Publications by authors named "Rebecca L Walker"

41 Publications

DIAPH1 Variants in Non-East Asian Patients With Sporadic Moyamoya Disease.

JAMA Neurol 2021 Jun 14. Epub 2021 Jun 14.

Yale Center for Genome Analysis, West Haven, Connecticut.

Importance: Moyamoya disease (MMD), a progressive vasculopathy leading to narrowing and ultimate occlusion of the intracranial internal carotid arteries, is a cause of childhood stroke. The cause of MMD is poorly understood, but genetic factors play a role. Several familial forms of MMD have been identified, but the cause of most cases remains elusive, especially among non-East Asian individuals.

Objective: To assess whether ultrarare de novo and rare, damaging transmitted variants with large effect sizes are associated with MMD risk.

Design, Setting, And Participants: A genetic association study was conducted using whole-exome sequencing case-parent MMD trios in a small discovery cohort collected over 3.5 years (2016-2019); data were analyzed in 2020. Medical records from US hospitals spanning a range of 1 month to 1.5 years were reviewed for phenotyping. Exomes from a larger validation cohort were analyzed to identify additional rare, large-effect variants in the top candidate gene. Participants included patients with MMD and, when available, their parents. All participants who met criteria and were presented with the option to join the study agreed to do so; none were excluded. Twenty-four probands (22 trios and 2 singletons) composed the discovery cohort, and 84 probands (29 trios and 55 singletons) composed the validation cohort.

Main Outcomes And Measures: Gene variants were identified and filtered using stringent criteria. Enrichment and case-control tests assessed gene-level variant burden. In silico modeling estimated the probability of variant association with protein structure. Integrative genomics assessed expression patterns of MMD risk genes derived from single-cell RNA sequencing data of human and mouse brain tissue.

Results: Of the 24 patients in the discovery cohort, 14 (58.3%) were men and 18 (75.0%) were of European ancestry. Three of 24 discovery cohort probands contained 2 do novo (1-tailed Poisson P = 1.1 × 10-6) and 1 rare, transmitted damaging variant (12.5% of cases) in DIAPH1 (mammalian diaphanous-1), a key regulator of actin remodeling in vascular cells and platelets. Four additional ultrarare damaging heterozygous DIAPH1 variants (3 unphased) were identified in 3 other patients in an 84-proband validation cohort (73.8% female, 77.4% European). All 6 patients were non-East Asian. Compound heterozygous variants were identified in ena/vasodilator-stimulated phosphoproteinlike protein EVL, a mammalian diaphanous-1 interactor that regulates actin polymerization. DIAPH1 and EVL mutant probands had severe, bilateral MMD associated with transfusion-dependent thrombocytopenia. DIAPH1 and other MMD risk genes are enriched in mural cells of midgestational human brain. The DIAPH1 coexpression network converges in vascular cell actin cytoskeleton regulatory pathways.

Conclusions And Relevance: These findings provide the largest collection to date of non-East Asian individuals with sporadic MMD harboring pathogenic variants in the same gene. The results suggest that DIAPH1 is a novel MMD risk gene and impaired vascular cell actin remodeling in MMD pathogenesis, with diagnostic and therapeutic ramifications.
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http://dx.doi.org/10.1001/jamaneurol.2021.1681DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8204259PMC
June 2021

Phase I trial compensation: How much do healthy volunteers actually earn from clinical trial enrollment?

Clin Trials 2021 Aug 2;18(4):477-487. Epub 2021 May 2.

University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.

Background/aims: Financial compensation for research participation is a major focus of ethical concern regarding human subject recruitment. Phase I trials are sometimes considered to be a lucrative source of income for healthy volunteers, encouraging some people to become "professional guinea pigs." Yet, little is known about how much these clinical trials actually pay and how much healthy volunteers earn from them.

