBO

2. April 23, 2014 2
Human Subjects Protection
• Applied biomedical ethics derives from historical
failures in protecting human subjects (e.g. Nuremberg
code, Belmont Report, etc.) Principles and institutions
followed:
• Principles include: beneficence, justice, non-
malificence, and dignity
• Principles enforced through institutions such as
• IRBs (US)
• Ethics comittees (EU)

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Human Subjects Protection
• Disparate IRBs and ECs decide on the ethics of a
proposed protocol based upon common principles. In
theory, this depends upon clarity and coherence of
terms:
• What is a “minimal risk” vs. a “risk”?
• What is autonomy
• What is justice?
• What is dignity?

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Human Subjects Protection
• Currently, IRB and EC members are expected to
educate themselves as to the current standards of
review practice.
• Journals
• Newsletters
• Case notes and abstracts
• Continuing education programs

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Human Subjects Protection
• How can currently accepted parameters of a critical
term be captured and disseminated so that searching
can best be accommodated?
• How can EC and IRB members in diverse places
ensure that principles are applied similarly in similar
cases?
• How to deal with an overwhelming amount of largely
wasted data?

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Clarity and Coherence
Benefits:
- assistance to those seeking clarity or
consensus about how to apply ethical
principles in similar situations
- fostering detection of inconsistencies in use of
terminologies

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Clarity and Coherence
Benefits:
• generating standardized forms
• standardized vocabulary for submissions to
regulatory agencies
• improving collection of data from past studies

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Clarity and Coherence
• How do we achieve these benefits?
ONE WAY:
A Biomedical Ethics Ontology (BMEO)

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Alternative Approaches
• Thesaurus Ethics in the Life Sciences (TELS)
German Reference Centre for Ethics in the Life
Sciences (DRZE), University of Bonn:
http://www.drze.de/BELIT/thesaurus/
- string matching, at best
e.g., find all string instances of the word:
‘risk’

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TELS
- no reasoning
Ontology
- some reasoning
brain part_of nervous system, and
nervous system part_of body, therefore
brain part_of body.
West Texas petroleum is_a petroleum, and
petroleum is_a flammable liquid, therefore
West Texas petroleum is_a flammable liquid.
is_a and part_of
are transitive

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TELS
Search= ‘animal’ Result= ‘animal x’, ‘animal y’

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Clarity and Coherence
• An ontology provides a controlled, structured
vocabulary that supports reasoning and which includes
a standardized consensus-based list of terms for use
by all of those working in a given community, above all
when describing data to be entered into a computer

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Clarity and Coherence
Ontologies help:
• ensure that the different bodies of information collected by
different researchers in the same domain should all be
represented in the same way, which assists interoperability
and shareability of that information
• improve retrieval and dissemination of information
• make the information more easily searchable by human
beings and more efficiently and reliably processable by
computers

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Clinical Trial Reviews
• “It’s a huge paperwork mess.”
—Randy Juhl, University of Pittsburgh Vice Chancellor
for Research Conduct and Compliance
(University of Pittsburgh, University Times: The Faculty
and Staff Newspaper, 36 (21), 2004)

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Biomedical Ethics
Ontology (BMEO)

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Biomedical Ethics
Ontology (BMEO)
- detect inconsistencies in use of
terminologies
- provides a standardized vocabulary for
submissions to regulatory agencies
-assistance to those seeking clarity or
consensus about how to apply ethical
principles in similar situations

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Biomedical Ethics
Ontology (BMEO)
- improving the collection of data
from past studies
- generating standardized forms, in a
compatible way, across investigations

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Clinical Trial Reviews
TEST CASE:
• STEP ONE (BFO methodology):
list the terms that correspond to the entities, and
provide clear and coherent definitions.

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Clinical Trials ReviewFigure 5: Typical IRB Review Form:
I. ResearchDesign YES
NO NA
A. Rationale x
B. Objective/Problem Statement x
C. Background, Previous Studies x
D. Methods 1. experimental vs.standard x
2a.requiredfor standard care x
2b. required only for purposeof research
3. useof placebo (if applicable)
4. likelihood of accomplishing objective x
E. DateSafety Monitoring Plan x
F. Statistical Plan x
G. Mechanism for Reporting SAE’s(seriousadverseevents) x
III. Risks/Benefits YES
NO NA
A. Minimal Risk x
B. Greater than Minimal Riskbut presenting theprospectof directbenefit x
C. Greater than Minimal Riskand no prospect of directbenefit butlikely to
yield generalizable knowledge
D. Protectionsin placefor vulnerablepopulations x
Standard documents provide
A starting point for picking
The low-hanging fruit

