Lainie Friedman Ross

Recommendations for Returning Genomic Incidental Findings? We Need to Talk!

The American College of Medical Genetics and Genomics recently issued recommendations for reporting incidental findings from clinical whole-genome sequencing and whole-exome sequencing. The recommendations call for evaluating a specific set of genes as part of all whole-genome sequencing/whole-exome sequencing and reporting all pathogenic variants irrespective of patient age. The genes are associated with highly penetrant disorders for which treatment or prevention is available. The effort to generate a list of genes with actionable findings is commendable, but the recommendations raise several concerns. They constitute a call for opportunistic screening, through intentional effort to identify pathogenic variants in specified genes unrelated to the clinical concern that prompted testing. Yet for most of the genes, we lack evidence about the predictive value of testing, genotype penetrance, spectrum of phenotypes, and efficacy of interventions in unselected populations. Furthermore, the recommendations do not allow patients to decline the additional findings, a position inconsistent with established norms. Finally, the recommendation to return adult-onset disease findings when children are tested is inconsistent with current professional consensus, including other policy statements of the American College of Medical Genetics and Genomics. Instead of premature practice recommendations, we call for robust dialogue among stakeholders to define a pathway to normatively sound, evidence-based guidelines.Genet Med 15 11, 854–859.Genetics in Medicine (2013); 15 11, 854–859. doi:10.1038/gim.2013.113

Newborn screening technology: proceed with caution.

The American College of Medical Genetics (ACMG) recommends a significant expansion in the number of conditions targeted by newborn screening (NBS) programs.1 In this commentary we advocate a more cautious approach. NBS dates to the early 1960s, when the technology developed to conduct large-scale testing on dried blood spots for phenylketonuria (PKU).2 PKU remains the paradigm condition for NBS because of features of the disease and its treatment, which are particularly advantageous to population screening. It is a condition that silently causes neurologic devastation but is amenable to early detection and effective prevention with a diet of moderate burden and complexity.3 Many children affected with PKU and their families have benefited from state screening programs over the past 4 decades because of collaboration between health departments, families, primary care providers, and metabolic specialists. However, PKU screening is not an unmitigated success.4,5 There was initial uncertainty about whether children with variant forms of hyperphenylalaninemia required treatment and about whether affected children require life-long dietary management.6 Indeed, some children with benign conditions were seriously harmed from unnecessary restrictions in their diets.5 In addition, long-term studies demonstrate decrements in cognitive function for affected children and adolescents who are not fully adherent to the diet,7,8 yet adherence to the diet is challenging because of its poor palatability, high cost, and limits on insurance coverage in many policies. Affected women who are off the diet are at high risk of bearing severely neurologically impaired children.9 Only recently have many programs begun tracking affected women to enable notification, education, and management. These difficulties by no means negate the value of NBS for PKU, but they highlight the problems with the successful implementation of a population-based screening program even when a model condition is targeted. … Address correspondence to Jeffrey R. Botkin, MD, MPH, Research Administration Building, 75 South 2000 East #108, Salt Lake City, UT 84112-8930. E-mail: jeffrey.botkin{at}hsc.utah.edu

The challenges of collaboration for academic and community partners in a research partnership: Points to consider

The philosophical underpinning of Community-Engaged Research (CEnR) entails a collaborative partnership between academic researchers and the community. The Community-Based Participatory Research (CBPR) model is the partnership model most widely discussed in the CEnR literature and is the primary model we draw upon in this discussion of the collaboration between academic researchers and the community. In CPBR, the goal is for community partners to have equal authority and responsibility with the academic research team, and that the partners engage in respectful negotiation both before the research begins and throughout the research process to ensure that the concerns, interests, and needs of each party are addressed. The negotiation of a fair, successful, and enduring partnership requires transparency and understanding of the different assets, skills and expertise that each party brings to the project. Delineating the expectations of both parties and documenting the terms of agreement in a memorandum of understanding or similar document may be very useful. This document is structured to provide a “points- to-consider” roadmap for academic and community research partners to establish and maintain a research partnership at each stage of the research process.

