Philosophies of funding.

Successful scientific practice encompasses broader and more varied modes of investigation than can be captured by focusing on hypothesis-driven research. We examine the emphases that major US and UK funding agencies place on particular modes of research practice and suggest that funding agency guidelines should be informed by a more dynamic and multidimensional account of scientific practice.

Mutation Clearance after Transplantation for Myelodysplastic Syndrome.

BACKGROUND: Allogeneic hematopoietic stem-cell transplantation is the only curative treatment for patients with myelodysplastic syndrome (MDS). The molecular predictors of disease progression after transplantation are unclear. METHODS: We sequenced bone marrow and skin samples from 90 adults with MDS who underwent allogeneic hematopoietic stem-cell transplantation after a myeloablative or reduced-intensity conditioning regimen. We detected mutations before transplantation using enhanced exome sequencing, and we evaluated mutation clearance by using error-corrected sequencing to genotype mutations in bone marrow samples obtained 30 days after transplantation. In this exploratory study, we evaluated the association of a mutation detected after transplantation with disease progression and survival. RESULTS: Sequencing identified at least one validated somatic mutation before transplantation in 86 of 90 patients (96%); 32 of these patients (37%) had at least one mutation with a maximum variant allele frequency of at least 0.5% (equivalent to 1 heterozygous mutant cell in 100 cells) 30 days after transplantation. Patients with disease progression had mutations with a higher maximum variant allele frequency at 30 days than those who did not (median maximum variant allele frequency, 0.9% vs. 0%; P<0.001). The presence of at least one mutation with a variant allele frequency of at least 0.5% at day 30 was associated with a higher risk of progression (53.1% vs. 13.0%; conditioning regimen-adjusted hazard ratio, 3.86; 95% confidence interval [CI], 1.96 to 7.62; P<0.001) and a lower 1-year rate of progression-free survival than the absence of such a mutation (31.3% vs. 59.3%; conditioning regimen-adjusted hazard ratio for progression or death, 2.22; 95% CI, 1.32 to 3.73; P=0.005). The rate of progression-free survival was lower among patients who had received a reduced-intensity conditioning regimen and had at least one persistent mutation with a variant allele frequency of at least 0.5% at day 30 than among patients with other combinations of conditioning regimen and mutation status (P≤0.001). Multivariate analysis confirmed that patients who had a mutation with a variant allele frequency of at least 0.5% detected at day 30 had a higher risk of progression (hazard ratio, 4.48; 95% CI, 2.21 to 9.08; P<0.001) and a lower 1-year rate of progression-free survival than those who did not (hazard ratio for progression or death, 2.39; 95% CI, 1.40 to 4.09; P=0.002). CONCLUSIONS: The risk of disease progression was higher among patients with MDS in whom persistent disease-associated mutations were detected in the bone marrow 30 days after transplantation than among those in whom these mutations were not detected. (Funded by the Leukemia and Lymphoma Society and others.).

The value-ladenness of transparency in science: Lessons from Lyme disease.

Both philosophers and scientists have recently promoted transparency as an important element of responsible scientific practice. Philosophers have placed particular emphasis on the ways that transparency can assist with efforts to manage value judgments in science responsibly. This paper examines a potential challenge to this approach, namely, that efforts to promote transparency can themselves be value-laden. This is particularly problematic when transparency incorporates second-order value judgments that are underwritten by the same values at stake in the desire for transparency about the first-order value judgments involved in scientific research. The paper uses a case study involving research on Lyme disease to illustrate this worry, but it responds by elucidating a range of scenarios in which transparency can still play an effective role in managing value judgments responsibly.

Conflict of Interest Mitigation Procedures May Have Little Influence on the Perceived Procedural Fairness of Risk-Related Research.

