Sequencing projects will screen 200,000 newborns for disease.

U.K. and New York City efforts face cost and ethical issues.

[Ethical boundaries of the legal regulation of genome sequencing in Russia and abroad.] / Этические границы правового регулирования полногеномного секвенирования в России и за рубежом.

The relevance of the chosen topic is due to the need to resolve ethical problems that arise in the framework of legal regulation of genome-wide sequencing in Russia and foreign countries. The purpose of this research is to form ethical principles that should become a reference point for law - making in this area. In order to achieve this goal, we have solved the tasks of studying the normative legal acts of Russia and a number of foreign countries from an ethical point of view. General scientific, private scientific and special methods of scientific knowledge (system-structural, formal-legal) are used. In order to comply with the ethical boundaries of legal regulation, to store access and protect full-genome sequencing data in Russia and foreign countries, it is proposed to develop a set of restrictions that prevent possible discrimination on genetic grounds, to create the necessary conditions for the inadmissibility of disclosure of personalized data, disclosure of information about a genetic disease to the subject and his relatives, as well as the boundaries of editing the genome of a human embryo. For the first time, the authors substantiate the need to establish clear ethical boundaries in the implementation of genome-wide sequencing in Russia based on foreign experience.

Consent and Privacy in the Era of Precision Medicine and Biobanking Genomic Data.

"Big Data represents a challenge that points to the need for collective and political approaches to self-protection rather than solely individual, atomistic approaches."- Anita Allen, "Protecting One's Own Privacy in a Big Data Economy".

Exploring broad consent in the context of the 100,000 Genomes Project: a mixed methods study.

The 100,000 Genomes Project (100kGP)-a hybrid clinical-research initiative-was set up to analyse whole-genome sequences (WGS) from patients living with a rare disease or cancer. The project positioned participant consent as being of central importance, but consent in the context of genomic testing raises challenging issues. In this mixed method study, we surveyed 1337 100kGP participants regarding their experiences of taking part in the project and conducted in-depth interviews with 24 survey respondents to explore these findings further. Survey responses were analysed using descriptive statistics and interview data were analysed thematically. The consent approach of the 100kGP resulted in a proportion of our study's participants not understanding the complexities of the project and what types of results they might receive; for example, 20% of participants who we surveyed from the cancer arm did not recall what decisions they had made regarding additional findings. It is not surprising that a project such as this, with such diverse aims and participant groups, would throw up at least some challenges. However, participants reported being satisfied with their experience of the project to date. Our study highlights that in the context of consent for more complex endeavours, such as the 100kGP, it is important to assess (and document) an agreement to take part, but complicated decisions about what and when to communicate may need revisiting over time in response to changing contexts. We discuss the implications of our findings with reference to participants of the 100kGP and the newly formed NHS Genomic Medicine Service.

Discouraging Elective Genetic Testing of Minors: A Norm under Siege in a New Era of Genomic Medicine.

Consistently, the field of genetic counseling has advocated that parents be advised to defer elective genetic testing of minors until adulthood to prevent a range of potential harms, including stigma, discrimination, and the loss of the child's ability to decide for him- or herself as an adult. However, consensus around the policy of "defer-when-possible" obscures the extent to which this norm is currently under siege. Increasingly, routine use of full or partial genome sequencing challenges our ability to control what is discovered in childhood or, when applied in a prenatal context, even before birth. The expansion of consumer-initiated genetic testing services challenges our ability to restrict what is available to minors. As the barriers to access crumble, medical professionals should proceed with caution, bearing in mind potential risks and continuing to assess the impact of genetic testing on this vulnerable population.

Parents of newborns in the NICU enrolled in genome sequencing research: hopeful, but not naïve.

PURPOSE: In 2014, our institution launched a randomized controlled trial (RCT) comparing rapid genome sequencing (GS) to standard clinical evaluations of infants with suspected genetic disorders. This study aimed to understand parental response to the use of GS for their newborn babies. METHODS: Twenty-three of 128 parents whose infant had enrolled in the RCT completed a retrospective survey and interview addressing attitudes about GS and responses to receiving diagnostic information. We also collected information about participants' genetic literacy, genetic knowledge, numeracy, and symptoms of anxiety and depression. RESULTS: The majority reported positive (13; 56.5%) or neutral 4 (4; 17.4%) feelings when approached about GS for their infant and 100% felt that GS was generally beneficial. The 12 participants who had received a unifying diagnosis for their child's symptoms described personal utility of the information. Some reported the diagnosis led to changes in medical care. Participants showed understanding of some of the psychological risks of GS. For example, 21 (91.3%) agreed or strongly agreed that genetic testing could reveal disturbing results. CONCLUSIONS: Parents who enrolled their newborn in a RCT of GS demonstrated awareness of a psychological risk, but generally held positive beliefs about GS and perceived the benefits outweighed the risk.

