Challenging the dogma of the healthy heterozygote: Implications for newborn screening policies and practices.

Heterozygous (carrier) status for an autosomal recessive condition is traditionally considered to lack significance for an individual's health, but this assumption has been challenged by a growing body of evidence. Carriers of several autosomal recessive disorders and some X-linked diseases are potentially at risk for the pathology manifest in homozygotes. This minireview provides an overview of the literature regarding health risks to carriers of two common autosomal recessive conditions on the Recommended Uniform Screening Panel: sickle cell disease [sickle cell trait (SCT)] and cystic fibrosis (CF). We also consider and comment on bioethical and policy implications for newborn blood screening (NBS). Health risks for heterozygotes, while relatively low for individuals, are often influenced by intrinsic (e.g., other genomic variants or co-morbidities) and extrinsic (environmental) factors, which present opportunities for personalized genomic medicine and risk counseling. They create a special challenge, however, for developing screening/follow-up policies and for genetic counseling, particularly after identification and reporting of heterozygote status through NBS. Although more research is needed, this minireview of the SCT and CF literature to date leads us to propose that blanket terms such as "healthy heterozygotes" or "unaffected carriers" should be superseded in communications about NBS results, in favor of a more nuanced paradigm of setting expectations for health outcomes with "genotype-to-risk." In the molecular era of NBS, it remains clear that public health needs to become better prepared for the full range of applied genetics.

Newborn screening system: Safety, technology, advocacy.

Newborn screening (NBS) is more than 50 years old and has proven to be a powerful and successful public health system. NBS must be regarded as a system and not simply as a test. We need to work as a community to improve the culture of safety for the NBS system and thereby to reduce the risk of babies being missed by the NBS system. Adding new technologies will not prevent system failures; that will require adherence to the culture of safety. Some have argued that every newborn should have their genome sequenced at birth and this sequencing could be part of NBS. However, NBS has depended on biomarker phenotypes throughout its history and our understanding of the relationships between genotype and phenotype is imperfect. Therefore, we should avoid being seduced by genomic sequencing technology and continue to focus on phenotypic biomarkers in NBS.

Emerging issues in public health genomics.

This review highlights emerging areas of interest in public health genomics. First, we describe recent advances in newborn screening (NBS), with a focus on the practice and policy implications of current and future efforts to expand NBS programs (e.g., via next-generation sequencing). Next, we detail research findings from the rapidly progressing field of epigenetics and epigenomics, highlighting ways in which our emerging understanding in these areas could guide future intervention and research efforts in public health. We close by considering various ethical, legal, and social issues posed by recent developments in public health genomics; these include policies to regulate access to personal genomic information, the need to enhance genetic literacy in both health professionals and the public, and challenges in ensuring that the benefits (and burdens) of genomic discoveries and applications are equitably distributed. We also note needs for future genomic research that integrates across basic and social sciences.

Reporting Newborn Audiologic Results to State EHDI Programs.

OBJECTIVES: All US states and territories have an Early Hearing Detection and Intervention (EHDI) program to facilitate early hearing evaluation and intervention for infants who are deaf or hard of hearing. To ensure efficient coordination of care, the state EHDI programs rely heavily on audiologists' prompt reporting of a newborn's hearing status. Several states have regulations requiring mandatory reporting of a newborn's hearing status. This is an important public health responsibility of pediatric audiologists. Reasons for failing to report vary. DESIGN: The Early Hearing Detection and Intervention-Pediatric Audiology Links to Services (EHDI) facility survey was used to inform reporting compliance of audiology facilities throughout the United States. The survey was disseminated via articles, newsletters, and call-to-action notices to audiologists. RESULTS: Among 1024 facilities surveyed, 88 (8.6%) reported that they did not report newborn's hearing findings to their state EHDI program. Not knowing how to report to the state EHDI program was the most frequently chosen reason (60%). However, among the 936 facilities that were compliant with the reporting requirements, 51 estimated that they reported less than two-third of all hearing evaluation results (5.4%). Some facilities did not report a normal-hearing result and some failed to report because they assumed another facility would report the hearing results. CONCLUSIONS: Survey results indicated that audiologists were compliant reporting hearing results to the state EHDI programs. However, there is room for improvement. Regular provider outreach and training by the state EHDI program is necessary to ensure those who are not reporting will comply and to clarify reporting requirements for those who are already compliant.

Association of US State Implementation of Newborn Screening Policies for Critical Congenital Heart Disease With Early Infant Cardiac Deaths.

