Wilson and Jungner Revisited: Are Screening Criteria Fit for the 21st Century?

Driven by technological innovations, newborn screening (NBS) panels have been expanded and the development of genomic NBS pilot programs is rapidly progressing. Decisions on disease selection for NBS are still based on the Wilson and Jungner (WJ) criteria published in 1968. Despite this uniform reference, interpretation of the WJ criteria and actual disease selection for NBS programs are highly variable. A systematic literature search [PubMED search "Wilson" AND "Jungner"; last search 16.07.22] was performed to evaluate the applicability of the WJ criteria for current and future NBS programs and the need for adaptation. By at least two reviewers, 105 publications (systematic literature search, N = 77; manual search, N = 28) were screened for relevant content and, finally, 38 publications were evaluated. Limited by the study design of qualitative text analysis, no statistical evaluation was performed, but a structured collection of reported aspects of criticism and proposed improvements was instead collated. This revealed a set of general limitations of the WJ criteria, such as imprecise terminology, lack of measurability and objectivity, missing pediatric focus, and absent guidance on program management. Furthermore, it unraveled specific aspects of criticism on clinical, diagnostic, therapeutic, and economical aspects. A major obstacle was found to be the incompletely understood natural history and phenotypic diversity of rare diseases prior to NBS implementation, resulting in uncertainty about case definition, risk stratification, and indications for treatment. This gap could be closed through the systematic collection and evaluation of real-world evidence on the quality, safety, and (cost-)effectiveness of NBS, as well as the long-term benefits experienced by screened individuals. An integrated NBS public health program that is designed to continuously learn would fulfil these requirements, and a multi-dimensional framework for future NBS programs integrating medical, ethical, legal, and societal perspectives is overdue.

Actionability of unanticipated monogenic disease risks in newborn genomic screening: Findings from the BabySeq Project.

Newborn genomic sequencing (NBSeq) to screen for medically important genetic information is of considerable interest but data characterizing the actionability of such findings, and the downstream medical efforts in response to discovery of unanticipated genetic risk variants, are lacking. From a clinical trial of comprehensive exome sequencing in 127 apparently healthy infants and 32 infants in intensive care, we previously identified 17 infants (10.7%) with unanticipated monogenic disease risks (uMDRs). In this analysis, we assessed actionability for each of these uMDRs with a modified ClinGen actionability semiquantitative metric (CASQM) and created radar plots representing degrees of penetrance of the condition, severity of the condition, effectiveness of intervention, and tolerability of intervention. In addition, we followed each of these infants for 3-5 years after disclosure and tracked the medical actions prompted by these findings. All 17 uMDR findings were scored as moderately or highly actionable on the CASQM (mean 9, range: 7-11 on a 0-12 scale) and several distinctive visual patterns emerged on the radar plots. In three infants, uMDRs revealed unsuspected genetic etiologies for existing phenotypes, and in the remaining 14 infants, uMDRs provided risk stratification for future medical surveillance. In 13 infants, uMDRs prompted screening for at-risk family members, three of whom underwent cancer-risk-reducing surgeries. Although assessments of clinical utility and cost-effectiveness will require larger datasets, these findings suggest that large-scale comprehensive sequencing of newborns will reveal numerous actionable uMDRs and precipitate substantial, and in some cases lifesaving, downstream medical care in newborns and their family members.

Parents' decision-making regarding whether to receive adult-onset only genetic findings for their children: Findings from the BabySeq Project.

PURPOSE: Most professional guidelines recommend against genetic screening for adult-onset only (AO) conditions until adulthood, yet others argue that there may be benefit to disclosing such results. We explored parents' decision-making on this issue in the BabySeq Project, a clinical trial of newborn genomic sequencing. METHODS: We conducted interviews with parents (N = 24) who were given the option to receive actionable AO results for their children. Interviews explored parents' motivations to receive and reasons to decline AO genetic disease risk information, their decision-making process, and their suggestions for supporting parents in making this decision. RESULTS: Parents noted several motivations to receive and reasons to decline AO results. Most commonly, parents cited early intervention/surveillance (n = 11), implications for family health (n = 7), and the ability to prepare (n = 6) as motivations to receive these results. The most common reasons to decline were protection of the child's future autonomy (n = 4), negative effect on parenting (n = 3), and anxiety about future disease (n = 3). Parents identified a number of ways to support parents in making this decision. CONCLUSION: Results show considerations to better support parental decision-making that aligns with their values when offering AO genetic information because it is more commonly integrated into pediatric clinical care.