Methods: As part of a mixed-methods, longitudinal study of healthy volunteers, we required participants to complete clinical trial diaries, or surveys that captured detailed information about screening and enrollment in Phase I trials. Over a 3-year period, participants provided information online or via telephone about each clinical trial for which they screened (e.g. the clinic name, the study's therapeutic area, the length of the trial, the number of nights spent in the clinic, and the study compensation), and whether they qualified for trial inclusion. Clinical trial diaries generated data about whether participants continued to screen for and enroll in clinical trials and how much money they earned from their participation.

Results: 131 participants routinely completed clinical trial diaries or confirmed that they had not screened for any new clinical trials. Together, these participants screened for 1001 clinical trials at 73 research facilities during a 3-year period. Overall, the median clinical trial compensation was US$3070 (range = US$150-US$13,000). Participants seeking new healthy volunteer trials tended to screen for three studies per year, participate in one or two studies, and earn roughly US$4000 annually. Participants who were unemployed earned the most income from clinical trials compared to those with full-time or part-time jobs, and those individuals whom we label "occupational" participants because of their persistent pursuit of clinical trials earned more than people who screened occasionally. Notably, the median annual trial compensation was well below US$10,000 for all employment groups, and most occupational healthy volunteers also earned less than US$10,000 each year. The 10% of participants who earned the most had a median annual income of US$18,885 from clinical trials, and there was significant volatility in these individuals' earnings from year to year.

Conclusion: Despite the perception that Phase I enrollment can generate significant earnings, it was exceedingly rare for anyone in this study to make more than US$20,000 in a single year, and unusual to earn even between US$10,000 and US$20,000. From an ethics perspective, individual trials might appear to unduly induce enrollment by offering significant sums of money, but given our findings, the larger problem for low-income participants may be the unrealistic perception that clinical trials alone could be a way of earning a living.
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http://dx.doi.org/10.1177/17407745211011069DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8290991PMC
August 2021

Biomedical Researchers' Perceptions of the NIH's Sex as a Biological Variable Policy for Animal Research: Results from a U.S. National Survey.

J Womens Health (Larchmt) 2021 Apr 8. Epub 2021 Apr 8.

Department of Social Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.

In 2015, the National Institutes of Health (NIH) established a policy on sex as a biological variable (SABV) in an effort to address the overrepresentation of men and male animals in biomedical research and the lack of attention to sex-based responses to medical treatments. However, questions remain regarding how U.S. biomedical researchers perceive the impact of the SABV policy on their own research and on translational science more broadly. A national survey of U.S. scientists who use vertebrate animals in their research was conducted. Respondents were asked how they select and use animal species as model organisms as well as how they perceive the impact of the SABV policy on their research practices. Almost all respondents reported that they had previously heard of the NIH SABV policy, and over one-third had altered their study designs to comply with the policy. There were robust differences in perceptions of the SABV policy based on researchers' primary species of model organism. However, there was no significant difference in the likelihood of researchers analyzing their results by sex based on whether they had received recent NIH funding. While many researchers report adhering to the SABV policy requirements, more work needs to be done to ensure that the policy is being evenly applied to researchers using all types of animal models and that researchers adhere to the policy after receiving NIH funding, particularly in terms of reporting on and analyzing SABV in their study findings for publication.
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http://dx.doi.org/10.1089/jwh.2020.8997DOI Listing
April 2021

Evaluating the National Institutes of Health's Sex as a Biological Variable Policy: Conflicting Accounts from the Front Lines of Animal Research.

J Womens Health (Larchmt) 2021 03 18;30(3):348-354. Epub 2020 Nov 18.

Department of Social Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.

