H E A LT H P O L I C Y
Whole-Genome Sequencing in Newborn Screening Programs Bartha M. Knoppers,1* Karine Sénécal,1 Pascal Borry,2 Denise Avard1 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. Te 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). Tey have saved thousands of lives, and their success has prompted more than 64 countries to provide newborn screening (3). Tese 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. Te 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 suffciently robust and afordable, all newborns may have their genomes sequenced at birth (7). Tey 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. Tere are potential psychosocial harms and legal consequences associated with both the primary and “incidental” fndings revealed by wholegenome sequencing. Incidental fndings can be defned as results outside of the original objectives of the genomic screen. We must tread carefully in interpreting the scientifc 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 “Profling the Newborn” (12). It rejected the introduction of such screening at birth owing to costs and insufcient benefts to health and viewed it as too futuristic. It also cautioned that newborn profling raises important social, legal, and ethical issues. Perhaps, 7 years later, the time is ripe for further discussion (13).
1
Department of Human Genetics, McGill University, Montreal, Quebec H3A OG1, Canada. 2Department of Public Health and Primary Care, University of Leuven, Leuven, 3000 Leuven, Belgium. *Corresponding author. E-mail: bartha.knoppers@ mcgill.ca
KICKSTARTING THE CONVERSATION Even in the absence of a specifc 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 ofer 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 lateonset conditions until adulthood (14). Te 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 efective, or institutional review board–approved research (17). ACMG further stated that WGS should not be used as a “frst-tier approach for newborn screening” (16). Te 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 felds in research and the clinic should set up structures for sharing experiences and establishing testing guidelines. Te 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 specifc 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. Te Public Population Project in Genomics and Society (P3G), an international consortium, suggested that
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the possible return (or not) Tus, one central question is of WGS results in pediatric the extent to which WGS may research should be discussed change existing paradigms during the informed-consent of research, testing, and care. process. Any WGS results that Targeted or staged approaches are “scientifcally valid, clinito WGS could flter the numcally useful, and reveal condiber of fndings. In contrast, tions that are preventable and broader approaches might actionable during childhood” provide more information but should be ofered to the paralso more incidental fndings. ents (21). However, mutations One possible solution is to that predispose the child to perfom WGS but to have a list develop an adult-onset disorof pediatric conditions to be der generally should not be communicated. Other WGSreturned. On a case-by-case Fig. 1. Questions and considerations for WGS. From data management NBS results would be rebasis, an exception could be to shaking up the health care system to education, WGS in NBS programs trieved for later disclosure: eimade if the child would ben- should be discussed carefully and thoroughly. ther when they gain scientifc eft, on balance, from disclovalidity and clinical utility and sure because of the potential when parents have had more beneft to the family from knowing about a test and the test results, the confdentiality time to consider the consequences or when highly penetrant gene that poses serious risk of genetic information, the voluntariness the results can be reported to the “mature” to health and that is preventable or treatable of the request, the responsibility toward child directly. Tis, however, would place the in family members. biological relatives, and the psychological family physician or pediatrician as the keepMost importantly, the use of WGS im- impact of a test (24). Any introduction of er of the timing of release and responsible for plies revealing the present and future ge- WGS into NBS would require rethinking the currency of its interpretation. netic “report card” of all children at birth, the rights of parents to access such informaImpact on health care systems. If even though most of the information ac- tion, the best interests of children, the right WGS in NBS is implemented, the public quired will only become relevant later in to know or not to know, privacy rights, the health care system would have to be relife. Revealing this information may un- clinical utility of retrieved information, the vamped to handle the massive amount of dermine the right of children to decide for type of consent, the duty to recontact and to information generated. Although the new themselves once mature enough to do so. follow of health care professionals, and the data could improve personalized, prevenAt the same time, the results could also re- associated counseling issues and their asso- tive, and therapeutic strategies, WGS-NBS veal immediately actionable implications ciated costs to the health care system. may lead to an increase in false-positive (prevention or treatment) for them and for Even if NBS programs would create results, depending on the panels performed their siblings. Moreover, the use of WGS as a WGS panel with a specifed number of and the integration of variants of unclear part of a population screening program (for conditions to be reported, we have already clinical signifcance. Tis information could the management of public health) would raised the issue of clinically signifcant, in- impose an incredible burden both on famirequire a diferent evidence threshold for cidental fndings. What to do with carrier lies and on the resources of a health care clinical validity and utility than that used status, for instance? Today, screening pro- system (25). in a