Parental Attitudes Toward Standard Newborn Screening and Newborn Genomic Sequencing: Findings From the BabySeq Study.

Introduction: With increasing utility and decreasing cost of genomic sequencing, augmentation of standard newborn screening (NBS) programs with newborn genomic sequencing (nGS) has been proposed. Before nGS can be integrated into newborn screening, parents' perspectives must be better understood. Objective: Using data from surveys administered to parents of healthy newborns who were enrolled in the BabySeq Project, a randomized clinical trial of nGS alongside NBS, this paper reports parents' attitudes regarding population-based NBS and nGS assessed 3 months after results disclosure. Methods: Parental attitudes regarding whether all newborns should receive, and whether informed consent should be required for, NBS and nGS, as well as whether nGS should be mandated were assessed using 5-point scales from strongly disagree (=1) to strongly agree (=5). Parents' interest in receiving types of results from nGS was assessed on a 5-point scale from not at all interested (=1) to very interested (=5). Survey responses were analyzed using Fisher's exact tests, paired t-tests, and repeated measures ANOVA. Results: At 3 months post-disclosure, 248 parents of 174 healthy newborns submitted a survey. Support for every newborn receiving standard NBS (mean 4.67) was higher than that for every newborn receiving nGS (mean 3.60; p < 0.001). Support for required informed consent for NBS (mean 3.44) was lower than that for nGS (mean 4.27, p < 0.001). Parents' attitudes toward NBS and nGS were not significantly associated with self-reported political orientation. If hypothetically receiving nGS outside of the BabySeq Project, most parents reported being very interested in receiving information on their baby's risk of developing a disease in childhood that can be prevented, treated, or cured (86.8%) and their risk of developing a disease during adulthood that can be prevented, treated, or cured (84.6%). Discussion: Parents' opinions are crucial to inform design and delivery of public health programs, as the success of the program hinges on parents' trust and participation. To accommodate parents' preferences without affecting the current high participation rates in NBS, an optional add-on consent to nGS in addition to NBS may be a feasible approach. Trial Registration ClinicalTrials.gov Identifier: NCT02422511.

Cribado neonatal genómico. Perspectiva de la Comisión de ética de la Asociación Española de Genética Humana. Parte II: Aspectos Éticos, Legales y Sociales (AELS) de la Introducción de las Tecnologías de Secuenciación Masiva (NGS) en un programa de cribado neonatal de Salud Pública / Genomic newborn screening. Perspective from the Ethics Commission of the Spanish Society for Human Genetics. Part II: Ethical, legal and social issues (ELSIs) of the introduction of next generation sequencing technologies in a public health newborn screening program

La secuenciación genómica es una tecnología extraordinariamente atractiva, tanto como lo es la idea de poder aplicarla a todos los recién nacidos, estableciendo con ello una etapa de cuidados médicos para toda la vida y acciones preventivas a medida del genoma de cada niño. En la parte I de este artículo se analizaron las limitaciones y oportunidades que presentan las tecnologías de secuenciación de nueva generación (NGS). La parte II relaciona el conocimiento científico con los aspectos éticos, legales y sociales (AELS) de su introducción en un programa de cribado neonatal de salud pública de aplicación universal a población vulnerable y asintomática, que debe ser guiada por los principios fundamentales de “no hacer daño” y de actuar “en el mejor interés del niño”. Para ello se contemplan en primer lugar los principios éticos de la medicina y de la salud pública que rigen el cribado neonatal, a continuación se resumen los principales aspectos de nuestro marco legal al respecto y finalmente en el ámbito social se analizan la influencia del imperativo tecnológico, la de los actores comerciales, los grupos de apoyo de pacientes y por último la perspectiva de los padres y aspectos psicosociales. Las conclusiones son que en este contexto la secuenciación genómica completa no debe ser implementada como cribado neonatal universal, sin embargo el uso de las NGS podría ser una oportunidad para ampliar los programas incluyendo enfermedades infantiles tratables que no pudiesen ser detectadas con otros métodos. Realizando para ello una aproximación dirigida a enfermedades/genes concretos, a fin de identificar variantes genómicas bien conocidas, altamente penetrantes confiriendo riesgo elevado de enfermedad prevenible o tratable, para la cual el tratamiento deba iniciarse en el periodo neonatal.(AU)