Since the National Institutes of Health (NIH) Revitalization Act of 1993, focus on the equitable inclusion of women in clinical research has been ongoing. NIH's 2015 sex as a biological variable (SABV) policy aims to transform research design, analysis, and reporting in the preclinical sphere by including male and female organisms in vertebrate animal research as well as human studies. However, questions remain regarding how researchers and members of research oversight committees perceive the value and need of the SABV policy. Based on 62 interviews with animal researchers and oversight personnel, we analyze what the animal research community knows about the policy and sees as the benefits and challenges of implementation. We found that the 62 interviewees disagreed about the need for the policy, with some being supportive and others questioning whether the policy is based on science or is politically motivated. There were also tensions in how interviewees conceptualized the challenges to and resources needed for implementing the SABV policy. For instance, while some thought implementation would require a significant increase in numbers of animals used for each study, others explicitly rejected this claim. We conclude by discussing the practical and social implications of our findings about the views of members of the animal research community regarding the SABV policy.
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http://dx.doi.org/10.1089/jwh.2020.8674DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7957378PMC
March 2021

Erratum to: Virtue Ethics and Laboratory Animal Research.

Authors:
Rebecca L Walker

ILAR J 2020 Oct 27. Epub 2020 Oct 27.

Department of Social Medicine, University of North Carolina, Chapel Hill, North Carolina.

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http://dx.doi.org/10.1093/ilar/ilaa019DOI Listing
October 2020

Can We Do without Respect and Justice in Animal Research Ethics?

Authors:
Rebecca L Walker

Hastings Cent Rep 2020 Sep;50(5):46-47

This book review essay discusses Principles of Animal Research Ethics (2020), by Tom L. Beauchamp and David DeGrazia.
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http://dx.doi.org/10.1002/hast.1187DOI Listing
September 2020

Exome sequencing implicates genetic disruption of prenatal neuro-gliogenesis in sporadic congenital hydrocephalus.

Nat Med 2020 11 19;26(11):1754-1765. Epub 2020 Oct 19.

Departments of Neurosurgery, Engineering Science & Mechanics, and Physics; Center for Neural Engineering and Infectious Disease Dynamics, The Pennsylvania State University, University Park, PA, USA.

Congenital hydrocephalus (CH), characterized by enlarged brain ventricles, is considered a disease of excessive cerebrospinal fluid (CSF) accumulation and thereby treated with neurosurgical CSF diversion with high morbidity and failure rates. The poor neurodevelopmental outcomes and persistence of ventriculomegaly in some post-surgical patients highlight our limited knowledge of disease mechanisms. Through whole-exome sequencing of 381 patients (232 trios) with sporadic, neurosurgically treated CH, we found that damaging de novo mutations account for >17% of cases, with five different genes exhibiting a significant de novo mutation burden. In all, rare, damaging mutations with large effect contributed to ~22% of sporadic CH cases. Multiple CH genes are key regulators of neural stem cell biology and converge in human transcriptional networks and cell types pertinent for fetal neuro-gliogenesis. These data implicate genetic disruption of early brain development, not impaired CSF dynamics, as the primary pathomechanism of a significant number of patients with sporadic CH.
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http://dx.doi.org/10.1038/s41591-020-1090-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7871900PMC
November 2020

Correction to: Picking and Choosing Among Phase I Trials.

J Bioeth Inq 2021 Mar;18(1):193

Department of Social Medicine and Center for Bioethics, University of North Carolina at Chapel Hill, CB 7240, Chapel Hill, NC, 27599-7240, USA.

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http://dx.doi.org/10.1007/s11673-020-10031-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8043866PMC
March 2021

Integrative Genomics for the Interpretation of Genetic Loci Implicated in Neurodevelopmental Disorders.

Authors:
Rebecca L Walker

Biol Psychiatry 2020 09;88(6):438-439

Department of Neurology, Center for Autism Research and Treatment, Semel Institute, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California; Broad Institute of MIT and Harvard, Cambridge, Massachusetts. Electronic address:

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http://dx.doi.org/10.1016/j.biopsych.2020.07.003DOI Listing
September 2020

The Unfinished Business of Respect for Autonomy: Persons, Relationships, and Nonhuman Animals.

Authors:
Rebecca L Walker

J Med Philos 2020 07;45(4-5):521-539

University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.