diagnostic setting (18). We sum up the grams already generate carrier status results For a health care system and its citiquestions and considerations for WGS in that may or may not be revealed. Te WGS zens to truly “beneft” from such data, a NBS in Fig. 1. expansion of NBS programs would also lead WGS-NBS program would need the state What information to report? Te to the inadvertent identifcation of carrier to foresee targeted interventions that adapplication of WGS in NBS could create status for a greater number of conditions. dress the needs of new “at-risk” subpopulaan unlimited expansion of the amount of Being a carrier has implications for future tions. Tese targeted interventions would health information and nonmedical infor- reproductive choices, but this information no longer follow populations via the usual mation to be found for a newborn, ranging is not benefcial to the health of an indi- age, demographic, or gender classifcations from single-gene to multiple-gene disor- vidual. Contradictory policies and practices but rather be identifed by polygenic clusders; from preventable and treatable to non- with regard to the disclosure of carrier sta- tering of at-risk subpopulations. Owing to preventable and nontreatable conditions; tus have existed in both the clinical genetics the overwhelming amount of genomic and from childhood-onset to adult-onset con- context and the NBS context, and this will clinical data from WGS, it could be argued ditions; as well as pharmacogenomic, treat- afect the resolution of the communication that the sustainability of universal health ment, or carrier status information (22). of fndings in WGS-NBS. care will depend on the systemic ability to Currently, genetic testing in minors is only Other types of incidental fndings could use WGS-NBS for such targeting. Te enrecommended when established and efec- include genealogical information, nonpater- suing greater need for physicians, nurses, tive medical treatment can be ofered (23). nity, consanguinity, disease susceptibility (a and counselors and for tracking systems Careful consideration is given to the future continuum between slightly increased or de- to facilitate regrouping into medically acautonomy of the child once an adult, as well creased risk to highly predictive), reproduc- tionable subpopulations might result in the as to the transfer of information about the tive risks, or pharmacogenomic information. implosion of NBS programs. To cover these www.ScienceTranslationalMedicine.org 26 March 2014 Vol 6 Issue 229 229cm2
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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.
additional resources, the state must evaluate how much NBS programs are worth. Furthermore, the state must consider providing coverage for attendant health care needs. Mandatory versus voluntary. Te public health motivation for NBS has long held sway. Current “classical” NBS programs are still considered to be for the child’s beneft, and, more recently, additional aims such as familial beneft 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 beneft of the child. It is possible that many parents would choose to forgo screening altogether. Parents need frst to be informed so as to understand the diference between “classical” and WGS screening. Perhaps, mandatory screening with a targeted list can remain in place for disorders of which genomic knowledge could directly beneft the infant during childhood. Parental consent would then be required for disorders for which the direct-beneft standard is not met (13). Health professionals and parents. Many clinicians have received little training in genetics and lack experience and conf-
dence 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 difcult situations requiring ethical and social debate; more importantly, it promotes public trust in health care programs, such as WGS-NBS. Tus, 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 ofce, and they may be onboard with a state-run public health program ofering 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. Tus, “NBS in an untargeted fashion might reduce public participation” (29). Communication of results over time. Te 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 fndings has not received the same attention (30). Tey would challenge the hard-won tenet of not testing children for late-onset diseases. Moreover, as mentioned, the return of NBS-WGS results would afect 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 singlegene disorders. Across the population, it would allow comparison of the efect on individuals of diferent environments and family history over time. It could be argued that
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traditional single-gene NBS programmes should be lef 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. Tere 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 ofer 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 diferent inheritance patterns of genes and/or diferent phenotypes and/or diferent 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 fle, and if so, under what conditions and for how long? Some have argued that it could be stored in the patient fle for future use (23). Tis 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. Tis 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. Te introduction of WGS into NBS programs including the storage of WGS data would in efect create newborn “biobanks” (33). Insurability. In WGS-NBS, the “data” obtained will be part of the medical record. Because insurance companies ofen 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 afect 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 efective interventions for genetic risk factors, and recognize that interventions early in life provide signifcant advantages, it will become more and more
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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 benefts 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. Te 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-internationalpaediatric-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 specifcally address the issue of the use of WGS in NBS in 2014.
