Pharmacogenetics: the bioethical problem of DNA investment banking

Concern about the ethics of clinical drug trials research on patients and healthy volunteers has been the subject of significant ethical analysis and policy development--protocols are reviewed by Research Ethics Committees and subjects are protected by informed consent procedures. More recently attention has begun to be focused on DNA banking for clinical and pharmacogenetics research. It is, however, surprising how little attention has been paid to the commercial nature of such research, or the unique issues that present when subjects are asked to consent to the storage of biological samples. Our contention is that in the context of pharmacogenetic add-on studies to clinical drug trials, the doctrine of informed consent fails to cover the broader range of social and ethical issues. Applying a sociological perspective, we foreground issues of patient/subject participation or 'work', the ambiguity of research subject altruism, and the divided loyalties facing many physicians conducting clinical research. By demonstrating the complexity of patient and physician involvement in clinical drug trials, we argue for more comprehensive ethical review and oversight that moves beyond reliance on informed consent to incorporate understandings of the social, political and cultural elements that underpin the diversity of ethical issues arising in the research context.     

Medical crowdfunding and the virtuous donor

Patients and families are increasingly turning to crowdfunding to help them cover the cost of medical care. The ethics of crowdfunding has garnered some attention in the bioethical literature. In this paper I examine an ethical aspect of medical crowdfunding (MCF) that has received limited attention: the role of donors. I defend a virtue ethical approach to analyzing the role of donors in MCF. Vicious donation, where donors do not exercise the relevant virtues, can compound some of the ethical risks associated with MCF, as seen in the several recent, high‐profile cases. My primary contention in this paper is that encouraging donors to think about how donating to a particular campaign would measure against the virtues I outline could help to discourage acts of ethically problematic donation to MCF campaigns.     

Ethical challenges at the science-policy interface: an ethical risk assessment and proposition of an ethical infrastructure

Developing an interface between knowledge holders, stakeholders and decision makers on biodiversity issues, just as any science-policy interface, will face many challenges. In the crucial endeavour to tackle all those challenges, determining an ethical course of actions will be essential to the prestige and credibility of such an interface. The paper identifies and assesses potential ethical risks that may arise in interactions between science, society and policy and uses the Network of Knowledge (NoK) process as an example to show how an ethical infrastructure could be developed for minimizing the ethical risks and their potential consequences. Indeed, when various actors from different spheres (politics, academia, lobbyism, media, etc.) are called upon to interact within one process as complex as the NoK, the integrity and credibility of the latter are at high risk of being compromised if the ethical risks are not adequately addressed. In order to limit those risks, which science-policy interfaces such as IPCC and IPBES have already encountered, we propose to set up an ethical governance infrastructure that will guide (and regulate) interactions among internal actors of the NoK (knowledge coordination body, secretariat, expert working groups, etc.) as well as with external actors (requesters, stakeholders, etc.). A thorough evaluation of the interaction between the actors for every step of the process is carried out and potential ethical risks are identified. Suggestions as to how the risks can be handled and prevented are presented and integrated as part of an ethical infrastructure. The main objective of the paper is to address how a science-policy interface and the scientific community as a whole would benefit from implementing ethical measures and instruments to help prevent sensitive issues and undesired consequences undermining credibility and legitimacy.     

What risks should be permissible in controlled human infection model studies?

Controlled human infection model (CHIM) studies involve the intentional exposure of healthy research volunteers to infectious agents. These studies contribute to knowledge about the cause or development of disease and to the advancement of vaccine research. But they also raise ethical questions about the kinds of risks that should be permissible and whether limits should be imposed on research risks in CHIM studies. Two possible risk thresholds have been considered for CHIM studies. The first suggests constraining ethically permissible risks according to a minimal risk threshold and the second endorses a higher risk threshold that excludes irreversible or fatal infections. I argue that neither of these thresholds is persuasive and situate questions about risk thresholds in CHIM studies within a broader debate about permissible risks in research. I argue that risks in CHIM studies should be constrained according to limits on research risks that do not offer corresponding benefits in all studies rather than developing a unique risk threshold for CHIM studies. I then propose five recommendations for the ethical assessment of risk in CHIM studies.     

Accepting space radiation risks

The human exploration of space inevitably involves exposure to radiation. Associated with this exposure are multiple risks, i.e., probabilities that certain aspects of an astronaut’s health or performance will be degraded. The management of these risks requires that such probabilities be accurately predicted, that the actual exposures be verified, and that comprehensive records be maintained. Implicit in these actions is the fact that, at some point, a decision has been made to accept a certain level of risk. This paper examines ethical and practical considerations involved in arriving at a determination that risks are acceptable, roles that the parties involved may play, and obligations arising out of reliance on the informed consent paradigm seen as the basis for ethical radiation risk acceptance in space.     