This essay explores three issues in respect for autonomy that pose unfinished business for the concept. By this, I mean that the dialogue over them is ongoing and essentially unresolved. These are: (1) whether we ought to respect persons or their autonomous choices; (2) the role of relational autonomy; and (3) whether nonhuman animals can be autonomous. In attending to this particular set of unfinished business, I highlight some critical moral work left aside by the concept of respect for autonomy as understood in Beauchamp and Childress' Principles of Biomedical Ethics. Specifically, while significant pragmatic traction is gained by the authors' focus on autonomous choice, carving such a focus out from the broader questions of moral respect and the autonomy of the person leaves aside a number of questions that we might have thought a view about respect for autonomy in biomedicine ought to answer. These include: How should physicians respond when autonomous patients make decisions that appear nonautonomous? What is the impact of the view that autonomy is "relational" for cross-cultural differences in how autonomy is respected? If chimpanzees (and by extension young children) can be autonomous, what does that mean for how they should be treated?
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http://dx.doi.org/10.1093/jmp/jhaa016DOI Listing
July 2020

"My Body is One of the Best Commodities": Exploring the Ethics of Commodification in Phase I Healthy Volunteer Clinical Trials.

Kennedy Inst Ethics J 2019 ;29(4):305-331

In phase I clinical trials, healthy volunteers are dosed with investigational drugs and subjected to blood draws and other bodily monitoring procedures while they are confined to clinic spaces. In exchange, they are paid. These participants are, in a direct sense, selling access to their bodies for pharmaceutical companies and their associates to run drugs through. However, commodification is rarely investigated as an ethical dimension of phase I trial participation. We address this gap in the literature by bringing the voices of phase I healthy volunteers into conversation with philosophical perspectives on body commodification. Querying the intersection of commodification and phase I clinical trials illuminates important features of healthy volunteers' experiences, disentangles commodification from a dominant narrative about exploitation, and brings focus to the question of what, if any, market norms will best protect the multiple ways in which healthy volunteers' welfare is impacted by clinical trial participation.
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http://dx.doi.org/10.1353/ken.2019.0028DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6989025PMC
July 2020

From Mice to Monkeys? Beyond Orthodox Approaches to the Ethics of Animal Model Choice.

Animals (Basel) 2020 Jan 1;10(1). Epub 2020 Jan 1.

Institute of Biomedical Ethics and History of Medicine, University of Zurich; 8006 Zurich, Switzerland.

Recent developments in genome editing tools, along with limits in the translational potential of rodent models of human disease, have spurred renewed biomedical research interest in large mammals like nonhuman primates, pigs, and dogs. Such scientific developments raise ethical issues about the use of these animals in comparison with smaller mammals, such as mice and rats. To examine these ethical questions, we first consider standard (or "orthodox") approaches, including ethics oversight within biomedical research communities, and critical theoretical reflections on animal research, including rights-based and utilitarian approaches. We argue that oversight of biomedical research offers guidance on the profession's permitted uses of animals within a research setting and orthodox approaches to animal ethics questions when and whether animals should be used in biomedicine; however, neither approach sufficiently investigates the nuances of ethical practices within the research setting. To fill this lacuna, we consider a virtue ethical approach to the use of specific animal models in biomedicine. From this perspective, we argued that limitations on flourishing for large mammals in a research setting, as well as potential human-animal bonds, are two sources of likely ethical tensions in animal care and use in the context of larger mammals.
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http://dx.doi.org/10.3390/ani10010077DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7022287PMC
January 2020

Picking and Choosing Among Phase I Trials : A Qualitative Examination of How Healthy Volunteers Understand Study Risks.

J Bioeth Inq 2019 Dec 12;16(4):535-549. Epub 2019 Nov 12.

Department of Social Medicine and Center for Bioethics, University of North Carolina at Chapel Hill, CB 7240, Chapel Hill, NC, 27599-7240, USA.