Two between-subject experiments explored perceived conflict of interest (COI)-operationalized as perceived procedural unfairness-in a hypothetical public-private research partnership to study the health risks of trans fats. Perceived fairness was measured as subjects' perceptions that health researchers would be willing to listen to a range of voices and minimize bias (i.e., COI) in the context of a research project. Experiment 1 (n = 1,263) randomly assigned research subjects to a partnership that included (1) a combination of an industry partner, a university partner, and a nongovernmental organization (NGO) partner; and (2) one of three processes aimed at mitigating the potential for COI to harm the quality of the research. The procedures included an arm's-length process meant to keep the university-based research team from being influenced by the other partners, an independent advisory board to oversee the project, and a commitment to making all data and analyses openly available. The results suggest that having an industry partner has substantial negative effects on perceived fairness and that the benefit of employing a single COI-mitigation process may be relatively small. Experiment 2 (n = 1,076) assessed a partnership of (1) a university and either an NGO or industry partner and (b) zero, one, two, or three of the three COI-mitigation procedures. Results suggest there is little value in combining COI-mitigation procedures. The study has implications for those who aim to foster confidence in scientific findings for which the underlying research may benefit from industry funding.

Using Drones to Study Human Beings: Ethical and Regulatory Issues.

Researchers have used drones to track wildlife populations, monitor forest fires, map glaciers, and measure air pollution but have only begun to consider how to use these unmanned aerial vehicles to study human beings. The potential use of drones to study public gatherings or other human activities raises novel issues of privacy, confidentiality, and consent, which this article explores in depth. It argues that drone research could fall into several different categories: non-human subjects research (HSR), exempt HSR, or non-exempt HSR. In the case of non-exempt HSR, it will be difficult for institutional review boards to approve studies unless they are designed so that informed consent can be waived. Whether drone research is non-HSR, exempt HSR, or non-exempt HSR, it is important for investigators to consult communities which could be affected by the research.

Value-entanglement and the integrity of scientific research.

Throughout much of the 20th century, philosophers of science maintained a position known as the value-free ideal, which holds that non-epistemic (e.g., moral, social, political, or economic) values should not influence the evaluation and acceptance of scientific results. In the last few decades, many philosophers of science have rejected this position by arguing that non-epistemic values can and should play an important role in scientific judgment and decision-making in a variety of contexts, including the evaluation and acceptance of scientific results. Rejecting the value-free ideal creates some new and vexing problems, however. One of these is that relinquishing this philosophical doctrine may undermine the integrity of scientific research if practicing scientists decide to allow non-epistemic values to impact their judgment and decision-making. A number of prominent philosophers of science have sought to show how one can reject the value-free ideal without compromising the integrity of scientific research. In this paper, we examine and critique their views and offer our own proposal for protecting and promoting scientific integrity. We argue that the literature on research ethics and its focus on adherence to norms, rules, policies, and procedures that together promote the aims of science can provide a promising foundation for building an account of scientific integrity. These norms, rules, policies, and procedures provide a level of specificity that is lacking in most philosophical discussions of science and values, and they suggest an important set of tasks for those working in science and values-namely, assessing, justifying, and prioritizing them. Thus, we argue that bringing together the literature on research ethics with the literature on science and values will enrich both areas and generate a more sophisticated and detailed account of scientific integrity.

Genomic analysis of germ line and somatic variants in familial myelodysplasia/acute myeloid leukemia.