Genome sequencing is a very attractive technology as it is also the idea of sequencing children at birth, with the aim to establish medical care and preventive actions during their whole life, tailored to the genome of each newborn. Part I of this article analyses limitations and opportunities of next generation sequencing technologies (NGS). Part II relates scientific knowledge with ethical, legal and social issues (ELSIs) concerning its application to a newborn screening program. This program is offered universally to a vulnerable and asymptomatic population and must be guided by principles of “do not harm” and to act in the “best interest of child”. With this purpose, this article considers, first of all, ethical principles of bioethics and public health that govern newborn screening. Then it summarizes main issues of our legal framework. And finally, in social context, it analyzes influences of technological imperative, commercial actors and patient ́s advocacy groups, as well as parent’s perspective and psychosocial aspects. In this context, conclusion is that whole genome sequencing should not be implemented as universal newborn screening. Nevertheless, the use of NGS could be an opportunity to extend these programs, including treatable infantile diseases that cannot be detected with other technologies. That means realizing a directed approach in order to identify well known genomic variants, highly penetrant, that confer a high risk of preventable or treatable diseases for which treatment must begin at the neonatal period. The implementation of such directed genomic screening should follow current evidence based model for newborn screening.(AU)

[Genomic newborn screening. Perspective from the Ethics Commission of the Spanish Society for Human Genetics. Part II: Ethical, legal and social issues (ELSIs) of the introduction of next generation sequencing technologies in a public health newborn screening program.] / Cribado neonatal genómico. Perspectiva de la Comisión de ética de la Asociación Española de Genética Humana. Parte II: Aspectos Éticos, Legales y Sociales (AELS) de la Introducción de las Tecnologías de Secuenciación Masiva (NGS) en un programa de cribado neonatal de Salud Pública.

Genome sequencing is a very attractive technology as it is also the idea of sequencing children at birth, with the aim to establish medical care and preventive actions during their whole life, tailored to the genome of each newborn. Part I of this article analyses limitations and opportunities of next generation sequencing technologies (NGS). Part II relates scientific knowledge with ethical, legal and social issues (ELSIs) concerning its application to a newborn screening program. This program is offered universally to a vulnerable and asymptomatic population and must be guided by principles of "do not harm" and to act in the "best interest of child". With this purpose, this article considers, first of all, ethical principles of bioethics and public health that govern newborn screening. Then it summarizes main issues of our legal framework. And finally, in social context, it analyzes influences of technological imperative, commercial actors and patient´s advocacy groups, as well as parent's perspective and psychosocial aspects. In this context, conclusion is that whole genome sequencing should not be implemented as universal newborn screening. Nevertheless, the use of NGS could be an opportunity to extend these programs, including treatable infantile diseases that cannot be detected with other technologies. That means realizing a directed approach in order to identify well known genomic variants, highly penetrant, that confer a high risk of preventable or treatable diseases for which treatment must begin at the neonatal period. The implementation of such directed genomic screening should follow current evidence based model for newborn screening. This model shows three features: recognition of the importance of the evaluation of empirical, epidemiological and clinical data before taking the decision to include a disease; evaluation of benefits and risks (proportionality) and evaluation of benefits and costs (distributive justice); and finally, consideration of public consensus, because this kind of decisions have a value that concerns society as a whole.