This article empirically examines how healthy volunteers evaluate and make sense of the risks of phase I clinical drug trials. This is an ethically important topic because healthy volunteers are exposed to risk but can gain no medical benefit from their trial participation. Based on in-depth qualitative interviews with 178 healthy volunteers enrolled in various clinical trials, we found that participants focus on myriad characteristics of clinical trials when assessing risk and making enrolment decisions. These factors include the short-term and long-term effects; required medical procedures; the type of trial, including its design, therapeutic area of investigation, and dosage of the drug; the amount of compensation; and trust in the research clinic. In making determinations about the study risks, participants rely on information provided during the consent process, their own and others' experiences in clinical trials, and comparisons among studies. Our findings indicate that the informed consent process succeeds in communicating well about certain types of risk information while simultaneously creating lacunae that are problematically filled by participants through their collective experiences and assumptions about risk. We discuss the ethical implications of these findings and make recommendations for improving the consent process in healthy volunteer trials.
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http://dx.doi.org/10.1007/s11673-019-09946-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6938537PMC
December 2019

Genetic Control of Expression and Splicing in Developing Human Brain Informs Disease Mechanisms.

Cell 2019 10;179(3):750-771.e22

Department of Neurology, Center for Autism Research and Treatment, Semel Institute, David Geffen School of Medicine, University of California, Los Angeles, 695 Charles E. Young Drive South, Los Angeles, CA 90095, USA; Program in Neurobehavioral Genetics, Semel Institute, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; Department of Psychiatry, Semel Institute, David Geffen School of Medicine, University of California, Los Angeles, 695 Charles E. Young Drive South, Los Angeles, CA 90095, USA. Electronic address:

Tissue-specific regulatory regions harbor substantial genetic risk for disease. Because brain development is a critical epoch for neuropsychiatric disease susceptibility, we characterized the genetic control of the transcriptome in 201 mid-gestational human brains, identifying 7,962 expression quantitative trait loci (eQTL) and 4,635 spliceQTL (sQTL), including several thousand prenatal-specific regulatory regions. We show that significant genetic liability for neuropsychiatric disease lies within prenatal eQTL and sQTL. Integration of eQTL and sQTL with genome-wide association studies (GWAS) via transcriptome-wide association identified dozens of novel candidate risk genes, highlighting shared and stage-specific mechanisms in schizophrenia (SCZ). Gene network analysis revealed that SCZ and autism spectrum disorder (ASD) affect distinct developmental gene co-expression modules. Yet, in each disorder, common and rare genetic variation converges within modules, which in ASD implicates superficial cortical neurons. More broadly, these data, available as a web browser and our analyses, demonstrate the genetic mechanisms by which developmental events have a widespread influence on adult anatomical and behavioral phenotypes.
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http://dx.doi.org/10.1016/j.cell.2019.09.021DOI Listing
October 2019

Is Enhancement the Price of Prevention in Human Gene Editing?

CRISPR J 2018 12 26;1:351-354. Epub 2018 Nov 26.

1 Department of Social Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.

New gene-editing tools challenge conventional policy proscriptions of research aimed at either human germline gene editing or human enhancement by potentially lowering technical barriers to both kinds of intervention. Some recent gene-editing reports have begun to take up the prospect of germline editing, but most experts are in broad agreement that research should prioritize medical applications over attempts to enhance human traits. However, there is little consensus about what counts as human enhancement in this context, or how to deal with the issues it flags. Moreover, several influential reports interpret medical applications to include disease prevention as well as treatment as a goal for gene-editing research. This challenges the current policy consensus because using gene editing to prevent disease would incidentally facilitate human enhancement applications in a variety of ways. If such research efforts are penalized by policy concerns about enhancement, then their preventive health benefits could be lost. To avoid being caught off guard by such challenges, science policy makers will need to think more carefully about what "prevention" might mean in the gene-editing context, and develop research governance that can anticipate and address the human enhancement concerns it will raise. To accomplish the latter, the scope of policy making will need to expand from its narrow focus on human clinical trials to engage with basic researchers driving the translational pipeline toward preventive gene editing and the science policy makers who have to address its "off-label" uses.
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http://dx.doi.org/10.1089/crispr.2018.0040DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6636863PMC
December 2018

Advancing Ethics and Policy for Healthy-Volunteer Research through a Model-Organism Framework.