Who should access germline genome sequencing? A mixed methods study of patient views.

Implementation of any new medical test, including germline genome sequencing (GS) to inform cancer risk, should take place only when a test is effective, ethically justifiable and acceptable to a population. Little empirical evidence exists on patient views regarding GS for cancer risk. The aim of this study was to elicit opinions on who should be offered GS and who should pay for it. Participants with a probable genetic basis for their cancer (n = 335) and blood relatives (n = 199) were recruited to undergo GS and invited to complete questionnaires at baseline. A subset (n = 40) also participated in qualitative interviews about their views regarding access to GS to detect cancer risk. Our response rate was 92% for questionnaires and 100% for interviews. Participants expressed high enthusiasm overall for access to GS for those with a family history of cancer and anyone who requested testing, but enthusiasm was lower for universal access, if opting out was possible and finances not an issue. Rationales for these views reflected maximising the sound use of resources. Challenges to introducing community screening via GS to limit cancer burden were raised, including the current limits of science and individual ability to cope with uncertain results. Participants undergoing GS supported cancer risk testing for those with a family history of cancer but were concerned about the challenges of designing and implementing a population-based GS cancer-screening program.

Trust and the ethical challenges in the use of whole genome sequencing for tuberculosis surveillance: a qualitative study of stakeholder perspectives.

BACKGROUND: Emerging genomic technologies promise more efficient infectious disease control. Whole genome sequencing (WGS) is increasingly being used in tuberculosis (TB) diagnosis, surveillance, and epidemiology. However, while the use of WGS by public health agencies may raise ethical, legal, and socio-political concerns, these challenges are poorly understood. METHOD: Between November 2017 and April 2018, we conducted semi-structured interviews with 22 key stakeholders across the fields of governance and policy, public health, and laboratory sciences representing the major jurisdictions currently using WGS in national TB programs. Thematic analysis of the interviews was conducted using NVivo 11. RESULTS: Respondents identified several ethical and practical challenges associated with WGS in TB care and surveillance, all related to issues of trust, including: 1) the power of public health; 2) data sharing and profits derived from surveillance efforts; and 3) concerns regarding who has access to, and can benefit from, the technology. Additional challenges included: the potential utility that WGS adds to a public health program, the risks associated with linking necessary epidemiological metadata to the genomic data, and challenges associated with jurisdictional capacity to implement the technology. CONCLUSIONS: Successful implementation of WGS is dependent on fostering relationships of trust between those working with genomics technology and those directly impacted by it, including clinicians. Building trust (a) between the public and the public health agencies and (b) within public health agencies themselves is critical due to the inherent complexity of WGS and its implementation for communicable disease control purposes.

Return of individual genomic research results: are laws and policies keeping step?

Efforts are underway to harmonise the return of individual results and incidental findings from whole genome sequencing (WGS) across research contexts and countries. We reviewed international, regional and national laws and policies applying to return across 20 countries to identify areas of convergence and divergence. Discrepancies between laws and policies are most problematic where they cannot be reconciled through harmonisation of project-level governance. Rules for the return of results apply at different levels in different jurisdictions (e.g., human subjects research, biobanks, clinical trials, genomic sequencing, and genetic/personal data), complicating comparison. A particular concern for harmonisation are the (often contradictory) rules about when results must, should, may, or must not be returned. Adding confusion are different thresholds for utility (medical, familial, reproductive, and/or personal). The importance of respecting individual choices to know or not know is widely recognised, though some norms emphasise respect for personal preferences. Another troubling observation is that requirements for data quality, variant assessment, and the effective communication of results are evolving in uneven ways. There is a growing gap between researchers with the expertise, infrastructure, and resources to meet these requirements and those without, threatening international collaboration. Best practices for the return of individual genomic results are sorely needed to inform not only the ethical return of results, but also future legislative and policy efforts.

Ethical and Psychosocial Issues in Whole Genome Sequencing (WGS) for Newborns.