La secuenciación genómica es una tecnología extraordinariamente atractiva, tanto como lo es la idea de poder aplicarla a todos los recién nacidos, estableciendo con ello una etapa de cuidados médicos para toda la vida y acciones preventivas a medida del genoma de cada niño. En la parte I de este artículo se analizaron las limitaciones y oportunidades que presentan las tecnologías de secuenciación de nueva generación (NGS). La parte II relaciona el conocimiento científico con los aspectos éticos, legales y sociales (AELS) de su introducción en un programa de cribado neonatal de salud pública de aplicación universal a población vulnerable y asintomática, que debe ser guiada por los principios fundamentales de "no hacer daño" y de actuar "en el mejor interés del niño". Para ello se contemplan en primer lugar los principios éticos de la medicina y de la salud pública que rigen el cribado neonatal, a continuación se resumen los principales aspectos de nuestro marco legal al respecto y finalmente en el ámbito social se analizan la influencia del imperativo tecnológico, la de los actores comerciales, los grupos de apoyo de pacientes y por último la perspectiva de los padres y aspectos psicosociales. Las conclusiones son que en este contexto la secuenciación genómica completa no debe ser implementada como cribado neonatal universal, sin embargo el uso de las NGS podría ser una oportunidad para ampliar los programas incluyendo enfermedades infantiles tratables que no pudiesen ser detectadas con otros métodos. Realizando para ello una aproximación dirigida a enfermedades/genes concretos, a fin de identificar variantes genómicas bien conocidas, altamente penetrantes confiriendo riesgo elevado de enfermedad prevenible o tratable, para la cual el tratamiento deba iniciarse en el periodo neonatal. Su incorporación al cribado neonatal debería seguir el modelo actual basado en la evidencia, evaluando los datos empíricos, epidemiológicos y clínicos antes de tomar una decisión sobre la inclusión de una enfermedad, así como los beneficios y riesgos (proporcionalidad) y si los beneficios justifican los costes (justicia distributiva), tomando en consideración el consenso público en tanto que las decisiones tienen una carga de valores que conciernen a la sociedad en su conjunto.

[Genomic newborn screening. Perspective from the Ethics commission of the Spanish Society for Human Genetics. Part I. Next generation sequencing technologies applied to newborn screening. Challenges and opportunities.] / Cribado neonatal genómico. Perspectiva de la Comisión de ética de la Asociación Española de Genética Humana. Parte I. Las tecnologías de secuenciación masiva (NGS) y su aplicación al cribado neonatal. Desafíos y oportunidades.

In 2003 at the ending of the Human Genome Project, it aroused the idea that all newborns could be sequenced and its genome archived in the clinical record, in order to manage risks of diseases and response to medicaments along his whole life. Eighteen years later, promises of genomic medicine and tremendous decrease of costs of next generation sequencing technologies, continues feeding this dream that shows important practical, ethical and social challenges and genomic sequencing is presented as the next historical change in newborn screening programs. In this paper we analyze challenges and opportunities of next generation sequencing technologies, their real costs, problems associated to management, storage and protection of the enormous amount of genomic data produced and finally, according to conclusions of recent researches, there are considered the conclusions in two contexts, sick newborn with diagnostic purposes and healthy asymptomatic newborns with public health purposes (newborn screening programs). In a second part of this article it will be considered ethical, legal and social issues (ELSI). Final objective is to contribute to scientific, professional, ethics and social debate in order to promote that genome sequencing in newborn don't be used indiscriminately constituting a risk, but properly done, as a partner in the promotion of health and prevention of consequences of genetic diseases.

En 2003, cuando finalizó el Proyecto Genoma Humano, surgió la idea de secuenciar el genoma a todos los recién nacidos, archivarlo en la historia clínica y usarlo a lo largo de toda la vida para manejar riesgos de enfermedades y respuesta a medicamentos. Dieciocho años más tarde, las promesas de la medicina genómica y el extraordinario abaratamiento de las tecnologías secuenciadoras, siguen alimentando este sueño que todavía plantea grandes desafíos prácticos, éticos y sociales y la secuenciación genómica se presenta como el próximo gran cambio histórico en los programas de cribado neonatal. En el presente artículo, se analizan los retos y oportunidades de las tecnologías secuenciadoras de nueva generación, sus costos reales, la problemática inherente a la gestión, almacenamiento y protección de la enorme cantidad de datos genómicos que generan y finalmente, en base a las conclusiones de investigaciones recientes, se considera el potencial y limitaciones de su aplicación en dos escenarios, el recién nacido enfermo con finalidades diagnósticas y el recién nacido sano, asintomático, con finalidades de salud pública(programas de cribado neonatal). En una segunda parte de este artículo se tendrán en cuenta los aspectos éticos, legales y sociales (AELS). El objetivo final es contribuir al debate científico, profesional, ético y social, promoviendo que la secuenciación genómica en el recién nacido no sea usada indiscriminadamente constituyendo un riesgo, sino que bien empleada sea una aliada en la promoción de la salud y prevención de las consecuencias de las enfermedades genéticas.