Ethics Hum Res 2019 Jan;41(1):4-14

Professor in the Department of Social Medicine and the Center for Bioethics at the University of North Carolina at Chapel Hill.

Nonhuman animal research and phase I healthy-volunteer clinical trials are both critical components of testing the safety of investigational drugs as part of the development of new pharmaceuticals. In addition, these types of research share important structural features, as both take place in confinement and both use subjects that are dissimilar to the target population. By mobilizing a model-organism framework for phase I trials, we employ concepts and mechanisms typical to animal research to query gaps in the human subjects ethics and policy framework. By bringing these two research worlds together, we aim to illustrate how the model-organism framework can enhance healthy volunteers' welfare during trials, improve research oversight, and more critically assess the science value of current phase I trials.
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http://dx.doi.org/10.1002/eahr.500001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6410705PMC
January 2019

Transcriptome-wide isoform-level dysregulation in ASD, schizophrenia, and bipolar disorder.

Science 2018 12;362(6420)

Most genetic risk for psychiatric disease lies in regulatory regions, implicating pathogenic dysregulation of gene expression and splicing. However, comprehensive assessments of transcriptomic organization in diseased brains are limited. In this work, we integrated genotypes and RNA sequencing in brain samples from 1695 individuals with autism spectrum disorder (ASD), schizophrenia, and bipolar disorder, as well as controls. More than 25% of the transcriptome exhibits differential splicing or expression, with isoform-level changes capturing the largest disease effects and genetic enrichments. Coexpression networks isolate disease-specific neuronal alterations, as well as microglial, astrocyte, and interferon-response modules defining previously unidentified neural-immune mechanisms. We integrated genetic and genomic data to perform a transcriptome-wide association study, prioritizing disease loci likely mediated by cis effects on brain expression. This transcriptome-wide characterization of the molecular pathology across three major psychiatric disorders provides a comprehensive resource for mechanistic insight and therapeutic development.
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http://dx.doi.org/10.1126/science.aat8127DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6443102PMC
December 2018

Healthy volunteers' perceptions of risk in US Phase I clinical trials: A mixed-methods study.

PLoS Med 2018 11 20;15(11):e1002698. Epub 2018 Nov 20.

Department of Social Medicine and Center for Bioethics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America.

Background: There is limited research on healthy volunteers' perceptions of the risks of Phase I clinical trials. In order to contribute empirically to long-standing ethical concerns about healthy volunteers' involvement in drug development, it is crucial to assess how these participants understand trial risks. The objectives of this study were to investigate (1) participants' views of the overall risks of Phase I trials, (2) their views of the risk of personally being harmed in a trial, and (3) how risk perceptions vary across participants' clinical trial history and sociodemographic characteristics.

Methods And Findings: We qualitatively and quantitatively analyzed semi-structured interviews conducted with 178 healthy volunteers who had participated in a diverse range of Phase I trials in the United States. Participants had collective experience in a reported 1,948 Phase I trials (mean = 10.9; median = 5), and they were interviewed as part of a longitudinal study of healthy volunteers' risk perceptions, their trial enrollment decisions, and their routine health behaviors. Participants' qualitative responses were coded, analyzed, and subsequently quantified in order to assess correlations between their risk perceptions and demographics, such as their race/ethnicity, gender, age, educational attainment, employment status, and household income. We found that healthy volunteers often viewed the overall risks of Phase I trials differently than their own personal risk of harm. The majority of our participants thought that Phase I trials were medium, high, or extremely high risk (118 of 178), but most nonetheless felt that they were personally safe from harm (97 of 178). We also found that healthy volunteers in their first year of clinical trial participation, racial and ethnic minority participants, and Hispanic participants tended to view the overall trial risks as high (respectively, Jonckheere-Terpstra, -2.433, p = 0.015; Fisher exact test, p = 0.016; Fisher exact test, p = 0.008), but these groups did not differ in regard to their perceptions of personal risk of harm (respectively, chi-squared, 3.578, p = 0.059; chi-squared, 0.845, p = 0.358; chi-squared, 1.667, p = 0.197). The main limitation of our study comes from quantitatively aggregating data from in-depth interviews, which required the research team to interpret participants' nonstandardized risk narratives.

