Gut microbiome and metabolome profiling in Framingham heart study reveals cholesterol-metabolizing bacteria.

Accumulating evidence suggests that cardiovascular disease (CVD) is associated with an altered gut microbiome. Our understanding of the underlying mechanisms has been hindered by lack of matched multi-omic data with diagnostic biomarkers. To comprehensively profile gut microbiome contributions to CVD, we generated stool metagenomics and metabolomics from 1,429 Framingham Heart Study participants. We identified blood lipids and cardiovascular health measurements associated with microbiome and metabolome composition. Integrated analysis revealed microbial pathways implicated in CVD, including flavonoid, γ-butyrobetaine, and cholesterol metabolism. Species from the Oscillibacter genus were associated with decreased fecal and plasma cholesterol levels. Using functional prediction and in vitro characterization of multiple representative human gut Oscillibacter isolates, we uncovered conserved cholesterol-metabolizing capabilities, including glycosylation and dehydrogenation. These findings suggest that cholesterol metabolism is a broad property of phylogenetically diverse Oscillibacter spp., with potential benefits for lipid homeostasis and cardiovascular health.

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

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.

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

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.

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

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?

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

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.

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

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?

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

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.

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

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.

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

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.

Bioethics methods in the ethical, legal, and social implications of the human genome project literature.

While bioethics as a field has concerned itself with methodological issues since the early years, there has been no systematic examination of how ethics is incorporated into research on the Ethical, Legal and Social Implications (ELSI) of the Human Genome Project. Yet ELSI research may bear a particular burden of investigating and substantiating its methods given public funding, an explicitly cross-disciplinary approach, and the perceived significance of adequate responsiveness to advances in genomics. We undertook a qualitative content analysis of a sample of ELSI publications appearing between 2003 and 2008 with the aim of better understanding the methods, aims, and approaches to ethics that ELSI researchers employ. We found that the aims of ethics within ELSI are largely prescriptive and address multiple groups. We also found that the bioethics methods used in the ELSI literature are both diverse between publications and multiple within publications, but are usually not themselves discussed or employed as suggested by bioethics method proponents. Ethics in ELSI is also sometimes undistinguished from related inquiries (such as social, legal, or political investigations).

Care or Complicity? Medical Personnel in Prisons.

Imprisonment may sometimes be a justified form of punishment. Yet the U.S. carceral system suffers from appalling problems of justice-in who is put into prisons, in how imprisoned people are treated, and in downstream personal and community health impacts. Medical personnel working in prisons and jails take on risky work for highly vulnerable and underserved patients. They are to be lauded for their professional commitments. Yet at the same time, prison care undercuts the ability of medical personnel to uphold their own professional standards and sometimes fails in even basic health protection. Doctors in prisons are stuck between their commitment to vulnerable patients and complicity in a system that requires their participation to uphold its constitutionality. Medical ethics is frayed in prisons, and the problem deserves our attention.

Challenging the Boundaries Between Treatment, Prevention, and Enhancement in Human Genome Editing.

Traditional distinctions between treatment and enhancement goals for human genome editing (HGE) have animated oversight considerations, yet these categories have been complicated by the addition of prevention as a possible target for HGE applications. To assess the role these three categories might play in continued HGE governance efforts, we report on interviews with genome editing scientists and governance group members. While some accepted traditional distinctions between treatment and enhancement and rejected the latter as unacceptable, others argued that the concept of enhancement is largely irrelevant or not as morally problematic as suggested. Others described how preventive goals for HGE create gray zones where prevention and enhancement may be difficult to distinguish, which may stymie uses of HGE. We conclude by discussing the governance implications of these various understandings of treatment, prevention, and enhancement as HGE research moves beyond the treatment of serious disease to embrace longer range preventive goals.

Cross-ancestry atlas of gene, isoform, and splicing regulation in the developing human brain.