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21. B. M. Knoppers, D. Avard, K. Sénécal, M. Zawati, P3G International Paediatrics Platform, Return of wholegenome sequencing results in paediatric research: A statement of the P3G international paediatrics platform. Eur. J. Hum. Genet. 176, 1–3 (2013). 22. C. H. Wade, B. A. Tarini, B. S. Wilfond, Growing up in the genomic era: Implications of whole-genome sequencing for children, families, and pediatric practice. Annu. Rev. Genomics Hum. Genet. 14, 535–555 (2013). 23. W. J. Dondorp, G. M. de Wert, The ‘thousand-dollar genome’: An ethical exploration. Eur. J. Hum. Genet. 21, (Suppl 1), S6–S26 (2013). 24. M. Cornel, T. Rigter, S. Weinreich, P. Burgard, G. Hoffmann, M. Lindner, G. Loeber, K. Rupp, D. Taruscio, L. Vittozzi, Newborn screening in Europe: Expert opinion document. Eur. J. Hum. Genet. 22, 12–17 (2014). 25. T. Caulfield, J. Evans, A. McGuire, C. McCabe, T. Bubela, R. Cook-Deegan, J. Fishman, S. Hogarth, F. A. Miller, V. Ravitsky, B. Biesecker, P. Borry, M. K. Cho, J. C. Carroll, H. Etchegary, Y. Joly, K. Kato, S. S. Lee, K. Rothenberg, P. Sankar, M. J. Szego, P. Ossorio, D. Pullman, F. Rousseau, W. J. Ungar, B. Wilson, Reflections on the cost of “low-cost” whole genome sequencing: Framing the health policy debate. PLOS Biol. 11, e1001699 (2013). 26. United Nations Educational, Scientific and Cultural Organization, Universal Declaration on the Human Genome and Human Rights (1997); http://portal.unesco.org/en/ ev.php-URL_ID=13177&URL_DO=DO_TOPIC&URL_ SECTION=201.html. 27. S. Suther, P. Goodson, Barriers to the provision of genetic services by primary care physicians: A systematic review of the literature. Genet. Med. 5, 70–76 (2003). 28. A. J. Goldenberg, D. S. Dodson, M. M. Davis, B. A. Tarini, Parents’ interest in whole-genome sequencing of newborns. Genet. Med. 16, 78–84 (2014). 29. Y. Bombard, F. A. Miller, R. Z. Hayeems, C. Barg, C. Cressman, J. C. Carroll, B. J. Wilson, J. Little, D. Avard, M. Painter-Main, J. Allanson, Y. Guiguere, P. Chakraborty, Public views on participating in newborn screening using genome sequencing. Eur. J. Hum. Genet. (2014). 10.1038/ ejhg.2014.22 30. A. J. Goldenberg, R. R. Sharp, The ethical hazards and programmatic challenges of genomic newborn screening. J. Am. Med. Assoc. 307, 461–462 (2012). 31. E. W. Clayton, A. L. McGuire, The legal risks of returning results of genomics research. Genet. Med. 14, 473–477 (2012). 32. W. G. Feero, Clinical application of whole-genome sequencing: proceed with care. JAMA 311, 1017–1019 (2014). 33. B. M. Knoppers, D. Avard, K. Sénécal, Newborn screening programmes: Emerging biobanks? Norsk Epidemiologi 21, 163–168 (2012). 34. F. S. Collins, The Language of Life: DNA and the Revolution in Personalized Medicine (Harper Perennial, New York, 2010). Acknowledgments: The authors thank M. Hétu and S. Shuang for their editorial assistance. 10.1126/scitranslmed.3008494 Citation: B. M. Knoppers, K. Sénécal, P. Borry, D. Avard, Wholegenome sequencing in newborn screening programs. Sci. Transl. Med. 6, 229cm2 (2014).