IMPORTANCE: In 2011, critical congenital heart disease was added to the US Recommended Uniform Screening Panel for newborns, but whether state implementation of screening policies has been associated with infant death rates is unknown. OBJECTIVE: To assess whether there was an association between implementation of state newborn screening policies for critical congenital heart disease and infant death rates. DESIGN, SETTING, AND PARTICIPANTS: Observational study with group-level analyses. A difference-in-differences analysis was conducted using the National Center for Health Statistics' period linked birth/infant death data set files for 2007-2013 for 26 546 503 US births through June 30, 2013, aggregated by month and state of birth. EXPOSURES: State policies were classified as mandatory or nonmandatory (including voluntary policies and mandates that were not yet implemented). As of June 1, 2013, 8 states had implemented mandatory screening policies, 5 states had voluntary screening policies, and 9 states had adopted but not yet implemented mandates. MAIN OUTCOMES AND MEASURES: Numbers of early infant deaths (between 24 hours and 6 months of age) coded for critical congenital heart disease or other/unspecified congenital cardiac causes for each state-month birth cohort. RESULTS: Between 2007 and 2013, there were 2734 deaths due to critical congenital heart disease and 3967 deaths due to other/unspecified causes. Critical congenital heart disease death rates in states with mandatory screening policies were 8.0 (95% CI, 5.4-10.6) per 100 000 births (n = 37) in 2007 and 6.4 (95% CI, 2.9-9.9) per 100 000 births (n = 13) in 2013 (for births by the end of July); for other/unspecified cardiac causes, death rates were 11.7 (95% CI, 8.6-14.8) per 100 000 births in 2007 (n = 54) and 10.3 (95% CI, 5.9-14.8) per 100 000 births (n = 21) in 2013. Early infant deaths from critical congenital heart disease through December 31, 2013, decreased by 33.4% (95% CI, 10.6%-50.3%), with an absolute decline of 3.9 (95% CI, 3.6-4.1) deaths per 100 000 births after states implemented mandatory screening compared with prior periods and states without screening policies. Early infant deaths from other/unspecified cardiac causes declined by 21.4% (95% CI, 6.9%-33.7%), with an absolute decline of 3.5 (95% CI, 3.2-3.8) deaths per 100 000 births. No significant decrease was associated with nonmandatory screening policies. CONCLUSIONS AND RELEVANCE: Statewide implementation of mandatory policies for newborn screening for critical congenital heart disease was associated with a significant decrease in infant cardiac deaths between 2007 and 2013 compared with states without these policies.

Evolution of Italian Universal Newborn Hearing Screening Programs.

BACKGROUND: The aim of this study was to evaluate the state of implementation of the Universal Newborn Hearing Screening Programs in Italy and to determine the effect that an ad hoc legislation may have on the percentage of infants screened for detection of hearing impairment in nurseries. MATERIAL AND METHODS: Italian Newborn Hearing Screening data were obtained during four national surveys (years 2003, 2006, 2008, and 2011). The screening rates obtained by the Regions which adopted or did not adopt a legislation to increase the newborns' coverage were compared. RESULTS: In 2011, the average coverage rate was 78.3%, but in 12 out of 20 Regions it exceeded 95%. Coverage rate was greater in Regions that implemented an ad hoc legislation compared to Regions that did not. As a matter of fact, Regions which passed the legislation screened more than 95% of infants, whereas Regions without legislation reported a mean screening rate of nearly 67% of newborns. CONCLUSION: Current results seem to confirm that a specific legislation might have a decisive effect on the increase of rate of coverage of newborn hearing screenings.

The Use of Economic Evaluation to Inform Newborn Screening Policy Decisions: The Washington State Experience.

POLICY POINTS: Newborn screening not only saves lives but can also yield net societal economic benefit, in addition to benefits such as improved quality of life to affected individuals and families. Calculations of net economic benefit from newborn screening include the monetary equivalent of avoided deaths and reductions in costs of care for complications associated with late-diagnosed individuals minus the additional costs of screening, diagnosis, and treatment associated with prompt diagnosis. Since 2001 the Washington State Department of Health has successfully implemented an approach to conducting evidence-based economic evaluations of disorders proposed for addition to the state-mandated newborn screening panel. CONTEXT: Economic evaluations can inform policy decisions on the expansion of newborn screening panels. This article documents the use of cost-benefit models in Washington State as part of the rule-making process that resulted in the implementation of screening for medium-chain acyl-CoA dehydrogenase (MCAD) deficiency and 4 other metabolic disorders in 2004, cystic fibrosis (CF) in 2006, 15 other metabolic disorders in 2008, and severe combined immune deficiency (SCID) in 2014. METHODS: We reviewed Washington State Department of Health internal reports and spreadsheet models of expected net societal benefit of adding disorders to the state newborn screening panel. We summarize the assumptions and findings for 2 models (MCAD and CF) and discuss them in relation to findings in the peer-reviewed literature. FINDINGS: The MCAD model projected a benefit-cost ratio of 3.4 to 1 based on assumptions of a 20.0 percentage point reduction in infant mortality and a 13.9 percentage point reduction in serious developmental disability. The CF model projected a benefit-cost ratio of 4.0-5.4 to 1 for a discount rate of 3%-4% and a plausible range of 1-2 percentage point reductions in deaths up to age 10 years. CONCLUSIONS: The Washington State cost-benefit models of newborn screening were broadly consistent with peer-reviewed literature, and their findings of net benefit appear to be robust to uncertainty in parameters. Public health newborn screening programs can develop their own capacity to project expected costs and benefits of expansion of newborn screening panels, although it would be most efficient if this capacity were shared among programs.