Neuropsychiatric genome-wide association studies (GWASs), including those for autism spectrum disorder and schizophrenia, show strong enrichment for regulatory elements in the developing brain. However, prioritizing risk genes and mechanisms is challenging without a unified regulatory atlas. Across 672 diverse developing human brains, we identified 15,752 genes harboring gene, isoform, and/or splicing quantitative trait loci, mapping 3739 to cellular contexts. Gene expression heritability drops during development, likely reflecting both increasing cellular heterogeneity and the intrinsic properties of neuronal maturation. Isoform-level regulation, particularly in the second trimester, mediated the largest proportion of GWAS heritability. Through colocalization, we prioritized mechanisms for about 60% of GWAS loci across five disorders, exceeding adult brain findings. Finally, we contextualized results within gene and isoform coexpression networks, revealing the comprehensive landscape of transcriptome regulation in development and disease.

Mission Creep or Mission Lapse? Scientific Review in Research Oversight.

BACKGROUND: The ethical use both of human and non-human animals in research is predicated on the assumption that it is of a high quality and its projected benefits are more significant than the risks and harms imposed on subjects. Yet questions remain about whether and how IRBs and IACUCs should consider the scientific value of proposed research studies. METHODS: We draw upon 45 interviews with IRB and IACUC members and researchers with oversight experience about their perceptions of their own roles in reviewing the quality and value of scientific protocols. Interview transcripts were memoed to highlight specific findings, which were then used to identify key themes through an iterative process. RESULTS: IRB and IACUC members expressed broad trust in the need for and value of research, and they often assumed that protocols had social value or that prior review, especially when associated with funding, affirmed both the rigor and merit of those protocols. Some oversight members also took an explicit stance against scientific review by stating that such review is not within the regulatory mandates governing their parts in the oversight system. Yet other interviewees expressed uneasiness about the current paradigm for evaluating the quality and overall value of science, suggesting that IRB and IACUC members perceive gaps in the oversight systems. CONCLUSIONS: These findings reveal many similarities in how IRB and IACUC members understand the roles and limitations of their respective oversight committees. We conclude with a discussion of how the lack of a clear mandate regarding scientific review within US federal regulations may undermine ethical engagement of whether human and animal research is scientifically justified, resulting in a "mission lapse" wherein no organizational body is clearly responsible for ensuring that the research being conducted has the potential to advance science and benefit society.

Lectin-Seq: A method to profile lectin-microbe interactions in native communities.

Soluble human lectins are critical components of innate immunity. Genetic models suggest that lectins influence host-resident microbiota, but their specificity for commensal and mutualist species is understudied. Elucidating lectins' roles in regulating microbiota requires an understanding of which microbial species they bind within native communities. To profile human lectin recognition, we developed Lectin-Seq. We apply Lectin-Seq to human fecal microbiota using the soluble mannose-binding lectin (MBL) and intelectin-1 (hItln1). Although each lectin binds a substantial percentage of the samples (10 to 20%), the microbial interactomes of MBL and hItln1 differ markedly in composition and diversity. MBL binding is highly selective for a small subset of species commonly associated with humans. In contrast, hItln1's interaction profile encompasses a broad range of lower-abundance species. Our data uncover stark differences in the commensal recognition properties of human lectins.

Cross-ancestry, cell-type-informed atlas of gene, isoform, and splicing regulation in the developing human brain.

Genomic regulatory elements active in the developing human brain are notably enriched in genetic risk for neuropsychiatric disorders, including autism spectrum disorder (ASD), schizophrenia, and bipolar disorder. However, prioritizing the specific risk genes and candidate molecular mechanisms underlying these genetic enrichments has been hindered by the lack of a single unified large-scale gene regulatory atlas of human brain development. Here, we uniformly process and systematically characterize gene, isoform, and splicing quantitative trait loci (xQTLs) in 672 fetal brain samples from unique subjects across multiple ancestral populations. We identify 15,752 genes harboring a significant xQTL and map 3,739 eQTLs to a specific cellular context. We observe a striking drop in gene expression and splicing heritability as the human brain develops. Isoform-level regulation, particularly in the second trimester, mediates the greatest proportion of heritability across multiple psychiatric GWAS, compared with eQTLs. Via colocalization and TWAS, we prioritize biological mechanisms for ~60% of GWAS loci across five neuropsychiatric disorders, nearly two-fold that observed in the adult brain. Finally, we build a comprehensive set of developmentally regulated gene and isoform co-expression networks capturing unique genetic enrichments across disorders. Together, this work provides a comprehensive view of genetic regulation across human brain development as well as the stage-and cell type-informed mechanistic underpinnings of neuropsychiatric disorders.