Joint Modeling of Multivariate Longitudinal Data and Competing Risks Using Multiphase Sub-models

In many clinical studies that involve follow-up, it is common to observe one or more sequences of longitudinal measurements, as well as one or more time to event outcomes. A competing risks situation arises when the probability of occurrence of one event is altered/hindered by another time to event. Recently, there has been much attention paid to the joint analysis of a single longitudinal response and a single time to event outcome, when the missing data mechanism in the longitudinal process is non-ignorable. We, in this paper, propose an extension where multiple longitudinal responses are jointly modeled with competing risks (multiple time to events). Our shared parameter joint model consists of a system of multiphase non-linear mixed effects sub-models for the multiple longitudinal responses, and a system of cause-specific non-proportional hazards frailty sub-models for competing risks, with associations among multiple longitudinal responses and competing risks modeled using latent parameters. The joint model is applied to a data set of patients who are on mechanical circulatory support and are awaiting heart transplant, using readily available software. While on the mechanical circulatory support, patient liver and renal functions may worsen and these in turn may influence one of the two possible competing outcomes: (i) death before transplant; (ii) transplant. In one application, we propose a system of multiphase cause-specific non-proportional hazard sub-model where frailty can be time varying. Performance under different scenarios was assessed using simulation studies. By using the proposed joint modeling of the multiphase sub-models, one can identify: (i) non-linear trends in multiple longitudinal outcomes; (ii) time-varying hazards and cumulative incidence functions of the competing risks; (iii) identify risk factors for the both types of outcomes, where the effect may or may not change with time; and (iv) assess the association between multiple longitudinal and competing risks outcomes, where the association may or may not change with time.     

HOW TO CONNECT BIOETHICS AND ENVIRONMENTAL ETHICS: HEALTH, SUSTAINABILITY, AND JUSTICE

In this paper, I explore one way to bring bioethics and environmental ethics closer together. I focus on a question at the interface of health, sustainability, and justice: How well does a society promote health with the use of no more than a just share of environmental capacity? To address this question, I propose and discuss a mode of assessment that combines a measurement of population health, an estimate of environmental sustainability, and an assumption about what constitutes a fair or just share. This mode of assessment provides an estimate of the just and sustainable life expectancy of a population. It could be used to monitor how well a particular society promotes health within just environmental limits. It could also serve as a source of information that stakeholders use when they deliberate about programs, policies, and technologies. The purpose of this work is to focus attention on an ethical task: the need to fashion institutions and forms of life that promote health in ways that recognize the claims of sustainability and justice.     

Risk, unexpected uncertainty, and estimation uncertainty: Bayesian learning in unstable settings

Recently, evidence has emerged that humans approach learning using Bayesian updating rather than (model-free) reinforcement algorithms in a six-arm restless bandit problem. Here, we investigate what this implies for human appreciation of uncertainty. In our task, a Bayesian learner distinguishes three equally salient levels of uncertainty. First, the Bayesian perceives irreducible uncertainty or risk: even knowing the payoff probabilities of a given arm, the outcome remains uncertain. Second, there is (parameter) estimation uncertainty or ambiguity: payoff probabilities are unknown and need to be estimated. Third, the outcome probabilities of the arms change: the sudden jumps are referred to as unexpected uncertainty. We document how the three levels of uncertainty evolved during the course of our experiment and how it affected the learning rate. We then zoom in on estimation uncertainty, which has been suggested to be a driving force in exploration, in spite of evidence of widespread aversion to ambiguity. Our data corroborate the latter. We discuss neural evidence that foreshadowed the ability of humans to distinguish between the three levels of uncertainty. Finally, we investigate the boundaries of human capacity to implement Bayesian learning. We repeat the experiment with different instructions, reflecting varying levels of structural uncertainty. Under this fourth notion of uncertainty, choices were no better explained by Bayesian updating than by (model-free) reinforcement learning. Exit questionnaires revealed that participants remained unaware of the presence of unexpected uncertainty and failed to acquire the right model with which to implement Bayesian updating.     

Attractive sinks, or how individual behavioural decisions determine source–sink dynamics

Gundersen et al . (2001 , Source-sink dynamics: how sinks affect demography of sources. Ecol. Lett. , 4, 14–21.) suggested that sinks can severely affect the demography of populations in source habitats. We propose this is a common result when animals lack cues associated with reduced fitness inside sinks and consequently select habitat inappropriately. These attractive sinks can result either from undetected risks of mortality (as in the experiment of Gundersen et al . 2001 ) or from undetected poor breeding probabilities (due to bioaccumulation of pesticides, for instance). Thus, individual habitat choice is a key process underlying source–sink dynamics.     

