Drawing on ethical and legal frameworks in the Netherlands, the United States and France, we examine whether physicians are expected to inform patients about potentially relevant opportunities for expanded access to investigational drugs. While we found no definitive legal obligation, we argue that physicians have a moral obligation to discuss opportunities for expanded access with patients who have run out of treatment options to prevent inequality, to promote autonomy, and to achieve beneficence.

When seriously ill patients reach the end of the standard treatment trajectory for their condition, they may qualify for the use of unapproved, investigational drugs regulated via expanded access programs. In medical-ethical discourse, it is often argued that expanded access to investigational drugs raises ‘false hope’ among patients and is therefore undesirable. We set out to investigate what is meant by the false hope argument in this discourse. In this paper, we identify and analyze five versions of the false hope (...) argument which we call: (1) the limited chance at benefit argument, (2) the side effects outweighing benefits argument, (3) the opportunity costs argument, (4) the impossibility of making informed decisions argument, and (5) the difficulty of gaining access argument. We argue that the majority of these five versions do not provide normative ground for disqualifying patients’ hopes as false. Only when hope is rooted in a mistaken belief, for example, about the likelihood of benefits or chances on medical risks, or when hope is directed at something that cannot possibly be obtained, should it be considered false. If patients are adequately informed about their odds of obtaining medical benefit, however small, and about the risks associated with an investigational treatment, it is unjustified to consider patients’ hopes to be false, and hence, to deny them access to investigational drug based on that argument. (shrink)

Landgrebe and Smith provide an argument for the impossibility of Artificial General Intelligence based on the limits of simulating complex systems. However, their argument presupposes a very contemporary vision of artificial intelligence as a model trained on data to produce an algorithm executable in a modern digital computing system. The present contribution explores what it means to be artificial. Current artificial intelligence approaches on modern computing systems are not the only conceivable way in which artificial intelligence technology might be created. (...) If there are conceivable routes by which an artificial intelligence might be developed that are not constrained in the same way as the current generation of artificial neural networks, then these might be plausible routes towards the engineered generation of artificial general intelligence that are not precluded by the Landgrebe and Smith argument against the possibility of artificial general intelligence. (shrink)

Statements about the behavior of biological entities, e.g. about the interaction between two proteins, abound in the literature on molecular biology and are increasingly becoming the targets of information extraction and text mining techniques. We show that an accurate analysis of the semantics of such statements reveals a number of ambiguities that is necessary to take into account in the practice of biomedical ontology engineering. Several concurring formalizations are proposed. Emphasis is laid on the discussion of biological dispositions.

Statements about the behavior of biochemical entities (e.g., about the interaction between two proteins) abound in the literature on molecular biology and are increasingly becoming the targets of information extraction and text mining techniques. We show that an accurate analysis of the semantics of such statements reveals a number of ambiguities that have to be taken into account in the practice of biomedical ontology engineering: Such statements can not only be understood as event reporting statements, but also as ascriptions of (...) dispositions or tendencies that may or may not refer to collectives of interacting molecules or even to collectives of interaction events. (shrink)

The pivotal role of the relation part-of in the description of living organisms is widely acknowledged. Organisms are open systems, which means that in contradistinction to mechanical artifacts they are characterized by a continuous flow and exchange of matter. A closer analysis of the spatial relations in biological organisms reveals that the decision as to whether a given particular is part-of a second particular or whether it is only contained-in the second particular is often controversial. We here propose a rule-based (...) approach which allows us to decide on the basis of well-defined criteria which of the two relations holds between two anatomical objects, given that one spatially includes the other. We discuss the advantages and limitations of this approach, using concrete examples from human anatomy. (shrink)

Previous studies suggest in line with dual process models that interoceptive skills affect controlled decisions via automatic or implicit processing. The “framing effect” is considered to capture implicit effects of task-irrelevant emotional stimuli on decision-making. We hypothesized that cardiac awareness, as a measure of interoceptive skills, is positively associated with susceptibility to the framing effect. Forty volunteers performed a risky-choice framing task in which the effect of loss versus gain frames on decisions based on identical information was assessed. The results (...) show a positive association between cardiac awareness and the framing effect, accounting for 24% of the variance in the framing effect. These findings demonstrate that good interoceptive skills are linked to poorer performance in risky choices based on ambivalent information when implicit bias is induced by task-irrelevant emotional information. These findings support a dual process perspective on decision-making and suggest that interoceptive skills mediate effects of implicit bias on decisions. (shrink)