Cribado neonatal genómico. Perspectiva de la Comisión de ética de la Asociación Española de Genética Humana. Parte I. Las tecnologías de secuenciación masiva (NGS) y su aplicación al cribado neonatal. Desafíos y oportunidades / Genomic newborn screening. Perspective from the Ethics commission of the Spanish Society for Human Genetics. Part I. Next generation sequencing technologies applied to newborn screening. Challenges and opportunities

En 2003, cuando finalizó el Proyecto Genoma Humano, surgió la idea de secuenciar el genoma a todos los recién nacidos, archivarlo en la historia clínica y usarlo a lo largo de toda la vida para manejar riesgos de enfermedades y respuesta a medicamentos. Dieciocho años más tarde, las promesas de la medicina genómica y el extraordinario abaratamiento de las tecnologías secuenciadoras, siguen alimentando este sueño que todavía plantea grandes desafíos prácticos, éticos y sociales y la secuenciación genómica se presenta como el próximo gran cambio histórico en los programas de cribado neonatal. En el presente artículo, se analizan los retos y oportunidades de las tecnologías secuenciadoras de nueva generación, sus costos reales, la problemática inherente a la gestión, almacenamiento y protección de la enorme cantidad de datos genómicos que generan y finalmente, en base a las conclusiones de investigaciones recientes, se considera el potencial y limitaciones de su aplicación en dos escenarios, el recién nacido enfermo con finalidades diagnósticas y el recién nacido sano, asintomático, con finalidades de salud pública(programas de cribado neonatal). En una segunda parte de este artículo se tendrán en cuenta los aspectos éticos, legales y sociales (AELS). El objetivo final es contribuir al debate científico, profesional, ético y social, promoviendo que la secuenciación genómica en el recién nacido no sea usada indiscriminadamente constituyendo un riesgo, sino que bien empleada sea una aliada en la promoción de la salud y prevención de las consecuencias de las enfermedades genéticas.(AU)

In 2003 at the ending of the Human Genome Project, it aroused the idea that all newborns could be sequenced and its genome archived in the clinical record, in order to manage risks of diseases and response to medicaments along his whole life. Eighteen years later, promises of genomic medicine and tremendous decrease of costs of next generation sequencing technologies, continues feeding this dream that shows important practical, ethical and social challenges and genomic sequencing is presented as the next historical change in newborn screening programs. In this article we analyze challenges and opportunities of next generation sequencing technologies, their real costs, problems associated to management, storage and protection of the enormous amount of genomic data produced and finally, according to conclusions of recent researches, there are considered the conclusions in two contexts, sick newborn with diagnostic purposes and healthy asymptomatic newborns with public health purposes (newborn screening programs). In a second part of this article it will be considered ethical, legal and social issues (ELSI). Final objective is to contribute to scientific, professional, ethics and social debate in order to promote that genome sequencing in newborn don’t be used indiscriminately constituting a risk, but properly done, as a partner in the promotion of health and prevention of consequences of genetic diseases.(AU)

Expanded Newborn Screening and Genomic Sequencing in Latin America and the Resulting Social Justice and Ethical Considerations.

Newborn screening (NBS) has widely been utilized in developed countries as a cost-effective public health strategy that reduces morbidity and mortality. Developing countries, however, are new to the NBS scene and have their own unique challenges, both in instituting the program as well as effectively acting on the results. NBS offers numerous ethical issues on a global scale, however, here we argue that there are unique ethical issues surrounding the development and expansion of newborn screening in Latin America given its highly heterogenous population. Once a NBS program is effectively instated, ethical considerations continue when pursuing expansion of screening to include further conditions. While Latin America grapples with the ethics of expanded newborn screening (ENBS), some developed countries discuss utility of genomic sequencing technologies in the newborn population. When the ability to detect further pathology is expanded, one must know what to do with this information. As rare diseases are identified either on ENBS or via genome sequencing, access to treatments for these rare diseases can be a real challenge. If we consider newborn screening as a global initiative, then we need more than a deontology approach to analyze these challenges; we need an approach that considers the unique characteristics of each territory and tremendous heterogeneity that exists prior to the implementation of these programs. As genomic technology advances further in the developed world, while some developing countries still lack even basic newborn screening, there is a further widening of the gap in global health disparities. The question is posed as to who has responsibility for these newborns' lives on an international level. Without an approach towards newborn screening that accounts for the diverse global population, we believe optimal outcomes for newborns and families across the world will not be achieved.