Ethical issues surrounding controlled human infection challenge studies in endemic low-and middle-income countries

Controlled human infection challenge studies (CHIs) involve intentionally exposing research participants to, and/or thereby infecting them with, micro-organisms. There have been increased calls for more CHIs to be conducted in low- and middle-income countries (LMICs) where many relevant diseases are endemic. This article is based on a research project that identified and analyzed ethical and regulatory issues related to endemic LMIC CHIs via (a) a review of relevant literature and (b) qualitative interviews involving 45 scientists and ethicists with relevant expertise. In this article we argue that though there is an especially strong case for conducting CHIs in endemic (LMIC) settings, certain ethical issues related to the design and conduct of such studies (in such settings) nonetheless warrant particularly careful attention. We focus on ethical implications of endemic LMIC CHIs regarding (a) potential direct benefits for participants, (b) risks to participants, (c) third-party risks, (d) informed consent, (e) payment of participants, and (f) community engagement. We conclude that there is a strong ethical rationale to conduct (well-designed) CHIs in endemic LMICs, that certain ethical issues warrant particularly careful consideration, and that ethical analyses of endemic LMIC CHIs can inform current debates in research ethics more broadly.     

Timing, memory for intervals, and memory for untimed stimuli: The role of instructional ambiguity

Theories of animal timing have had to account for findings that the memory for the duration of a timed interval appears to be dramatically shorted within a short time of its termination. This finding has led to the subjective shortening hypothesis and it has been proposed to account for the poor memory that animals appear to have for the initial portion of a timed interval when a gap is inserted in the to-be-timed signal. It has also been proposed to account for the poor memory for a relatively long interval that has been discriminated from a shorter interval. I suggest here a simpler account in which ambiguity between the gap or retention interval and the intertrial interval results in resetting the clock, rather than forgetting the interval. The ambiguity hypothesis, together with a signal salience mechanism that determines how quickly the clock is reset at the start of the intertrial interval can account for the results of the reported timing experiments that have used the peak procedure. Furthermore, instructional ambiguity rather than memory loss may account for the results of many animal memory experiments that do not involve memory for time.     

Timing, memory for intervals, and memory for untimed stimuli: the role of instructional ambiguity

Theories of animal timing have had to account for findings that the memory for the duration of a timed interval appears to be dramatically shorted within a short time of its termination. This finding has led to the subjective shortening hypothesis and it has been proposed to account for the poor memory that animals appear to have for the initial portion of a timed interval when a gap is inserted in the to-be-timed signal. It has also been proposed to account for the poor memory for a relatively long interval that has been discriminated from a shorter interval. I suggest here a simpler account in which ambiguity between the gap or retention interval and the intertrial interval results in resetting the clock, rather than forgetting the interval. The ambiguity hypothesis, together with a signal salience mechanism that determines how quickly the clock is reset at the start of the intertrial interval can account for the results of the reported timing experiments that have used the peak procedure. Furthermore, instructional ambiguity rather than memory loss may account for the results of many animal memory experiments that do not involve memory for time.     

Principles and practice in ethical review of animal experiments across Europe: summary of the report of a FELASA working group on ethical evaluation of animal experiments

This paper summarizes a more detailed report produced by the Federation of European Laboratory Animal Science Associations (FELASA 2005), which describes and explores a set of principles for the conduct of ethical review of laboratory animal use. It presents a synopsis of results from a questionnaire that elicited information on how each of 20 countries represented in FELASA currently approaches such ethical review. This information suggests that, although local practices differ, there is an emerging consensus on the key elements that any ethical review process should involve. Drawing on the questionnaire findings, this summary also includes a brief discussion to support and amplify a series of recommendations, covering the objectives of ethical review; legal requirements; the scope of work reviewed and the 'level' at which review is approached; general principles for the organization of ethical review processes; the factors considered in the review; needs for ongoing review after initial authorization; participants in the review process; wider impacts of the review process; and strategies that can help to ensure quality and consistency of review outcomes. For further information and examples of current practice, as well as more detailed discussion to support the recommendations, readers are urged to refer to the complete report, available at http://www.lal.org.uk/pdffiles/FELASA_ethics_FULL_Report. pdf or via: http://www.felasa.eu/recommendations.htm.     

Adjusting the focus: A public health ethics approach to data research

This paper contends that a research ethics approach to the regulation of health data research is unhelpful in the era of population‐level research and big data because it results in a primary focus on consent (meta‐, broad, dynamic and/or specific consent). Two recent guidelines – the 2016 WMA Declaration of Taipei on ethical considerations regarding health databases and biobanks and the revised CIOMS International ethical guidelines for health‐related research involving humans – both focus on the growing reliance on health data for research. But as research ethics documents, they remain (to varying degrees) focused on consent and individual control of data use. Many current and future uses of health data make individual consent impractical, if not impossible. Many of the risks of secondary data use apply to communities and stakeholders rather than individual data subjects. Shifting from a research ethics perspective to a public health lens brings a different set of issues into view: how are the benefits and burdens of data use distributed, how can data research empower communities, who has legitimate decision‐making capacity? I propose that a public health ethics framework – based on public benefit, proportionality, equity, trust and accountability – provides more appropriate tools for assessing the ethical uses of health data. The main advantage of a public health approach for data research is that it is more likely to foster debate about power, justice and equity and to highlight the complexity of deciding when data use is in the public interest.     