The desideratum of semantic interoperability has been intensively discussed in medical informatics circles in recent years. Originally, experts assumed that this issue could be sufficiently addressed by insisting simply on the application of shared clinical terminologies or clinical information models. However, the use of the term ‘ontology’ has been steadily increasing more recently. We discuss criteria for distinguishing clinical ontologies from clinical terminologies and information models. Then, we briefly present the role clinical ontologies play in two multicentric research projects. Finally, (...) we discuss the interactions between these different kinds of knowledge representation artifacts and the stakeholders involved in developing interoperational real-world clinical applications. We provide ontology engineering examples from two EU-funded projects. (shrink)

Propomos uma tipologia dos artefatos de representação para as áreas de saúde e ciências biológicas, e a associação dessa tipologia com diferentes tipos de ontologia formal e lógica, chegando a conclusões quanto aos pontos fortes e limitações da ontologia de diferentes tipos de recursos lógicos, enquanto mantemos o foco na lógica descritiva. Consideramos quatro tipos de representação de área: (i) representação léxico-semântica, (ii) representação de tipos de entidades, (iii) representação de conhecimento prévio, e (iv) representação de indivíduos. Defendemos uma clara (...) distinção entre os quatro tipos de representação, de forma a oferecer uma base mais racional para o uso das ontologias e artefatos relacionados no avanço da integração de dados e interoperabilidade de sistemas de raciocínio associados. Destacamos que apenas uma pequena porção de fatos cientificamente relevantes em áreas como a biomedicina pode ser adequadamente representada por ontologias formais, quando estas últimas são concebidas como representações de tipos de entidades. Particularmente, a tentativa de codificar conhecimento padrão ou probabilístico pela utilização de ontologias assim concebidas é fadada à produção de modelos não intencionais e errôneos. (shrink)

BACKGROUND -/- In biomedical ontologies, mereological relations have always been subject to special interest due to their high relevance in structural descriptions of anatomical entities, cells, and biomolecules. This paper investigates two important subrelations of has_proper_part, viz. the relation has_grain, which relates a collective entity to its multiply occurring uniform parts (e.g., water molecules in a portion of water), and the relation has_component, which relates a compound to its constituents (e.g., molecules to the atoms they consist of). -/- METHOD -/- (...) We distinguish between four kinds of complex entities and characterize them in first order logic. We then discuss whether similar characterizations could be given in description logics, and finally apply the results to mixtures. -/- RESULTS -/- At first sight, collectives and compounds seem to be disjoint categories. Their disjointness, however, relies on agreement about what are uniform entities, and thus on the granularity of description. For instance, the distinction between isomeric subtypes of a molecule can be important in one use case but might be neglected in another one. We demonstrate that, as implemented in the BioTop domain upper level ontology, equivalence or subsumption between different descriptions of same or similar entities cannot be achieved. Using OWL-DL, we propose a new design pattern that avoids primitive subrelations at the expense of more complex descriptions and thus supports the needed inferences. (shrink)

Ontologies aim to represent what is general, by means of universal statements. In contrast, dispositional predications capture knowledge about what is likely to happen if a certain set of circumstances obtain, which is crucial in investigative research such as in drug discovery and systems biology, where entities which are constitutionally dissimilar can nevertheless have similar behavior in a biological context. While such dispositional properties are increasingly included in biomedical ontologies, the circumstances under which the dispositions are realized are seldom explicitly (...) modeled, and doing so is problematic due to the necessary restriction to binary relations in OWL ontologies. In this paper we address this shortcoming, focusing on the bioactivity of small molecules at varying levels of concentration within a living organism as our problem domain, although our approach is generalizable to other problems. We discuss the ontological nature and representation of dispositions and their realization; consider the nature of concentrations and their representation; and finally we detail an approach to linking dispositions to the conditions for their realization which regards conditions as triggers for the process in which the disposition is realized. (shrink)

SNOMED CT is a clinical terminology that uses logical axioms to provide terms with meaning. This enforces precise agreements about the ontological nature of the entities denoted by the terms, commo...