Conclusions: Our study demonstrates that healthy volunteers are generally aware of and reflective about Phase I trial risks. The discrepancy in healthy volunteers' views of overall and personal risk sheds light on why healthy volunteers might continue to enroll in clinical trials, even when they view trials on the whole as risky.
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http://dx.doi.org/10.1371/journal.pmed.1002698DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6245523PMC
November 2018

Healthy Volunteers' Perceptions of the Benefits of Their Participation in Phase I Clinical Trials.

J Empir Res Hum Res Ethics 2018 12 8;13(5):494-510. Epub 2018 Oct 8.

1 University of North Carolina at Chapel Hill, NC, USA.

Other than the financial motivations for enrolling in Phase I trials, research on how healthy volunteers perceive the benefits of their trial participation is scant. Using qualitative interviews conducted with 178 U.S. healthy volunteers enrolled in Phase I trials, we investigated how participants described the benefits of their study involvement, including, but not limited to, the financial compensation, and we analyzed how these perceptions varied based on participants' sociodemographic characteristics and clinical trial history. We found that participants detailed economic, societal, and noneconomic personal benefits. We also found differences in participants' perceived benefits based on gender, age, ethnicity, educational attainment, employment status, and number of clinical trials completed. Our study indicates that many healthy volunteers believe they gain more than just the financial compensation when they accept the risks of Phase I participation.
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http://dx.doi.org/10.1177/1556264618804962DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6235676PMC
December 2018

Virtue, Vice, and "Voracious" Science: How should we approach the ethics of primate research?.

Authors:
Rebecca L Walker

Perspect Biol Med 2018 ;61(1):130-146

Philosophical approaches to animal research have typically asked whether nonhuman animals have rights that would prohibit such research or whether the benefit of such research on the whole balances out the harms to animals. The professional ethics approach instead promotes compliance with regulatory norms that aim to support science progress. In Voracious Science and Vulnerable Animals: A Primate Scientist's Ethical Journey (2016), John Gluck struggles with issues that relate to each of these ethical frameworks, but the notion of an ethical "journey" also raises questions of character that are underdeveloped in animal research ethics. This essay considers how virtue ethics may allow us to revisit the ethical significance of the research of one of Gluck's mentors, Harry F. Harlow. Harlow's torturous, but highly influential, experiments with infant macaques made him one of the most controversial figures in animal research in the second half of the 20th century. A virtue ethical approach to his case poses a unique set of questions, including: Was Harlow compassionate or cruel? Why are human-animal bonds important in ethical primate research? And what is a good life for a research monkey?
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http://dx.doi.org/10.1353/pbm.2018.0032DOI Listing
October 2018

The Ethics of General Population Preventive Genomic Sequencing: Rights and Social Justice.

J Med Philos 2018 Jan;43(1):22-43

Occidental College, Los Angeles, California, USA.

Advances in DNA sequencing technology open new possibilities for public health genomics, especially in the form of general population preventive genomic sequencing (PGS). Such screening programs would sit at the intersection of public health and preventive health care, and thereby at once invite and resist the use of clinical ethics and public health ethics frameworks. Despite their differences, these ethics frameworks traditionally share a central concern for individual rights. We examine two putative individual rights-the right not to know, and the child's right to an open future-frequently invoked in discussions of predictive genetic testing, in order to explore their potential contribution to evaluating this new practice. Ultimately, we conclude that traditional clinical and public health ethics frameworks, and these two rights in particular, should be complemented by a social justice perspective in order adequately to characterize the ethical dimensions of general population PGS programs.
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http://dx.doi.org/10.1093/jmp/jhx034DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5901094PMC
January 2018

Serial Participation and the Ethics of Phase 1 Healthy Volunteer Research.