Exome sequencing in newborns with congenital deafness as a model for genomic newborn screening: the Baby Beyond Hearing project.

PURPOSE: Genomic newborn screening raises practical and ethical issues. Evidence is required to build a framework to introduce this technology safely and effectively. We investigated the choices made by a diverse group of parents with newborns when offered tiered genomic information from exome sequencing. METHODS: This population-derived cohort comprised infants with congenital deafness. Parents were offered exome sequencing and choice regarding the scope of analysis. Options were choice A, diagnostic analysis only; choice B, diagnostic analysis plus childhood-onset diseases with medical actionability; or choice C, diagnostic analysis plus childhood-onset diseases with or without medical actionability. RESULTS: Of the 106 participants, 72 (68%) consented to receive additional findings with 29 (27.4%) selecting choice B and 43 (40.6%) opting for choice C. Family size, ethnicity, and age of infant at time of recruitment were the significant predictors of choice. Parents who opted to have additional findings analysis demonstrated less anxiety and decisional conflict. CONCLUSIONS: These data provide evidence from a culturally diverse population that choice around additional findings is important and the age of the infant when this choice is offered impacts on their decision. We found no evidence that offering different levels of genomic information to parents of newborns has a negative psychological impact.

Interpretation of Genomic Sequencing Results in Healthy and Ill Newborns: Results from the BabySeq Project.

Genomic sequencing provides many opportunities in newborn clinical care, but the challenges of interpreting and reporting newborn genomic sequencing (nGS) results need to be addressed for its broader and effective application. The BabySeq Project is a pilot randomized clinical trial that explores the medical, behavioral, and economic impacts of nGS in well newborns and those admitted to a neonatal intensive care unit (NICU). Here we present childhood-onset and actionable adult-onset disease risk, carrier status, and pharmacogenomics findings from nGS of 159 newborns in the BabySeq Project. nGS revealed a risk of childhood-onset disease in 15/159 (9.4%) newborns; none of the disease risks were anticipated based on the infants' known clinical or family histories. nGS also revealed actionable adult-onset disease risk in 3/85 (3.5%) newborns whose parents consented to receive this information. Carrier status for recessive diseases and pharmacogenomics variants were reported in 88% and 5% of newborns, respectively. Additional indication-based analyses were performed in 29/32 (91%) NICU newborns and 6/127 (5%) healthy newborns who later had presentations that prompted a diagnostic analysis. No variants that sufficiently explained the reason for the indications were identified; however, suspicious but uncertain results were reported in five newborns. Testing parental samples contributed to the interpretation and reporting of results in 13/159 (8%) newborns. Our results suggest that nGS can effectively detect risk and carrier status for a wide range of disorders that are not detectable by current newborn screening assays or predicted based on the infant's known clinical or family history, and the interpretation of results can substantially benefit from parental testing.

The BabySeq project: implementing genomic sequencing in newborns.

BACKGROUND: The greatest opportunity for lifelong impact of genomic sequencing is during the newborn period. The "BabySeq Project" is a randomized trial that explores the medical, behavioral, and economic impacts of integrating genomic sequencing into the care of healthy and sick newborns. METHODS: Families of newborns are enrolled from Boston Children's Hospital and Brigham and Women's Hospital nurseries, and half are randomized to receive genomic sequencing and a report that includes monogenic disease variants, recessive carrier variants for childhood onset or actionable disorders, and pharmacogenomic variants. All families participate in a disclosure session, which includes the return of results for those in the sequencing arm. Outcomes are collected through review of medical records and surveys of parents and health care providers and include the rationale for choice of genes and variants to report; what genomic data adds to the medical management of sick and healthy babies; and the medical, behavioral, and economic impacts of integrating genomic sequencing into the care of healthy and sick newborns. DISCUSSION: The BabySeq Project will provide empirical data about the risks, benefits and costs of newborn genomic sequencing and will inform policy decisions related to universal genomic screening of newborns. TRIAL REGISTRATION: The study is registered in ClinicalTrials.gov Identifier: NCT02422511 . Registration date: 10 April 2015.