The Foundational Model of Anatomy (FMA) is a map of the human body. Like maps of other sorts – including the map-like representations we find in familiar anatomical atlases – it is a representation of a certain portion of spatial reality as it exists at a certain (idealized) instant of time. But unlike other maps, the FMA comes in the form of a sophisticated ontology of its objectdomain, comprising some 1.5 million statements of anatomical relations among some 70,000 anatomical kinds. (...) It is further distinguished from other maps in that it represents not some specific portion of spatial reality (say: Leeds in 1996), but rather the generalized or idealized spatial reality associated with a generalized or idealized human being at some generalized or idealized instant of time. It will be our concern in what follows to outline the approach to ontology that is represented by the FMA and to argue that it can serve as the basis for a new type of anatomical information science. We also draw some implications for our understanding of spatial reasoning and spatial ontologies in general. (shrink)

The desideratum of semantic interoperability has been intensively discussed in medical informatics circles in recent years. Originally, experts assumed that this issue could be sufficiently addressed by insisting simply on the application of shared clinical terminologies or clinical information models. However, the use of the term ‘ontology’ has been steadily increasing more recently. We discuss criteria for distinguishing clinical ontologies from clinical terminologies and information models. Then, we briefly present the role clinical ontologies play in two multicentric research projects. Finally, (...) we discuss the interactions between these different kinds of knowledge representation artifacts and the stakeholders involved in developing interoperational real-world clinical applications. We provide ontology engineering examples from two EU-funded projects. (shrink)

Background: SNOMED CT is a large terminology system designed to represent all aspects of healthcare. Its current form and content result from decades of bottom-up evolution. Due to SNOMED CT’s formal descriptions, it can be considered an ontology. The Basic Formal Ontology (BFO) is a foundational ontology that proposes a small set of disjoint, hierarchically ordered classes, supported by relations and axioms. In contrast, as a typical top-down endeavor, BFO was designed as a foundational framework for domain ontologies in the (...) natural sciences and related disciplines. Whereas it is mostly assumed that domain ontologies should be created as extensions of foundational ontologies, a post-hoc harmonization of consolidated domain ontologies in use, such as SNOMED CT, is known to be challenging. Methods: We explored the feasibility of harmonizing SNOMED CT with BFO, with a focus on the SNOMED CT Clinical Finding hierarchy. With more than 100,000 classes, it accounts for about one third of SNOMED CT’s content. In particular, we represented typical SNOMED CT finding/disorder concepts using description logics under BFO. Three representational patterns were created and the logical entailments analyzed. Results: Under a first scrutiny, the clinical intuition that diseases, disorders, signs and symptoms form a homogeneous ontological upper-level class appeared incompatible with BFO’s upper-level distinction into continuants and occurrents. The Clinical finding class seemed to be an umbrella for all kinds of entities of clinical interest, such as material entities, processes, states, dispositions, and qualities. This suggests the conclusion that Clinical finding would not be a suitable upper-level class from an BFO perspective. On closer inspection of the taxonomic links within this hierarchy and the implicit meaning derived thereof, it became clear that Clinical finding classes do not characterize the entity (e.g. a fracture, allergy, tumor, pain, hemorrhage, seizure, fever) in a literal sense but rather the condition of a patient having that fracture, allergy, pain etc. This gives sense to the current characteristic of the Clinical Finding hierarchy, in which complex classes are modeled as subclasses of their constituents. Most of these taxonomic links are inferred, as the consequence of the ‘role group’ design pattern, which is ubiquitous in SNOMED CT and has often been subject of controversy regarding its semantics. Conclusion: Our analyses resulted in the proposal of (i) equating SNOMED CT’s ‘role group’ property with the reflexive and transitive BFO relation ‘has occurrent part’; and (ii) reinterpreting Clinical Findings as Clinical Occurrents, i.e. temporally extended entities in an organism, having one or more occurrents as temporal parts that occur in continuants. This re-interpretation was corroborated by a manual analysis of classes under Clinical Finding, as well as the identification of similar modeling patterns in other ontologies. As a result, SNOMED CT does not require any content redesign to establish compatibility with BFO, apart from this re-interpretation, and a suggested re-labeling. Regarding the feasibility of harmonizing terminologies with principled foundational ontologies post-hoc, our results provide support to the assumption that this does not necessarily require major redesign efforts, but rather a careful analysis of the implicit assumptions of terminology curators and users. (shrink)