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Whole-Genome Sequencing in Newborn Screening Programs Bartha M. Knoppers,1* Karine Sénécal,1 Pascal Borry,2 Denise Avard1 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. Te 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). Tey have saved thousands of lives, and their success has prompted more than 64 countries to provide newborn screening (3). Tese 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. Te 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 suffciently robust and afordable, all newborns may have their genomes sequenced at birth (7). Tey 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. Tere are potential psychosocial harms and legal consequences associated with both the primary and “incidental” fndings revealed by wholegenome sequencing. Incidental fndings can be defned as results outside of the original objectives of the genomic screen. We must tread carefully in interpreting the scientifc 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 “Profling the Newborn” (12). It rejected the introduction of such screening at birth owing to costs and insufcient benefts to health and viewed it as too futuristic. It also cautioned that newborn profling raises important social, legal, and ethical issues. Perhaps, 7 years later, the time is ripe for further discussion (13).
1
Department of Human Genetics, McGill University, Montreal, Quebec H3A OG1, Canada. 2Department of Public Health and Primary Care, University of Leuven, Leuven, 3000 Leuven, Belgium. *Corresponding author. E-mail: bartha.knoppers@ mcgill.ca
KICKSTARTING THE CONVERSATION Even in the absence of a specifc 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 ofer 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 lateonset conditions until adulthood (14). Te 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 efective, or institutional review board–approved research (17). ACMG further stated that WGS should not be used as a “frst-tier approach for newborn screening” (16). Te 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 felds in research and the clinic should set up structures for sharing experiences and establishing testing guidelines. Te 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 specifc 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. Te Public Population Project in Genomics and Society (P3G), an international consortium, suggested that
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the possible return (or not) Tus, one central question is of WGS results in pediatric the extent to which WGS may research should be discussed change existing paradigms during the informed-consent of research, testing, and care. process. Any WGS results that Targeted or staged approaches are “scientifcally valid, clinito WGS could flter the numcally useful, and reveal condiber of fndings. In contrast, tions that are preventable and broader approaches might actionable during childhood” provide more information but should be ofered to the paralso more incidental fndings. ents (21). However, mutations One possible solution is to that predispose the child to perfom WGS but to have a list develop an adult-onset disorof pediatric conditions to be der generally should not be communicated. Other WGSreturned. On a case-by-case Fig. 1. Questions and considerations for WGS. From data management NBS results would be rebasis, an exception could be to shaking up the health care system to education, WGS in NBS programs trieved for later disclosure: eimade if the child would ben- should be discussed carefully and thoroughly. ther when they gain scientifc eft, on balance, from disclovalidity and clinical utility and sure because of the potential when parents have had more beneft to the family from knowing about a test and the test results, the confdentiality time to consider the consequences or when highly penetrant gene that poses serious risk of genetic information, the voluntariness the results can be reported to the “mature” to health and that is preventable or treatable of the request, the responsibility toward child directly. Tis, however, would place the in family members. biological relatives, and the psychological family physician or pediatrician as the keepMost importantly, the use of WGS im- impact of a test (24). Any introduction of er of the timing of release and responsible for plies revealing the present and future ge- WGS into NBS would require rethinking the currency of its interpretation. netic “report card” of all children at birth, the rights of parents to access such informaImpact on health care systems. If even though most of the information ac- tion, the best interests of children, the right WGS in NBS is implemented, the public quired will only become relevant later in to know or not to know, privacy rights, the health care system would have to be relife. Revealing this information may un- clinical utility of retrieved information, the vamped to handle the massive amount of dermine the right of children to decide for type of consent, the duty to recontact and to information generated. Although the new themselves once mature enough to do so. follow of health care professionals, and the data could improve personalized, prevenAt the same time, the results could also re- associated counseling issues and their asso- tive, and therapeutic strategies, WGS-NBS veal immediately actionable implications ciated costs to the health care system. may lead to an increase in false-positive (prevention or treatment) for them and for Even if NBS programs would create results, depending on the panels performed their siblings. Moreover, the use of WGS as a WGS panel with a specifed number of and the integration of variants of unclear part of a population screening program (for conditions to be reported, we have already clinical signifcance. Tis information could the management of public health) would raised the issue of clinically signifcant, in- impose an incredible burden both on famirequire a diferent evidence threshold for cidental fndings. What to do with carrier lies and on the resources of a health care clinical validity and utility than that used status, for instance? Today, screening pro- system (25). in a diagnostic