Chimpanzees and bonobos distinguish between risk and ambiguity

Although recent research has investigated animal decision-making under risk, little is known about how animals choose under conditions of ambiguity when they lack information about the available alternatives. Many models of choice behaviour assume that ambiguity does not impact decision-makers, but studies of humans suggest that people tend to be more averse to choosing ambiguous options than risky options with known probabilities. To illuminate the evolutionary roots of human economic behaviour, we examined whether our closest living relatives, chimpanzees (Pan troglodytes) and bonobos (Pan paniscus), share this bias against ambiguity. Apes chose between a certain option that reliably provided an intermediately preferred food type, and a variable option that could vary in the probability that it provided a highly preferred food type. To examine the impact of ambiguity on ape decision-making, we interspersed trials in which chimpanzees and bonobos had no knowledge about the probabilities. Both species avoided the ambiguous option compared with their choices for a risky option, indicating that ambiguity aversion is shared by humans, bonobos and chimpanzees.     

The role of community engagement in addressing bystander risks in research: The case of a Zika virus controlled human infection study

There is limited guidance on how to assess the ethical acceptability of research risks that extend beyond research participants to third parties (or “research bystanders”). Community or stakeholder engagement has been proposed as one way to address potential harms to community members, including bystanders. Despite widespread agreement on the importance of community engagement in biomedical research, this umbrella term includes many different goals and approaches, agreement on which is ethically required or recommended for a particular context. We analyse the case of a potential Zika virus human challenge trial to assess whether and how community engagement can help promote the ethical acceptability of research posing risks to bystanders. We conclude that, in addition to having intrinsic value, community engagement can improve the identification of bystander risks, effective approaches to minimizing them, and transparency about bystander risks for host communities.     

Extinction, colonization, and species occupancy in tidepool fishes

Despite the increasing sophistication of ecological models with respect to the size and spatial arrangement of habitat, there is relatively little empirical documentation of how species dynamics change as a function of habitat size and the fraction of habitat occupied. In an assemblage of tidepool fishes, I used maximum-likelihood estimation to test whether models which included habitat size provided a better fit to empirical data on extinction and colonization probabilities than models that assumed constant probabilities over all habitats. I found species differences in how extinction and colonization probabilities scaled with habitat size (and hence local population size). However, there was little evidence for a relationship between extinction and colonization probabilities and the fraction of occupied tidepools, as assumed in simple metapopulation models. Instead, colonization and extinction were independent of the fraction of occupied tidepools, favoring a MacArthur-Wilson island-mainland model. When I incorporated declines in extinction probability with tidepool volume in a simple simulation model, I found that predicted occupancy could change greatly, especially when colonization was low. However, the predicted fraction of occupied patches in the simulation model changed little when I incorporated the range of values reported here for extinction and colonization and the rate at which they scale with habitat size. Quantifying extinction and colonization patterns of natural populations is fundamental to understanding how species are distributed spatially and whether metapopulation models of species occupancy provide explanatory power for field populations. Received: 14 March 1997 / Accepted: 21 September 1997     

Vaccine mandates,value pluralism,and policy diversity

Political communities across the world have recently sought to tackle rising rates of vaccine hesitancy and refusal, by implementing coercive immunization programs, or by making existing immunization programs more coercive. Many academics and advocates of public health have applauded these policy developments, and they have invoked ethical reasons for implementing or strengthening vaccine mandates. Others have criticized these policies on ethical grounds, for undermining liberty, and as symptoms of broader government overreach. But such arguments often obscure or abstract away from the diverse values that are relevant to the ethical justifications of particular political communities’ vaccine‐mandate policies. We argue for an expansive conception of the normative issues relevant to deciding whether and how to establish or reform vaccine mandates, and we propose a schema by which to organize our thoughts about the ways in which different kinds of vaccine‐mandate policies implicate various values.     

An ambiguity in Habermas’s argument against liberal eugenics

In his book The future of human nature, Jürgen Habermas argues against a scenario of liberal eugenics, in which parents are free to prenatally manipulate their children’s genetic constitution via germline interventions. In this paper, I draw attention to the fact that his species‐ethical line of argument is pervaded by a substantial ambiguity between an argument from actual intervention (AAI) and an argument from mere controllability (AMC). Whereas the first argument focuses on threats for the autonomy and equality of prenatally modified persons, the second argument takes all human beings, whether they have been modified or not, into account. Hence, when invoking Habermas in these debates, bioethicists need to consider carefully which argument they are referring to.