CommentaryHealth Policy

Whole-Genome Sequencing in Newborn Screening Programs

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Science Translational Medicine  26 Mar 2014:
Vol. 6, Issue 229, pp. 229cm2
DOI: 10.1126/scitranslmed.3008494

Abstract

The availability of whole-genome sequencing (WGS) is likely to change the practice of population screening programs such as newborn screening (NBS). This Commentary raises key ethical, legal, and social issues surrounding WGS in NBS and suggests a need for deliberation regarding the policy challenges of introducing sequencing in such programs. Any change in the goals of NBS programs should be discussed carefully and should represent the best interests of the child.

“We expect that, over the next decade, there will be calls to integrate genotyping within existing neonatal screening programmes to facilitate personalised screening for common cancers and many other chronic conditions” (1).

PROFILING THE NEWBORN

Pediatric research and clinical care have long been guided by the best interests of the child. The goal of newborn screening (NBS) programs has been to screen the asymptomatic newborn population for a number of severe, rare conditions that could be treated early and in a timely fashion. NBS programs have been hailed by the Centers for Disease Control and Prevention as one of the 10 most important public health achievements (2). They have saved thousands of lives, and their success has prompted more than 64 countries to provide newborn screening (3). These programs are usually state-mandated and, unlike many genetic tests, are conducted without explicit consent (4) because they are in the best interests of the child.

Whole-genome sequencing (WGS) may one day reduce both the cost and the time required to sequence an entire human genome and therefore increase its potential use in pediatric care. The use of WGS is growing and may soon be on the verge of entering NBS programs. In October 2013, the U.S. National Institutes of Health (NIH) funded four studies to the tune of $25 million to study the medical and ethical implications of sequencing the exomes or whole genomes of newborns at birth (5, 6). Some predict that once WGS technologies are sufficiently robust and affordable, all newborns may have their genomes sequenced at birth (7). They argue that if adopted, WGS will likely change the current delivery of NBS programs by facilitating more accurate diagnosis (8), allowing for the detection of more conditions, managing disorders with a strong heritable component (9), revealing pharmacogenetics information (10), and so improving person-centered care.

However, the possible integration of WGS as part of a routine NBS program raises new challenges and controversies. There are potential psychosocial harms and legal consequences associated with both the primary and “incidental” findings revealed by whole-genome sequencing. Incidental findings can be defined as results outside of the original objectives of the genomic screen. We must tread carefully in interpreting the scientific validity, clinical utility, and medical actionability of WGS results, as well as whether and when to disclose and how to manage them over time if introduced for all newborns (11).

Despite emerging controversies about WGS in NBS programs, there is limited guidance to direct appropriate use. In fact, only the UK’s Human Genetics Commission issued a report in 2005 entitled “Profiling the Newborn” (12). It rejected the introduction of such screening at birth owing to costs and insufficient benefits to health and viewed it as too futuristic. It also cautioned that newborn profiling raises important social, legal, and ethical issues. Perhaps, 7 years later, the time is ripe for further discussion (13).

KICKSTARTING THE CONVERSATION

Even in the absence of a specific discussion on WGS in NBS, some professional societies are beginning to recognize that new technologies, including those for genetic testing and screening, require that their positions be updated to consider the associated ethical issues (14, 15). In this regard, the American College of Medical Genetics and Genomics (ACMG) and the American Academy of Pediatrics determined in 2013 that decisions about whether to offer genetic testing and screening “should be driven by the best interest of the child” (14, 16). As concerns the nature of pediatric genetic testing in general, both professional bodies reiterated the current professional recommendation to defer genetic testing for late-onset conditions until adulthood (14). The ACMG did not recommend genome and exome sequencing before the legal age of majority, except for phenotype-driven clinical diagnostic uses, circumstances in which early monitoring or interventions are available and effective, or institutional review board–approved research (17). ACMG further stated that WGS should not be used as a “first-tier approach for newborn screening” (16). The European Society of Human Genetics (ESHG) also stated that the challenge will be to avoid the broad scope of WGS unless based on a rigorous evaluation of clinical utility and other screening criteria (18). Similarly, the Foundation for Genomics and Population Health (PHG Foundation) does “not support the systematic genotyping of newborns or young children as a preliminary to risk assessment” (19).