Familial clustering of myelodysplastic syndromes (MDSs) and acute myeloid leukemia (AML) can be caused by inherited factors. We screened 59 individuals from 17 families with 2 or more biological relatives with MDS/AML for variants in 12 genes with established roles in predisposition to MDS/AML, and identified a pathogenic germ line variant in 5 families (29%). Extending the screen with a panel of 264 genes that are recurrently mutated in de novo AML, we identified rare, nonsynonymous germ line variants in 4 genes, each segregating with MDS/AML in 2 families. Somatic mutations are required for progression to MDS/AML in these familial cases. Using a combination of targeted and exome sequencing of tumor and matched normal samples from 26 familial MDS/AML cases and asymptomatic carriers, we identified recurrent frameshift mutations in the cohesin-associated factor PDS5B, co-occurrence of somatic ASXL1 mutations with germ line GATA2 mutations, and recurrent mutations in other known MDS/AML drivers. Mutations in genes that are recurrently mutated in de novo AML were underrepresented in the familial MDS/AML cases, although the total number of somatic mutations per exome was the same. Lastly, clonal skewing of hematopoiesis was detected in 67% of young, asymptomatic RUNX1 carriers, providing a potential biomarker that could be used for surveillance in these high-risk families.

Low hepatitis E virus RNA prevalence in a large-scale survey of United States source plasma donors.

BACKGROUND: Hepatitis E virus (HEV) is a small, nonenveloped, single-stranded, RNA virus of emerging concern in industrialized countries. HEV transmission through transfusion of blood components has been reported, but not via plasma-derived medicinal products (PDMPs) manufactured with virus inactivation and/or removal steps. This study aimed to determine the prevalence of HEV among US source plasma donors. STUDY DESIGN AND METHODS: Samples were collected from US source plasma donors at centers across the United States and were initially screened for HEV RNA in 96-sample minipools using the Roche cobas HEV test on the cobas 8800 system. Assuming a sensitivity of 18.6 IU/mL, the minipool screening strategy allowed for reliable detection of individual donations with HEV RNA titers of more than 2 × 103 IU/mL. Reactive minipools were resolved to individual donations, which were further analyzed to quantify viral RNA concentration, determine HEV genotype, and immunoglobulin (Ig)G and IgM HEV antibody status. RESULTS: A total of 128,020 samples were collected from 96 CSL Plasma centers in the United States, representing 27 states. The prevalence of HEV RNA-positive samples was 0.002% with three unique HEV-positive donors identified, all HEV Subgenotype 3a. Virus titers of HEV-positive samples were relatively low (103 -104 IU HEV RNA/mL). One positive donation was HEV IgG seropositive. CONCLUSION: Routine screening of US source plasma donations for HEV would not substantially improve the safety of most PDMPs. The low prevalence and potential viral load of HEV, together with effective virus reduction steps in manufacturing processes, results in a low residual risk and acceptable safety margins for PDMPs derived from US plasma donors.

Clonal architecture of secondary acute myeloid leukemia defined by single-cell sequencing.

Next-generation sequencing has been used to infer the clonality of heterogeneous tumor samples. These analyses yield specific predictions-the population frequency of individual clones, their genetic composition, and their evolutionary relationships-which we set out to test by sequencing individual cells from three subjects diagnosed with secondary acute myeloid leukemia, each of whom had been previously characterized by whole genome sequencing of unfractionated tumor samples. Single-cell mutation profiling strongly supported the clonal architecture implied by the analysis of bulk material. In addition, it resolved the clonal assignment of single nucleotide variants that had been initially ambiguous and identified areas of previously unappreciated complexity. Accordingly, we find that many of the key assumptions underlying the analysis of tumor clonality by deep sequencing of unfractionated material are valid. Furthermore, we illustrate a single-cell sequencing strategy for interrogating the clonal relationships among known variants that is cost-effective, scalable, and adaptable to the analysis of both hematopoietic and solid tumors, or any heterogeneous population of cells.

Conceptions of Good Science in Our Data-Rich World.

Scientists have been debating for centuries the nature of proper scientific methods. Currently, criticisms being thrown at data-intensive science are reinvigorating these debates. However, many of these criticisms represent long-standing conflicts over the role of hypothesis testing in science and not just a dispute about the amount of data used. Here, we show that an iterative account of scientific methods developed by historians and philosophers of science can help make sense of data-intensive scientific practices and suggest more effective ways to evaluate this research. We use case studies of Darwin's research on evolution by natural selection and modern-day research on macrosystems ecology to illustrate this account of scientific methods and the innovative approaches to scientific evaluation that it encourages. We point out recent changes in the spheres of science funding, publishing, and education that reflect this richer account of scientific practice, and we propose additional reforms.