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Clinical Trials ReviewFigure 5: Typical IRB Review Form:
I. ResearchDesign YES
NO NA
A. Rationale x
B. Objective/Problem Statement x
C. Background, Previous Studies x
D. Methods 1. experimental vs.standard x
2a.requiredfor standard care x
2b. required only for purposeof research
3. useof placebo (if applicable)
4. likelihood of accomplishing objective x
E. DateSafety Monitoring Plan x
F. Statistical Plan x
G. Mechanism for Reporting SAE’s(seriousadverseevents) x
III. Risks/Benefits YES
NO NA
A. Minimal Risk x
B. Greater than Minimal Riskbut presenting theprospectof directbenefit x
C. Greater than Minimal Riskand no prospect of directbenefit butlikely to
yield generalizable knowledge
D. Protectionsin placefor vulnerablepopulations x
Minimal Risk
Vulnerable
Population
Standard Care

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Aristotelian Definitions
• an A is a B that/which is C (or Cs)
a board (A) is a group of persons (B) that is organized
to monitor, assess, and evaluate some activity (C)
a review board (A) is a board (B) that participates in
some review (C)
an institutional review board (A) is a review board (B)
that participates in a clinical trial review (C)

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Aristotelian Definitions
• a review is a process in which persons participate that
involves the understanding, assessing, and evaluating
of some idea or project
• a clinical trial review is a review that is performed by an
IRB of a proposed clinical trial (an investigation…
human subjects)
• an expedited clinical trial review is a clinical trial review
that is conducted by the institutional review board
chairperson because the proposed clinical trial involves
minimal risk

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Clinical Trial Reviews
• Less-complicated terms (procedures of review):
• institutional review board
• clinical trial
• clinical trial review
• More-complicated terms (principles):
• ethical duty
• risk
• justice

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Clinical Trial Reviews
TEST CASE
• STEP TWO:
list the terms that correspond to the relations, and
provide clear and coherent definitions

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Relations
• is_owed: Def.=a relationship between persons
whereby the person owed has a claim against those
who fail to abide by some duty
owes_a: Def.=a relationship between persons
whereby the person owing has a duty to perform some
action or intended action to the person owed
e.g.

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Social Ontologies and Biomedicine
• Objection: the terms and categories of ethics are
unclear and culturally relative.
• Response: and yet they are universalized in
international documents, and applied through ethics
committees
• The institutions assume to existence and reality of
principles
• We can collect decisions and help clarify principles
through application

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Social Ontologies and Biomedicine
• The fundamental principles of bioethics are re-
articulated and adopted world-wide since the
Nuremberg Code, including in The Belmont Report,
Declaration of Helsinki, Declaration of Geneva,
International ethical guidelines for biomedical research
involving human subjects. 2002 CIOMS.
• These reiterate basic principles of the Nuremberg
Code, adopted in regional (EU) and national laws and
codes

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Social Ontologies and Biomedicine
• An ontology can capture, express, or normalize local
differences in interpretation of universally-recognized
principles.
• Moreover, much of the “justice” of human subjects
research depends upon procedures, which are more
easily standardized than principles.