setting (18). We sum up the grams already generate carrier status results For a health care system and its citiquestions and considerations for WGS in that may or may not be revealed. Te WGS zens to truly “beneft” from such data, a NBS in Fig. 1. expansion of NBS programs would also lead WGS-NBS program would need the state What information to report? Te to the inadvertent identifcation of carrier to foresee targeted interventions that adapplication of WGS in NBS could create status for a greater number of conditions. dress the needs of new “at-risk” subpopulaan unlimited expansion of the amount of Being a carrier has implications for future tions. Tese targeted interventions would health information and nonmedical infor- reproductive choices, but this information no longer follow populations via the usual mation to be found for a newborn, ranging is not benefcial to the health of an indi- age, demographic, or gender classifcations from single-gene to multiple-gene disor- vidual. Contradictory policies and practices but rather be identifed by polygenic clusders; from preventable and treatable to non- with regard to the disclosure of carrier sta- tering of at-risk subpopulations. Owing to preventable and nontreatable conditions; tus have existed in both the clinical genetics the overwhelming amount of genomic and from childhood-onset to adult-onset con- context and the NBS context, and this will clinical data from WGS, it could be argued ditions; as well as pharmacogenomic, treat- afect the resolution of the communication that the sustainability of universal health ment, or carrier status information (22). of fndings in WGS-NBS. care will depend on the systemic ability to Currently, genetic testing in minors is only Other types of incidental fndings could use WGS-NBS for such targeting. Te enrecommended when established and efec- include genealogical information, nonpater- suing greater need for physicians, nurses, tive medical treatment can be ofered (23). nity, consanguinity, disease susceptibility (a and counselors and for tracking systems Careful consideration is given to the future continuum between slightly increased or de- to facilitate regrouping into medically acautonomy of the child once an adult, as well creased risk to highly predictive), reproduc- tionable subpopulations might result in the as to the transfer of information about the tive risks, or pharmacogenomic information. implosion of NBS programs. To cover these www.ScienceTranslationalMedicine.org 26 March 2014 Vol 6 Issue 229 229cm2
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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.
additional resources, the state must evaluate how much NBS programs are worth. Furthermore, the state must consider providing coverage for attendant health care needs. Mandatory versus voluntary. Te public health motivation for NBS has long held sway. Current “classical” NBS programs are still considered to be for the child’s beneft, and, more recently, additional aims such as familial beneft 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 beneft of the child. It is possible that many parents would choose to forgo screening altogether. Parents need frst to be informed so as to understand the diference between “classical” and WGS screening. Perhaps, mandatory screening with a targeted list can remain in place for disorders of which genomic knowledge could directly beneft the infant during childhood. Parental consent would then be required for disorders for which the direct-beneft standard is not met (13). Health professionals and parents. Many clinicians have received little training in genetics and lack experience and conf-
dence 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 difcult situations requiring ethical and social debate; more importantly, it promotes public trust in health care programs, such as WGS-NBS. Tus, 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 ofce, and they may be onboard with a state-run public health program ofering 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. Tus, “NBS in an untargeted fashion might reduce public participation” (29). Communication of results over time. Te 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 fndings has not received the same attention (30). Tey would challenge the hard-won tenet of not testing children for late-onset diseases. Moreover, as mentioned, the return of NBS-WGS results would afect 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 singlegene disorders. Across the population, it would allow comparison of the efect on individuals of diferent environments and family history over time. It could be argued that
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traditional single-gene NBS programmes should be lef 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. Tere 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 ofer 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 diferent inheritance patterns of genes and/or diferent phenotypes and/or diferent 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 fle, and if so, under what conditions and for how long? Some have argued that it could be stored in the patient fle for future use (23). Tis 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. Tis 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. Te introduction of WGS into NBS programs including the storage of WGS data would in efect create newborn “biobanks” (33). Insurability. In WGS-NBS, the “data” obtained will be part of the medical record. Because insurance companies ofen 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 afect 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 efective interventions for genetic risk factors, and recognize that interventions early in life provide signifcant advantages, it will become more and more
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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 benefts 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. Te 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-internationalpaediatric-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 specifcally address the issue of the use of WGS in NBS in 2014.
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