Independent premotor encoding of the sequence and structure of birdsong in avian cortex.

How the brain coordinates rapid sequences of learned behavior, such as human speech, remains a fundamental problem in neuroscience. Birdsong is a model of such behavior, which is learned and controlled by a neural circuit that spans avian cortex, basal ganglia, and thalamus. The songs of adult male zebra finches (Taeniopygia guttata), produced as rapid sequences of vocal gestures (syllables), are encoded by the cortical premotor region HVC (proper name). While the motor encoding of song within HVC has traditionally been viewed as unitary and distributed, we used an ablation technique to ask whether the sequence and structure of song are processed independently within HVC. Results revealed a functional topography across the medial-lateral axis of HVC. Bilateral ablation of medial HVC induced a positive disruption of song (increase in atypical syllable sequences), whereas bilateral ablation of lateral HVC induced a negative disruption (omission of individual syllables). Bilateral ablation of central HVC either had no effect on song or induced syllable omission, similar to lateral HVC ablation. We then investigated HVC connectivity and found parallel afferent and efferent pathways that transit medial and lateral HVC and converge at vocal motor cortex. In light of recent evidence that syntactic and lexical components of human speech are processed independently by neighboring regions of cortex (Menenti et al., 2012), our demonstration of anatomically distinct pathways that differentially process the sequence and structure of birdsong in parallel suggests that the vertebrate brain relies on a common approach to encode rapid sequences of vocal gestures.

It's Good to Share: Why Environmental Scientists' Ethics Are Out of Date.

Although there have been many recent calls for increased data sharing, the majority of environmental scientists do not make their individual data sets publicly available in online repositories. Current data-sharing conversations are focused on overcoming the technological challenges associated with data sharing and the lack of rewards and incentives for individuals to share data. We argue that the most important conversation has yet to take place: There has not been a strong ethical impetus for sharing data within the current culture, behaviors, and practices of environmental scientists. In this article, we describe a critical shift that is happening in both society and the environmental science community that makes data sharing not just good but ethically obligatory. This is a shift toward the ethical value of promoting inclusivity within and beyond science. An essential element of a truly inclusionary and democratic approach to science is to share data through publicly accessible data sets.

Bisphenol A and risk management ethics.

It is widely recognized that endocrine disrupting compounds, such as Bisphenol A, pose challenges for traditional paradigms in toxicology, insofar as these substances appear to have a wider range of low-dose effects than previously recognized. These compounds also pose challenges for ethics and policymaking. When a chemical does not have significant low-dose effects, regulators can allow it to be introduced into commerce or the environment, provided that procedures and rules are in place to keep exposures below an acceptable level. This option allows society to maximize the benefits from the use of the chemical while minimizing risks to human health or the environment, and it represents a compromise between competing values. When it is not possible to establish acceptable exposure levels for chemicals that pose significant health or environmental risks, the most reasonable options for risk management may be to enact either partial or complete bans on their use. These options create greater moral conflict than other risk management strategies, leaving policymakers difficult choices between competing values.

Structured Development and Promotion of a Research Field: Hormesis in Biology, Toxicology, and Environmental Regulatory Science.