Ethical issues in increasing living kidney donations by expanding kidney paired exchange programs.

INTRODUCTION In 1997, Ross et al. proposed to increase the supply of living kidney donations by using kidneys from living ABO-incompatible donors through an exchange arrangement between two living kidney donor-recipient pairs. Although many transplant centers are exploring this option, only a small fraction of potential donor-recipient pairs are eligible for an exchange on the basis of ABO incompatibility. In this article, we explore three variations that have potentially great clinical relevance. METHODS The three potential variations discussed are: (1) altruistically unbalanced living donor-recipient exchanges; (2) an indirect exchange (an exchange between a living donor-recipient pair with a cadaveric donor-recipient pair) on the basis of a positive crossmatch; and (3) an indirect exchange on the basis of ABO incompatibility. DISCUSSION The goal of kidney paired exchange programs is to increase the supply of kidneys available for transplantation ethically. We acknowledge that all exchanges increase the potential for coercion, and we currently reject the proposal of altruistically unbalanced exchanges because of the potential for coercion. However, we believe that voluntary consent can be achieved for indirect exchanges. The indirect ABO-compatible exchange creates no new ethical concerns to our original living paired exchange program and we support its implementation. The indirect ABO-incompatible exchange does create a new ethical concern because it may increase the vulnerability of O blood group recipients. If mechanisms can be developed to avoid increasing the waiting time for blood group O recipients, we would support the implementation of the indirect ABO-incompatible exchange.

Primum non nocere: avoiding harm to vulnerable wait list candidates in an indirect kidney exchange.

Background. One proposal to increase kidney transplantation is to exchange kidneys between pairs of ABO-incompatible (or cross-match–incompatible) living donors and their recipients. One variation that has greater potential exchanges living donor kidneys for cadaveric donor kidneys (indirect exchanges). A primary concern with indirect exchanges is the potential to disadvantage blood group O wait list candidates. Using wait list modeling, we examine whether this proposal would disadvantage cadaveric kidney blood group O wait list candidates, and present an approach for neutralizing these negative effects. Methods. A probability model estimated the total number and blood type frequencies of donor-recipient pairs that would participate in indirect exchanges. A supply-to-demand model for the cadaveric kidney wait list estimated the mean wait time under different allocation policies and donor selection mechanisms for candidates on the wait list classified according to the candidates’ race and blood type. Results. Indirect exchanges will reduce the mean wait time for cadaveric kidney wait list candidates. The mean wait time of blood group O cadaveric kidney wait list candidates increases when the participating living donors self-select and when kidney allocation is determined by efficiency. This is neutralized when the transplant team preferentially selects blood group O living donors and cadaveric kidney allocation is determined by need. Conclusion. Indirect exchange programs will significantly shorten the wait times for cadaveric kidney wait list candidates. The wait times of blood group O candidates will not be affected adversely if blood group O living donors are selected preferentially and if allocation is based on need.

Parental attitudes regarding newborn screening of PKU and DMD

The ability to perform predictive genetic testing of children raises ethical concerns. Current guidelines support the screening of newborns for conditions in which early treatment reduces morbidity and mortality, and oppose most other predictive genetic screening and testing in childhood. Little is known, however, about parental attitudes. We conducted focus groups to gain information on the attitudes, beliefs, and concerns of parents about newborn screening and testing for both treatable and untreatable conditions that present in childhood. Respondents across racial groups support mandatory newborn screening for treatable conditions like phenylketonuria (PKU), citing lack of parental knowledge, and concerns about immature parental decision‐makers. Parents do, however, want more information. Citing a variety of psychosocial concerns, respondents believe that parents should have access to predictive genetic testing for childhood onset conditions, even when there are no proven treatments. Respondents want this information to make reproductive and non‐reproductive plans and decisions. Although respondents varied in their personal interest in testing, overwhelmingly they believed that the decisions belong to the parents. Professional guidelines that proscribe predictive testing for untreatable childhood onset conditions should be re‐examined in light of consumer attitudes.