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Social Ontologies and Biomedicine
• A BMEO will interact with the OBI. The OBI ought to capture
data on social as well as scientific aspect of biomedical
investigations. There is already overlap.
how OBI would represent the term
will add to OBI based on this
work In OBI at this time Term BMEO Def additional notes
homo sapiens (alt term:person)
OBI DEF: a human being
regarded as an individual 〈 person:
a person is a human being that
is conscious and the bearer of
rights and privileges in a
society
(also see the issue of a natural
person, which turns out to be a
technical definition to distinguish
a human from a corporation)
add to OBI: Researcher role is a
worker role which inheres in a
person and realized through a
process of investigating and
seeking to explain and predict
some aspect of reality (cite
BMEO) 〈 researcher
a researcher is a role of a
person whereby that person is
investigating and seeking to
explain and predict some
aspect of reality
we would add this by the specific study design
used; if it is a clinical trial then the researcher
would necessarily be a clinical trial researcher 〈 clinical trial researcher:
a clinical trial researcher is a
researcher that conducts
research using human subjects
in a clinical trial
study subject role OBI DEF: a
study subject role is a study
participant role which inheres in
an entity and is realized by the
implementation of (1) an
observation design specifying
how the entity is to be observed
and/or (2) an intervention design
speci Study subject role
we would add this by defining the entity playing
the study subject role; in this case the entity
would be a person 〈 human subject:
a human subject is a role of a
person whereby that person is
the subject of study in a
clinical trial
we would add this by defining the entity playing
the study subject role; in this case the entity
would be "an organism other than human". At
the moment in OBI orgnaism includes homo
sapiens, and i would like to make a class of all
organisms with the exce 〈 animal subject:
an animal subject is a role of
an animal whereby that
animal is the subject of study
in a trial
OBI considers a clinical trial to be a type of
investigation, with study design being clinical
study design and subject role inhering in entity
= person. 〈 clinical trial:
a clinical trial is a process
aggregate where tests,
experiments, and other
evaluations are carried out on
human subjects in order to
assess the effects of a clinical
trial drug or clinical trial
device look at OBI and use
the definition from there
At the moment both of our
definitions exclude purely
observational clinical trials; we
should fix this in the future

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Social Ontologies and Biomedicine
Difficult part: defining basic ethical principles.
Q: what are “justice” or “dignity”
• “Justice: 1. The ethical principle that persons who
have similar circumstances and conditions should
be treated alike; sometimes known as distributive
justice.” -Medilexicon

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Social Ontologies and Biomedicine
Informed consent, autonomy, beneficence… can these
be satisfactorily defined from first principles?
No. But they are not treated as though they can be in
applied ethics. IRB members review cases, make
judgments based upon past experiences, and
generalize from those experiences to similar cases.

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Social Ontologies and Biomedicine
• Past instances of injustice, lack of autonomy, or failure
of informed consent currently provide the guide for
IRBs and ECs making decisions about proposed
research now…
• The BMEO will help coordinate by clarifying relations
among past instances, solidifying the present state of
these objects within and across various jurisdictions.
• Will assist with relating past instances with proposed
studies through ontology

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The Task
• Test cases must be devised, model ontology built:
• developing rigorous definitions of biomedical ethics terms
common to ethics committee reviews everywhere. For
instance, the term autonomy should be well defined, and
given the vast repository of cases in the literature, examples
of autonomy and counter-examples can be compared. The
same should be done with the terms: informed consent,
minimal risk, harm, study, research, human subject, sample,
vulnerable population, and other similarly critical terms.
• (source: central institutional documents for human subjects
research in Europe and the U.S., as well as other
internationally important documents and institutions directing
ethical treatment of human subjects)

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The Task
• Domain specialists (e.g. ethics committee members,
professional and theoretical ethicists, and lawyers) will
need to work with professional ontologists to construct
a working ontology. We will need to gather a group of
ontologists and domain specialists to generate a useful
number of terms and relations before putting it to real-
world tests.

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The Task
• Case studies will be developed as a proof of concept
for use in clinical trials for a hypothetical multi-national,
multi-center research study involving human subjects.
For the purpose of the study, hypothetical trials will be
devised, protocols written, and the various institutional
and governmental requirements for ethical human
subject research from between three and five legal
jurisdictions (with differing standards and institutions)
will be used

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The Task
• We will use a prototype Biomedical Ethics Ontology to
standardize review procedures and to fill out checklists
for requirements in an electronic review form and
consent documents incorporating ethical and
procedural requirements in protocol reviews across all
the hypothetical study centers. We will test these
hypothetical cases against real studies and real review
forms and associated comments that have been de-
identified or otherwise useable without breaching
confidentiality

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References:
• Koepsell D, Arp R, Fostel J, Smith B, “Creating a
controlled vocabulary for the ethics of human research:
towards a biomedical ethics ontology.” J Empir Res
Hum Res Ethics. 2009 Mar;4(1):43-58.
• Koepsell D., Smith B, “Letter to the Editor: Dealing with
Socially Constructed Concepts in an Ontology” J Empir
Res Hum Res Ethics. June 2009, Vol. 4, No. 2, Pages
75–76 , DOI 10.1525/jer.2009.4.2.75

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Thank you!
• This work was funded by the National Institutes of
Health through the NIH Roadmap for Biomedical
Research, Grant 1 U 54 HG004028.
• Information on the National Centers for Biomedical
Computing can be found at:
http://nihroadmap.nih.gov/bioinformatics.