In order to develop best practices in implementing WGS, stakeholders from relevant fields in research and the clinic should set up structures for sharing experiences and establishing testing guidelines. The recent 2013 ACMG recommendations specify that laboratories performing clinical sequencing report mutations in a panel of 56 condition genes, irrespective of age (20). In contrast, the ESHG has cautioned generally that in the case of testing minors, guidelines need to be established to balance the autonomy and interests of the child with parental rights and needs as well as with possible familial interests (18). Although there is a paucity of guidance specific to the context of WGS in NBS programs, there is an urgent need for discussion and some level of international professional and public consensus.

Any discussion on the use of WGS in NBS programs should also take into account recent recommendations on the use of WGS in pediatric research. The Public Population Project in Genomics and Society (P3G), an international consortium, suggested that the possible return (or not) of WGS results in pediatric research should be discussed during the informed-consent process. Any WGS results that are “scientifically valid, clinically useful, and reveal conditions that are preventable and actionable during childhood” should be offered to the parents (21). However, mutations that predispose the child to develop an adult-onset disorder generally should not be returned. On a case-by-case basis, an exception could be made if the child would benefit, on balance, from disclosure because of the potential benefit to the family from knowing about a highly penetrant gene that poses serious risk to health and that is preventable or treatable in family members.

Most importantly, the use of WGS implies revealing the present and future genetic “report card” of all children at birth, even though most of the information acquired will only become relevant later in life. Revealing this information may undermine the right of children to decide for themselves once mature enough to do so. At the same time, the results could also reveal immediately actionable implications (prevention or treatment) for them and for their siblings. Moreover, the use of WGS as part of a population screening program (for the management of public health) would require a different evidence threshold for clinical validity and utility than that used in a diagnostic setting (18). We sum up the questions and considerations for WGS in NBS in Fig. 1.

Fig. 1. Questions and considerations for WGS.

From data management to shaking up the health care system to education, WGS in NBS programs should be discussed carefully and thoroughly.

CREDIT: kupicoo/iStockphoto

What information to report? The application of WGS in NBS could create an unlimited expansion of the amount of health information and nonmedical information to be found for a newborn, ranging from single-gene to multiple-gene disorders; from preventable and treatable to nonpreventable and nontreatable conditions; from childhood-onset to adult-onset conditions; as well as pharmacogenomic, treatment, or carrier status information (22). Currently, genetic testing in minors is only recommended when established and effective medical treatment can be offered (23). Careful consideration is given to the future autonomy of the child once an adult, as well as to the transfer of information about the test and the test results, the confidentiality of genetic information, the voluntariness of the request, the responsibility toward biological relatives, and the psychological impact of a test (24). Any introduction of WGS into NBS would require rethinking the rights of parents to access such information, the best interests of children, the right to know or not to know, privacy rights, the clinical utility of retrieved information, the type of consent, the duty to recontact and to follow of health care professionals, and the associated counseling issues and their associated costs to the health care system.

Even if NBS programs would create a WGS panel with a specified number of conditions to be reported, we have already raised the issue of clinically significant, incidental findings. What to do with carrier status, for instance? Today, screening programs already generate carrier status results that may or may not be revealed. The WGS expansion of NBS programs would also lead to the inadvertent identification of carrier status for a greater number of conditions. Being a carrier has implications for future reproductive choices, but this information is not beneficial to the health of an individual. Contradictory policies and practices with regard to the disclosure of carrier status have existed in both the clinical genetics context and the NBS context, and this will affect the resolution of the communication of findings in WGS-NBS.