J Med Philos 2018 01;43(1):83-114

University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.

Phase 1 healthy volunteer clinical trials-which financially compensate subjects in tests of drug toxicity levels and side effects-appear to place pressure on each joint of the moral framework justifying research. In this article, we review concerns about phase 1 trials as they have been framed in the bioethics literature, including undue inducement and coercion, unjust exploitation, and worries about compromised data validity. We then revisit these concerns in light of the lived experiences of serial participants who are income-dependent on phase 1 trials. We show how participant experiences shift attention from discrete exchanges, behaviors, and events in the research enterprise to the ongoing and dynamic patterns of serial participation in which individual decision-making is embedded in collective social and economic conditions and shaped by institutional policies. We argue in particular for the ethical significance of structurally diminished voluntariness, routine powerlessness in setting the terms of exchange, and incentive structures that may promote pharmaceutical interests but encourage phase 1 healthy volunteers to skirt important rules.
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http://dx.doi.org/10.1093/jmp/jhx033DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5901090PMC
January 2018

Beyond Primates: Research Protections and Animal Moral Value.

Authors:
Rebecca L Walker

Hastings Cent Rep 2016 07;46(4):28-30

Should monkeys be used in painful and often deadly infectious disease research that may save many human lives? This is the challenging question that Anne Barnhill, Steven Joffe, and Franklin G. Miller take on in their carefully argued and compelling article "The Ethics of Infection Challenges in Primates." The authors offer a nuanced and even-handed position that takes philosophical worries about nonhuman primate moral status seriously and still appreciates the very real value of such research for human welfare. Overall, they argue for an extension and revision of the recommendations regarding chimpanzee research offered by the Institute of Medicine in 2011; the practical upshot of their argument would allow for infection challenge research for promising interventions for Ebola and Marburg virus diseases but not for smallpox or the common cold. The IOM recommendations regarding chimpanzee research put in motion an exceptionalist policy for this great ape population. Barnhill and colleagues' proposal would enlarge the scope of that exceptionalism to embrace NHPs other than great apes. But is such exceptionalism warranted? It is not obvious to me either that the more sophisticated capacities of a species as a whole give it greater ethical protections or that less intellectually or socially sophisticated animals ought to therefore receive less protection when it comes to painful experimental interventions.
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http://dx.doi.org/10.1002/hast.602DOI Listing
July 2016

Professionalism and ethics in animal research.

Nat Biotechnol 2015 Oct;33(10):1027-8

Veterinary University Vienna, Austria.

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http://dx.doi.org/10.1038/nbt.3363DOI Listing
October 2015

Looking for Trouble: Preventive Genomic Sequencing in the General Population and the Role of Patient Choice.

Am J Bioeth 2015 ;15(7):3-14

a University of North Carolina School of Medicine.

Advances in genomics have led to calls for developing population-based preventive genomic sequencing (PGS) programs with the goal of identifying genetic health risks in adults without known risk factors. One critical issue for minimizing the harms and maximizing the benefits of PGS is determining the kind and degree of control individuals should have over the generation, use, and handling of their genomic information. In this article we examine whether PGS programs should offer individuals the opportunity to selectively opt out of the sequencing or analysis of specific genomic conditions (the menu approach) or whether PGS should be implemented using an all-or-nothing panel approach. We conclude that any responsible scale-up of PGS will require a menu approach that may seem impractical to some, but that draws its justification from a rich mix of normative, legal, and practical considerations.
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http://dx.doi.org/10.1080/15265161.2015.1039721DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4493927PMC
February 2016
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