Two authors with decades of experience promoting human rights argue that, as the world changes around us, rights hardly imaginable today will come into being. A rights revolution is under way. Today the range of nonhuman entities thought to deserve rights is exploding-not just animals but ecosystems and even robots. Changes in norms and circumstances require the expansion of rights: What new rights, for example, are needed if we understand gender to be nonbinary? Does living in a corrupt state violate (...) our rights? And emerging technologies demand that we think about old rights in new ways: When biotechnology is used to change genetic code, whose rights might be violated? What rights, if any, protect our privacy from the intrusions of sophisticated surveillance techniques? Drawing on their vast experience as human rights advocates, William Schulz and Sushma Raman challenge us to think hard about how rights evolve with changing circumstances, and what rights will look like ten, twenty, or fifty years from now. Against those who hold that rights are static and immutable, Schulz and Raman argue that rights must adapt to new realities or risk being consigned to irrelevance. To preserve and promote the good society-one that protects its members' dignity and fosters an environment in which people will want to live-we must at times rethink the meanings of familiar rights and consider the introduction of entirely new rights. Now is one of those times. The Coming Good Society details the many frontiers of rights today and the debates surrounding them. Schulz and Raman equip us with the tools to engage the present and future of rights so that we understand their importance and know where we stand. (shrink)

Populism has taken root almost everywhere in the West. It is crucial to understand how it has come about, where its antagonistic worldview, its nativism, its illiberalism and its anti-pluralism will take us, and how we should seek to fend off this threat to liberal democracy. In particular, what could liberal answers look like? -/- This book is a collection of essays written by young and senior scholars in various fields from philosophy to economics. Part I explores populism’s nature and (...) causes, shedding light on the lure of sovereignty, the perceived representation gap and the process of radicalization, and human psychology. Part II is dedicated to observations inside the political arena, pitting liberalism and populism in a historical perspective, analyzing the risk of democratic backsliding, and asking how liberals should navigate the political need to make compromises. In Part III, the focus turns to liberal responses such as rules-based public deliberation, a liberal ethics attending to civic virtues, improved representation through the blockchain, and polycentric migration policies. Part IV, finally, houses critical engagements with influential relevant authors such as Foucault, Laclau, Berlin, and Harrington. (shrink)

The TNM classification (Tumor-Node-Metastasis) is the most important coding scheme used to stage tumors based on size and location. Its coding rules may change across different TNM versions, such t...

The electric activities of cortical pyramidal neurons are supported by structurally stable, morphologically complex axo-dendritic trees. Anatomical differences between axons and dendrites in regard to their length or caliber reflect the underlying functional specializations, for input or output of neural information, respectively. For a proper assessment of the computational capacity of pyramidal neurons, we have analyzed an extensive dataset of three-dimensional digital reconstructions from the NeuroMorphoOrg database, and quantified basic dendritic or axonal morphometric measures in different regions and layers of (...) the mouse, rat or human cerebral cortex. Physical estimates of the total number and type of ions involved in neuronal electric spiking based on the obtained morphometric data, combined with energetics of neurotransmitter release and signaling fueled by glucose consumed by the active brain, support highly efficient cerebral computation performed at the thermodynamically allowed Landauer limit for implementation of irreversible logical operations. Individual proton tunneling events in voltage-sensing S4 protein alpha-helices of Na+, K+ or Ca2+ ion channels are ideally suited to serve as single Landauer elementary logical operations that are then amplified by selective ionic currents traversing the open channel pores. This miniaturization of computational gating allows the execution of over 1.2 zetta logical operations per second in the human cerebral cortex without combusting the brain by the released heat. (shrink)

Otto Neurath (1882-1945) was a highly unorthodox thinker both in philosophy and economics. The contributions to this sparkling new book conclude that Neurath touched on many of the most critical problems of economic theory during its formative years as a modern discipline. His economics provide insights into the foundational problems of modern economics and should encourage contemporary economic theorists to critically reflect their own hidden presumptions.

The translational research community, in general, and the Clinical and Translational Science Awards (CTSA) community, in particular, share the vision of repurposing EHRs for research that will improve the quality of clinical practice. Many members of these communities are also aware that electronic health records (EHRs) suffer limitations of data becoming poorly structured, biased, and unusable out of original context. This creates obstacles to the continuity of care, utility, quality improvement, and translational research. Analogous limitations to sharing objective data in (...) other areas of the natural sciences have been successfully overcome by developing and using common ontologies. This White Paper presents the authors’ rationale for the use of ontologies with computable semantics for the improvement of clinical data quality and EHR usability formulated for researchers with a stake in clinical and translational science and who are advocates for the use of information technology in medicine but at the same time are concerned by current major shortfalls. This White Paper outlines pitfalls, opportunities, and solutions and recommends increased investment in research and development of ontologies with computable semantics for a new generation of EHRs. (shrink)