Other types of incidental findings could include genealogical information, nonpaternity, consanguinity, disease susceptibility (a continuum between slightly increased or decreased risk to highly predictive), reproductive risks, or pharmacogenomic information. Thus, one central question is the extent to which WGS may change existing paradigms of research, testing, and care. Targeted or staged approaches to WGS could filter the number of findings. In contrast, broader approaches might provide more information but also more incidental findings.

One possible solution is to perfom WGS but to have a list of pediatric conditions to be communicated. Other WGS-NBS results would be retrieved for later disclosure: either when they gain scientific validity and clinical utility and when parents have had more time to consider the consequences or when the results can be reported to the “mature” child directly. This, however, would place the family physician or pediatrician as the keeper of the timing of release and responsible for the currency of its interpretation.

Impact on health care systems. If WGS in NBS is implemented, the public health care system would have to be revamped to handle the massive amount of information generated. Although the new data could improve personalized, preventive, and therapeutic strategies, WGS-NBS may lead to an increase in false-positive results, depending on the panels performed and the integration of variants of unclear clinical significance. This information could impose an incredible burden both on families and on the resources of a health care system (25).

For a health care system and its citizens to truly “benefit” from such data, a WGS-NBS program would need the state to foresee targeted interventions that address the needs of new “at-risk” subpopulations. These targeted interventions would no longer follow populations via the usual age, demographic, or gender classifications but rather be identified by polygenic clustering of at-risk subpopulations. Owing to the overwhelming amount of genomic and clinical data from WGS, it could be argued that the sustainability of universal health care will depend on the systemic ability to use WGS-NBS for such targeting. The ensuing greater need for physicians, nurses, and counselors and for tracking systems to facilitate regrouping into medically actionable subpopulations might result in the implosion of NBS programs. To cover these additional resources, the state must evaluate how much NBS programs are worth. Furthermore, the state must consider providing coverage for attendant health care needs.

Screening newborns.

Knowing a newborn’s genetic mutations can help with treatment options and family-planning, but the ethical, legal, and practical issues need to be addressed.

CREDIT: ArtisticCaptures/iStockphoto

Mandatory versus voluntary. The public health motivation for NBS has long held sway. Current “classical” NBS programs are still considered to be for the child’s benefit, and, more recently, additional aims such as familial benefit have been added by reporting information that could be useful for reproductive decision-making. Currently, NBS is either mandated by law or uses presumed parental consent. NBS is part of the professional, pediatric standard of care. Expanding NBS to include WGS would lend more weight to parental objections, considering that the autonomy rights of individuals (children, parents, and family members) include the right not to know (26). It could also be argued that such an expansion would not be in the best interests or for the immediate benefit of the child. It is possible that many parents would choose to forgo screening altogether. Parents need first to be informed so as to understand the difference between “classical” and WGS screening. Perhaps, mandatory screening with a targeted list can remain in place for disorders of which genomic knowledge could directly benefit the infant during childhood. Parental consent would then be required for disorders for which the direct-benefit standard is not met (13).

Health professionals and parents. Many clinicians have received little training in genetics and lack experience and confidence providing genetic information to parents (22, 27). For this reason, there is a need to develop the genetic/genomic education of health professionals and parents (Fig. 1). Public involvement helps to address difficult situations requiring ethical and social debate; more importantly, it promotes public trust in health care programs, such as WGS-NBS. Thus, there is an increased need to communicate clearly with the parents about newborn screening, available tests, the potential consequences, and the choices they face. Parents are interested in WGS for their newborn, whether as part of NBS or in their pediatrician’s office, and they may be onboard with a state-run public health program offering WGS for newborns, according to recent studies (28). One study, however, showed that the public’s willingness to participate in NBS was reduced for untargeted WGS as compared with targeted WGS. Thus, “NBS in an untargeted fashion might reduce public participation” (29).

Communication of results over time. The validity of the tests as well as the communication and understanding of results over time pose numerous challenges. It is here that the programmatic aspects of NBS are advantageous for “at-risk” children—in other words, screening an asymptomatic population for at-risk individuals. Although currently the number of conditions screened for varies by country, if there was ongoing interpretation and care and follow-up of the health of children via a state-run WGS-NBS program, this could remove associated possible psychosocial burdens (29).