In this article, I review some of the ethical issues that have arisen in the past when genetic testing has been done in newborns. I then suggest how whole genome sequencing may raise a new set of issues. Finally, I introduce a series of other articles in which the authors address different controversies that arise when whole genome sequencing is used in the newborn period.

Rapid Challenges: Ethics and Genomic Neonatal Intensive Care.

NICUs are a priority implementation area for genomic medicine. Rapid genomic testing in the NICU is expected to be genomic medicine's "critical application," providing such clear benefits that it drives the adoption of genomics more broadly. Studies from multiple centers worldwide have now demonstrated the clinical utility and cost-effectiveness of rapid genomic sequencing in this setting, paving the way for widespread implementation. However, the introduction of this potentially powerful tool for predicting future impairment in the NICU also raises profound ethical challenges. Developing models of good practice that incorporate the identification, exploration, and analysis of ethical issues will be critical for successful implementation. In this article, we analyze 3 such issues: (1) the value and meaning of gaining consent to a complex test in a stressful, emotionally charged environment; (2) the effect of rapid diagnosis on parent-child bonding and its implications for medical and family decisions, particularly in relation to treatment limitation; and (3) distributive justice (ie, whether the substantial cost and diversion of resources to deliver rapid genomic testing in the NICU can be justified).

Opening the "black box" of informed consent appointments for genome sequencing: a multisite observational study.

PURPOSE: Little is known about how health-care professionals communicate with patients about consenting to genome sequencing. We therefore examined what topics health-care professionals covered and what questions patients asked during consent conversations. METHODS: Twenty-one genome sequencing consent appointments were audio recorded and analyzed. Participants were 35 individuals being invited to participate in the 100,000 Genomes Project (14 participants with rare diseases, 21 relatives), and 10 health-care professionals ("consenters"). RESULTS: Two-thirds of participants' questions were substantive (e.g., genetics and inheritance); one-third administrative (e.g., filling in the consent form). Consenters usually (19/21) emphasized participant choice about secondary findings, but less often (13/21) emphasized the uncertainty about associated disease risks. Consenters primarily used passive statements and closed-ended, rather than open-ended, questions to invite participants' questions and concerns. In two appointments, one parent expressed negative or uncertain views about secondary findings, but after discussion with the other parent opted to receive them. CONCLUSION: Health-care professionals need to be prepared to answer patients' questions about genetics to facilitate genome sequencing consent. Health-care professionals' education also needs to address how to effectively listen and elicit each patient's questions and views, and how to discuss uncertainty around the disease risks associated with secondary findings.

Factors influencing NCGENES research participants' requests for non-medically actionable secondary findings.

PURPOSE: Genomic sequencing can reveal variants with limited to no medical actionability. Previous research has assessed individuals' intentions to learn this information, but few report the decisions they made and why. METHODS: The North Carolina Clinical Genomic Evaluation by Next Generation Exome Sequencing (NCGENES) project evaluated adult patients randomized to learn up to six types of non-medically actionable secondary findings (NMASF). We previously found that most participants intended to request NMASF and intentions were strongly predicted by anticipated regret. Here we examine discrepancies between intentions and decisions to request NMASF, hypothesizing that anticipated regret would predict requests but that this association would be mediated by participants' intentions. RESULTS: Of the 76% who expressed intentions to learn results, only 42% made one or more requests. Overall, only 32% of the 155 eligible participants requested NMASF. Analyses support a plausible causal link between anticipated regret, intentions, and requests. CONCLUSIONS: The discordance between participants' expressed intentions and their actions provides insight into factors that influence patients' preferences for genomic information that has little to no actionability. These findings have implications for the timing and methods of eliciting preferences for NMASF and suggest that decisions to learn this information have cognitive and emotional components.

Secondary findings from clinical genomic sequencing: prevalence, patient perspectives, family history assessment, and health-care costs from a multisite study.