The ability of powerful and well-funded interest groups to steer scientific research in ways that advance their goals has become a significant social concern. This steering ability is increasingly being recognized in the peer-reviewed scientific literature and in findings of deliberative scientific bodies. This paper provides a case study that illustrates some of the major strategies that can be used to structure and advance a controversial research field. It focuses on hormesis, described as a type of dose-response relationship in toxicology and biology showing low-dose stimulation but high-dose inhibition, or the reverse. Hormesis proponents tout its significance, arguing that substances toxic at high doses and beneficial at lower doses should be regulated less stringently. We identify five strategies employed by hormesis proponents to foster its acceptance: (1) creating institutions focused on supporting hormesis; (2) developing terminology, study designs, and data interpretations that cast it in a favorable light; (3) using bibliometric techniques and surveys to attract attention; (4) aggressively advocating for the phenomenon and challenging critics; and (5) working with outside interest groups to apply the hormesis phenomenon in the economic and political spheres. We also suggest a number of oversight strategies that can be implemented to help promote credible and socially responsible research in cases like this one.

Words Matter: Reflective Science Communication and Tradeoffs in Environmental Health Research.

BACKGROUND: Scientists who communicate societally relevant information face challenging contexts in which misinformation, disinformation, hype, and spin are prevalent. As a result, they often face difficult decisions about how to frame their work in a socially responsible manner. OBJECTIVES: Drawing from the literature on science communication and framing, we identify tradeoffs that environmental health scientists face when deciding how to communicate their work, and we propose strategies for handling these tradeoffs. We use research on the human health effects of environmental endocrine disruptors as a case study to illustrate these challenges and strategies. DISCUSSION: We examine four major frames (i.e., ways of packaging information that draw attention to facets of an issue or topic) in discussions of the effects of endocrine-disrupting chemicals on sexual and neural development and obesity. We show how these frames can be beneficial (e.g., focusing public attention on environmental health threats and promoting actions to address environmental pollution) while simultaneously having harmful effects (e.g., contributing to stigmatization of particular groups or the promotion of harmful political ideologies). CONCLUSIONS: Researchers who seek to responsibly communicate societally relevant work can employ several strategies to mitigate difficult tradeoffs, including a) striving for sensitivity to the social context and its relationship to their framing choices, b) choosing to avoid some frames, c) employing frames that alleviate ethical tensions, d) fostering education to alleviate harms, e) developing interdisciplinary and community collaborations, and f) working with institutions like scientific societies and journals to develop guidance on responsible communication practices. https://doi.org/10.1289/EHP14527.

Axial organization of a brain region that sequences a learned pattern of behavior.

Neural activity within HVC (proper name), a premotor nucleus of the songbird telencephalon analogous to premotor cortical regions in mammals, controls the temporal structure of learned song in male zebra finches (Taeniopygia guttata). HVC is composed of a superficially isomorphic neuronal mosaic, implying that song is encoded in a distributed network within HVC. Here, we combined HVC microlesions (10% focal ablation) with singing-driven immediate-early gene (IEG) labeling to explore the network architecture of HVC during singing. Microlesions produce a transient disruption of HVC activity that results in a temporary (≈ 1 week) loss of vocal patterning. Results showed an asymmetrical reduction in the density of IEG-labeled cells 3-5 d after microlesions: swaths of unlabeled cells extended rostrally and/or caudally depending on the position of the HVC microlesion. Labeling returned once birds recovered their songs. Axial swaths of unlabeled cells occurred whether microlesions were located at rostral or caudal poles of HVC, indicating that the localized reduction in IEG labeling could not be attributable solely to transection of afferents that enter HVC rostrally. The asymmetrical pattern of reduced IEG labeling could be explained if synaptic connectivity within HVC is organized preferentially within the rostrocaudal axis. In vivo retrograde tracer injections and in vitro stimulation and recording experiments in horizontal slices of HVC confirmed a rostrocaudal organization of HVC neural connectivity. Our findings suggest that HVC contains an axially organized network architecture that may encode the temporal structure of song.

Science, Values, and the New Demarcation Problem.

