Biomedical Ethics Ontology

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Toward a Biomedical Ethics Ontology

David Koepsell, Delft University of Technology, NLRobert Arp, NCBO

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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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• 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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• 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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• 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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Benefits:

• generating standardized forms

• standardized vocabulary for submissions to regulatory agencies

• improving collection of data from past studies

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• 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 beste.g., find all string instances of the word:

‘risk’

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TELS- no reasoningOntology- some reasoning

brain part_of nervous system, andnervous system part_of body, thereforebrain part_of body.

West Texas petroleum is_a petroleum, andpetroleum is_a flammable liquid, thereforeWest Texas petroleum is_a flammable liquid.

is_a and part_of are transitive

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TELSSearch= ‘animal’ Result= ‘animal x’, ‘animal y’

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• 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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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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- 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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- improving the collection of data from past studies- generating standardized forms, in a compatible way, across investigations

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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. Research Design YES

NO NA

A. Rationale x

B. Objective/Problem Statement x

C. Background, Previous Studies x

D. Methods 1. experimental vs. standard x

2a. required for standard care x

2b. required only for purpose of research

3. use of placebo (if applicable)

4. li kelihood of accomplishing objective x

E. Date Safety Monitoring Plan x

F. Statistical Plan x

G. Mechanism for Reporting SAE’s (serious adverse events) x

III. Risks/Benefits YES

NO NA

A. Minimal Risk x

B. Greater than Minimal Risk but presenting the prospect of direct benefit x

C. Greater than Minimal Risk and no prospect of direct benefit but likely to

yield generalizable knowledge

D. Protections in place for vulnerable populations x

Standard documents provideA starting point for pickingThe low-hanging fruit

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Clinical Trials ReviewFigure 5: Typical IRB Review Form:

I. Research Design YES

NO NA

A. Rationale x

B. Objective/Problem Statement x

C. Background, Previous Studies x

D. Methods 1. experimental vs. standard x

2a. required for standard care x

2b. required only for purpose of research

3. use of placebo (if applicable)

4. li kelihood of accomplishing objective x

E. Date Safety Monitoring Plan x

F. Statistical Plan x

G. Mechanism for Reporting SAE’s (serious adverse events) x

III. Risks/Benefits YES

NO NA

A. Minimal Risk x

B. Greater than Minimal Risk but presenting the prospect of direct benefit x

C. Greater than Minimal Risk and no prospect of direct benefit but likely to

yield generalizable knowledge

D. Protections in place for vulnerable populations x

Minimal Risk

VulnerablePopulation

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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• 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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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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• 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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• 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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• 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 termwill 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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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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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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• 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.

Education

Biomedical Ethics Ontology