PURPOSE: Clinical sequencing emerging in health care may result in secondary findings (SFs). METHODS: Seventy-four of 6240 (1.2%) participants who underwent genome or exome sequencing through the Clinical Sequencing Exploratory Research (CSER) Consortium received one or more SFs from the original American College of Medical Genetics and Genomics (ACMG) recommended 56 gene-condition pair list; we assessed clinical and psychosocial actions. RESULTS: The overall adjusted prevalence of SFs in the ACMG 56 genes across the CSER consortium was 1.7%. Initially 32% of the family histories were positive, and post disclosure, this increased to 48%. The average cost of follow-up medical actions per finding up to a 1-year period was $128 (observed, range: $0-$678) and $421 (recommended, range: $141-$1114). Case reports revealed variability in the frequency of and follow-up on medical recommendations patients received associated with each SF gene-condition pair. Participants did not report adverse psychosocial impact associated with receiving SFs; this was corroborated by 18 participant (or parent) interviews. All interviewed participants shared findings with relatives and reported that relatives did not pursue additional testing or care. CONCLUSION: Our results suggest that disclosure of SFs shows little to no adverse impact on participants and adds only modestly to near-term health-care costs; additional studies are needed to confirm these findings.

What Genomic Sequencing Can Offer Universal Newborn Screening Programs.

Massively parallel sequencing, also known as next-generation sequencing, has the potential to significantly improve newborn screening programs in the United States and around the world. Compared to genetic tests whose use is well established, sequencing allows for the analysis of large amounts of DNA, providing more comprehensive and rapid results at a lower cost. It is already being used in limited ways by some public health newborn screening laboratories in the United States and other countries-and it is under study for broader and more widespread use, including as a core part of newborn screening programs. Sequencing technology has the potential to significantly improve these essential public health programs. For many of the conditions that newborns are already screened for, sequencing can return more specific and more sensitive results. The technology could also enable newborn screening programs to expand the list of rare pediatric conditions that they look for, thereby identifying more infants who can benefit from immediate care.

Families' Experiences with Newborn Screening: A Critical Source of Evidence.

Debates about expanding newborn screening with whole genome sequencing are fueled by data about public perception, public opinion, and the positions taken by public advocates and advocacy groups. One form of evidence that merits attention as we consider possible uses of whole-genome sequencing during the newborn period is parents' (and children's) diverse experiences with existing expanded screening protocols. What do we know about this experience base? And what implications might these data have for decisions about how we use whole genome sequencing and how we assess its impact in the future? Although the broader literature on genetic susceptibility testing suggests that testing usually does not have adverse effects on children's psychosocial well-being, certain newborn screening results have been demonstrated to cause distress, alter behavior, and even to influence the formation of new parental and family identities.

Sequencing Newborns: A Call for Nuanced Use of Genomic Technologies.

Many scientists and doctors hope that affordable genome sequencing will lead to more personalized medical care and improve public health in ways that will benefit children, families, and society more broadly. One hope in particular is that all newborns could be sequenced at birth, thereby setting the stage for a lifetime of medical care and self-directed preventive actions tailored to each child's genome. Indeed, commentators often suggest that universal genome sequencing is inevitable. Such optimism can come with the presumption that discussing the potential limits, cost, and downsides of widespread application of genomic technologies is pointless, excessively pessimistic, or overly cautious. We disagree. Given the pragmatic challenges associated with determining what sequencing data mean for the health of individuals, the economic costs associated with interpreting and acting on such data, and the psychosocial costs of predicting one's own or one's child's future life plans based on uncertain testing results, we think this hope and optimism deserve to be tempered. In the analysis that follows, we distinguish between two reasons for using sequencing: to diagnose individual infants who have been identified as sick and to screen populations of infants who appear to be healthy. We also distinguish among three contexts in which sequencing for either diagnosis or screening could be deployed: in clinical medicine, in public health programs, and as a direct-to-consumer service. Each of these contexts comes with different professional norms, policy considerations, and public expectations. Finally, we distinguish between two main types of genome sequencing: targeted sequencing, where only specific genes are sequenced or analyzed, and whole-exome or whole-genome sequencing, where all the DNA or all the coding segments of all genes are sequenced and analyzed. In a symptomatic newborn, targeted or genome-wide sequencing can help guide other tests for diagnosis or for specific treatment that is urgently needed. Clinicians use the infant's symptoms (or phenotype) to interrogate the sequencing data. These same complexities and uncertainties, however, limit the usefulness of genome-wide sequencing as a population screening tool. While we recognize considerable benefit in using targeted sequencing to screen for or detect specific conditions that meet the criteria for inclusion in newborn screening panels, use of genome-wide sequencing as a sole screening tool for newborns is at best premature. We conclude that sequencing technology can be beneficially used in newborns when that use is nuanced and attentive to context.