In 2013, the communication of WGS results issue became the major ethical and legal issue in genomics and genetic research and testing. But the communication of WGS pediatric findings has not received the same attention (30). They would challenge the hard-won tenet of not testing children for late-onset diseases. Moreover, as mentioned, the return of NBS-WGS results would affect all family members. It may well be the physician who will be the arbiter of communication to all concerned, although the legal implications of this open-ended responsibility are troublesome (31).

Treatment and follow-up. When treatment or prevention becomes available, an NBS health report card would be invaluable on an individual basis, especially for single-gene disorders. Across the population, it would allow comparison of the effect on individuals of different environments and family history over time. It could be argued that traditional single-gene NBS programmes should be left alone and that WGS should only become part of the standard care as a diagnostic tool (as costs decrease), when necessary for each individual rather than being part of a population-wide state-run program at birth. There are indications that WGS is already being used as a diagnostic tool for newborns presenting with unknown etiologies (8).

Validated variants. An important challenge in WGS-NBS is the ability to offer a standardized and accurate interpretation of the variants. A matter of ongoing debate is (i) the lack of maturity of the variant databases, with many variants in the genome being uninterpretable; (ii) the different inheritance patterns of genes and/or different phenotypes and/or different age of onset; (iii) variable penetrance; and (iv) gene–environment issues (32).

Storage of data. Should the raw data obtained through WGS be stored in the patient file, and if so, under what conditions and for how long? Some have argued that it could be stored in the patient file for future use (23). This assumes the costs of storing data do not outweigh the costs of sequencing anew and that newer sequencing technologies will not be more sensitive than current techniques. This storage issue also raises questions as to access and future biomedical research and public health surveillance—for example, to understand the role of the environment in disease pathophysiology. The introduction of WGS into NBS programs including the storage of WGS data would in effect create newborn “biobanks” (33).

Insurability. In WGS-NBS, the “data” obtained will be part of the medical record. Because insurance companies often ask for access to the medical record, this could lead to issues regarding life and disability insurability (or in some countries, health insurance) and potentially affect employability. Access to one’s whole genotype could also lead to adverse selection of life and health insurance by the applicants themselves (24). In other words, the individual could argue that certain risks will not appear or can be prevented or treated, arguing for lower premiums or better employment conditions (23).

POLICY POSITIONS

In 2010, Francis Collins stated, “as we learn more about effective interventions for genetic risk factors, and recognize that interventions early in life provide significant advantages, it will become more and more compelling to determine this information at birth” (34). Despite such optimism, in the absence of clear policy direction and public discussion on the possible future integration (or not) of WGS into NBS, parents may one day privately avail themselves of WGS for their newborns through the use of online direct-to-consumer testing. Hence, there is a need for medical and public education via training programs and for strong liaisons between medical schools, various professional associations, and consumer groups in order to understand the limits of WGS.

In short, when addressing WGS and newborn screening, it is important to consider not only the therapeutic and prevention benefits for the child but also the associated ethical, legal, and practical issues (11). Were NBS programs to incrementally expand their screening panels to introduce WGS, the reception may be discordant, disorganized, and disruptive. The policies of NBS should be discussed prospectively and carefully. To that end, we have seen that the NIH has directed funds to studies on this issue (6). It is also heartening that the Pediatric Platform of the P3G (www.p3g.org/p3g-international-paediatric-research-programme), the Ethics Committee of the Human Genome Organization (www.hugo-international.org/comm_hugoethicscommittee.php), and the Professional and Public Policy Committee of the ESHG (www.eshg.org/pppc.0.html) have decided to jointly begin to specifically address the issue of the use of WGS in NBS in 2014.

REFERENCES AND NOTES

  1. Acknowledgments: : The authors thank M. Hétu and S. Shuang for their editorial assistance.
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