In recent years, many philosophers of science have rejected the "value-free ideal" for science, arguing that non-epistemic values have a legitimate role to play in scientific inquiry. However, this philosophical position raises the question of how to distinguish between legitimate and illegitimate influences of values in science. In this paper, we argue that those seeking to address this "new" demarcation problem can benefit by drawing lessons from the "old" demarcation problem, in which philosophers tried to find a way of distinguishing between science and non-science. Many of those who worked on this problem ultimately found that efforts to provide necessary and sufficient conditions for defining science failed, and most concluded that the best solution to the problem was to characterize scientific hypotheses, theories, and research programs in terms of some common norms. We suggest that those seeking to distinguish between legitimate and illegitimate value influences on science would do well to adopt a similar approach. Rather than attempting to establish necessary and sufficient conditions for identifying appropriate value influences, it will be more fruitful to evaluate scientific activities based on their adherence to a set of epistemic and ethical norms that can be implemented in scientific practice by means of rules, conventions, policies, and procedures.

A Framework for Transparency in Precision Livestock Farming.

As precision livestock farming (PLF) technologies emerge, it is important to consider their social and ethical dimensions. Reviews of PLF have highlighted the importance of considering ethical issues related to privacy, security, and welfare. However, little attention has been paid to ethical issues related to transparency regarding these technologies. This paper proposes a framework for developing responsible transparency in the context of PLF. It examines the kinds of information that could be ethically important to disclose about these technologies, the different audiences that might care about this information, the challenges involved in achieving transparency for these audiences, and some promising strategies for addressing these challenges. For example, with respect to the information to be disclosed, efforts to foster transparency could focus on: (1) information about the goals and priorities of those developing PLF systems; (2) details about how the systems operate; (3) information about implicit values that could be embedded in the systems; and/or (4) characteristics of the machine learning algorithms often incorporated into these systems. In many cases, this information is likely to be difficult to obtain or communicate meaningfully to relevant audiences (e.g., farmers, consumers, industry, and/or regulators). Some of the potential steps for addressing these challenges include fostering collaborations between the developers and users of PLF systems, developing techniques for identifying and disclosing important forms of information, and pursuing forms of PLF that can be responsibly employed with less transparency. Given the complexity of transparency and its ethical and practical importance, a framework for developing and evaluating transparency will be an important element of ongoing PLF research.

Science, expertise, and democracy.

The combination of government's significant involvement in science, science's significant effects on the public, and public ignorance (of both politics and science) raise important challenges for reconciling scientific expertise with democratic governance. Nevertheless, there have recently been a variety of encouraging efforts to make scientific activity more responsive to social values and to develop citizens' capacity to engage in more effective democratic governance of science. This essay introduces a special issue of the Kennedy Institute of Ethics Journal, "Science, Expertise, and Democracy," consisting of five papers that developed from the inaugural Three Rivers Philosophy conference held at the University of South Carolina in April 2011. The pieces range from a general analysis of the in-principle compatibility of scientific expertise and democracy to much more concrete studies of the intersection between scientific practices and democratic values in areas such as weight-of-evidence analysis, climate science, and studies of locally undesirable land uses.

Authorship climate: A new tool for studying ethical issues in authorship.

Authorship of academic publications is central to scientists' careers, but decisions about how to include and order authors on publications are often fraught with difficult ethical issues. To better understand scholars' experiences with authorship, we developed a novel concept, authorship climate, which assesses perceptions of the procedural, informational, and distributive justice associated with authorship decisions. We conducted a representative survey of more than 3,000 doctoral students, postdoctoral researchers, and assistant professors from a stratified random sample of U.S. biology, economics, physics, and psychology departments. We found that individuals who tend to have more power on science teams perceived authorship climate to be more positive than those who tend to have less power. Alphabetical approaches for assigning authorship were associated with higher perceptions of procedural justice and informational justice but lower perceptions of distributive justice. Individuals with more marginalized identities also tended to perceive authorship climate more negatively than those with no marginalized identities. These results illustrate how the concept of authorship climate can facilitate enhanced understanding of early-career scholars' authorship experiences, and they highlight potential steps that can be taken to promote more positive authorship experiences for scholars of all identities.