Population screening for genetic disorders in the 21st century: evidence, economics, and ethics.

Background: Proposals for population screening for genetic diseases require careful scrutiny by decision makers because of the potential for harms and the need to demonstrate benefits commensurate with the opportunity cost of resources expended. Methods: We review current evidence-based processes used in the United States, the United Kingdom, and the Netherlands to assess genetic screening programs, including newborn screening programs, carrier screening, and organized cascade testing of relatives of patients with genetic syndromes. In particular, we address critical evidentiary, economic, and ethical issues that arise in the appraisal of screening tests offered to the population. Specific case studies include newborn screening for congenital adrenal hyperplasia and cystic fibrosis and adult screening for hereditary hemochromatosis. Results: Organizations and countries often reach different conclusions about the suitability of screening tests for implementation on a population basis. Deciding when and how to introduce pilot screening programs is challenging. In certain cases, e.g., hereditary hemochromatosis, a consensus does not support general screening although cascade screening may be cost-effective. Conclusion: Genetic screening policies have often been determined by technological capability, advocacy, and medical opinion rather than through a rigorous evidence-based review process. Decision making should take into account principles of ethics and opportunity costs.

Human Subjects Protections in Community-Engaged Research: A Research Ethics Framework

In the 30 years since the belmont Report, the role of the community in research has evolved and has taken on greater moral significance. Today, more and more translational research is being performed with the active engagement of individuals and communities rather than merely upon them. This engagement requires a critical examination of the range of risks that may arise when communities become partners in research. In attempting to provide such an examination, one must distinguish between established communities (groups that have their own organizational structure and leadership and exist regardless of the research) and unstructured groups (groups that may exist because of a shared trait but do not have defined leadership or internal cohesiveness). In order to participate in research as a community, unstructured groups must develop structure either by external means (by partnering with a Community-Based Organization) or by internal means (by empowering the group to organize and establish structure and leadership). When groups participate in research, one must consider risks to well-being due to process and outcomes. These risks may occur to the individual qua individual, but there are also risks that occur to the individual qua member of a group and also risks that occur to the group qua group. There are also risks to agency, both to the individual and the group. A 3-by-3 grid including 3 categories of risks (risks to well-being secondary to process, risks to well-being secondary to outcome and risks to agency) must be evaluated against the 3 distinct agents: Individuals as individual participants, individuals as members of a group (both as participants and as nonparticipants) and to communities as a whole. This new framework for exploring the risks in community-engaged research can help academic researchers and community partners ensure the mutual respect that community-engaged research requires.

From Genetics to Genomics: Ethics, Policy, and Parental Decision-making

OBJECTIVE Ethical evaluation of genetic testing in children is traditionally based on balancing clinical benefits and risks. However, this focus can be inconsistent with the general practice of respecting parental decision-making about their childrens health care. We argue that respect for parental decision-making should play a larger role in shaping pediatric genetic testing practices, and play a similar role regarding decisions to use emerging genomic technologies. METHODS Genomic testing involves the examination of thousands of DNA markers spanning genes throughout the genome and their interrelationships, yielding virtually limitless interpretations. We presume that parents and providers should proceed cautiously in applying genomic testing in children, as we explore how genomic testing will stress the fault lines of the traditional ethical analysis. RESULTS Empirical data about the psychosocial risks and benefits of genetic testing of children do not reveal serious harms, yet virtually no such data exist yet about genomic testing. Unless empirical social and behavioral data indicate that genomic testing is highly likely to cause serious harms to the children, parental decisions to obtain comprehensive genomic testing in their children should be respected. Once comprehensive genomic testing of children becomes routine, resultant information may be more easily integrated by families than anticipated. CONCLUSIONS Research on the social and behavioral impact of comprehensive genomic testing on children and their families is needed to further inform parents, clinicians, and policy makers.

Mandatory Extended Searches in All Genome Sequencing: “Incidental Findings,” Patient Autonomy, and Shared Decision Making

Should incidental findings discovered with whole-genome sequencing or testing be sought and reported to ordering clinicians and to patients (or their surrogates)? — NO.