Newborn screening of inherited metabolic disorders: the Italian situation.

Starting from an international overview of the current status of screening programs, the present paper focuses on the legal situation in Italy and the great differences among Italian regions. Since the introduction of tandem mass spectrometry (MS/MS) in the ‘90s the paradigm “one spot-one disease” changed. Only recently, some regions issued legislative acts to promote expanded newborn screening with MS/MS. This approach raises medico-legal and ethical issues because a fast neonatal diagnosis of an inborn error of metabolism (IEM) could increase chances of an early treatment and reduce disabilities, therefore citizens ought to have the same access to care countrywide. Enacting a mandatory standard for a disease screening panel using MS/MS and a few centers specialized in diagnosis, treatment and follow-up of patients affected by IEM (inborn errors of metabolism) can reduce legal and ethical issues.

Legal and Ethical Considerations in Allowing Parental Exemptions From Newborn Critical Congenital Heart Disease (CCHD) Screening.

Critical congenital heart disease (CCHD) screening is rapidly becoming the standard of care in the United States after being added to the Recommended Uniform Screening Panel (RUSP) in 2011. Newborn screens typically do not require affirmative parental consent. In fact, most states allow parents to exempt their baby from receiving the required screen on the basis of religious or personally held beliefs. There are many ethical considerations implicated with allowing parents to exempt their child from newborn screening for CCHD. Considerations include the treatment of religious exemptions in our current legal system, as well as medical and ethical principles in relation to the rights of infants. Although there are significant benefits to screening newborns for CCHD, when a parent refuses for religious or personal beliefs, in the case of CCHD screening, the parental decision should stand.

Drug Screening in Neonates.

Gestational substance exposure continues to be a significant problem. Neonates may be exposed to various substances including illicit drugs, prescription drugs, and other legal substances that are best not used during pregnancy because of their potential deleterious effects as possible teratogens or their potential to create dependence and thus withdrawal in the neonate. Screening the newborn for gestational substance exposure is important for both acute care and early intervention to promote the best possible long-term outcomes. This column provides insight into what is known about the extent of substance use by pregnant women, an overview of neonatal biologic matrices for drug testing, and a discussion of the legal implications of neonatal substance screening.

Implementing Universal Pulse Oximetry Screening in West Virginia: Findings from Year One.

BACKGROUND: In March 2012 the West Virginia legislature passed a law that mandates birth hospitals to perform pulse oximetry screening for all well-babies in the newborn nursery to improve the detection of critical congenital heart disease (CCHD). CCHD screening data collection began on September 1, 2012 at all 28 birthing hospitals. The purpose of this study was to review the first year of pulse oximetry screening outcomes and identify barriers to implementation and solutions to improve tracking and policy. METHODS: All WV birth hospitals were provided with the U.S. Department of Health and Human Services recommendations for CCHD screening, and the Center for Disease Control's recommended screening algorithm for review and reference. 20,115 infants were entered into the Birth Score database between September 1, 2012 and August 31, 2013. 19,283 (91%) infants were screened for CCHD. RESULTS: 17,101 (88.5%) infants passed, 19 infants failed, and 2,163 (11.2%) infants had missing data for the screening. 832 infants were not screened due to being admitted to the neonatal intensive care unit for reasons unknown. 17 of the 19 infants who failed the screening had a transthoracic echo report available for review. Of those 17 infants reviewed, seven were diagnosed with CCHD. CONCLUSIONS: 85% of the infants born in WV who received a Birth Score during the year reviewed were screened for CCHD. Given that the goal is to have 100% compliance with the pulse oximetry screening, additional investigations into factors affecting compliance may be necessary.

State Legislation, Regulations, and Hospital Guidelines for Newborn Screening for Critical Congenital Heart Defects - United States, 2011-2014.

Critical congenital heart defects (CCHD) occur in approximately two of every 1,000 live births. Newborn screening provides an opportunity for reducing infant morbidity and mortality. In September 2011, the U.S. Department of Health and Human Services (HHS) Secretary endorsed the recommendation that critical congenital heart defects be added to the Recommended Uniform Screening Panel (RUSP) for all newborns. In 2014, CDC collaborated with the American Academy of Pediatrics (AAP) Division of State Government Affairs and the Newborn Screening Technical Assistance and Evaluation Program (NewSTEPs) to assess states' actions for adopting newborn screening for CCHD. Forty-three states have taken action toward newborn screening for CCHD through legislation, regulations, or hospital guidelines. Among those 43, 32 (74%) are collecting or planning to collect CCHD screening data; however, the type of data collected by CCHD newborn screening programs varies by state. State mandates for newborn screening for CCHD will likely increase the number of newborns screened, allowing for the possibility of early identification and prevention of morbidity and mortality. Data collection at the state level is important for surveillance, monitoring of outcomes, and evaluation of state CCHD newborn screening programs.

Two faces of patient advocacy: the current controversy in newborn screening.

Newborn screening programmes began in the 1960s, have traditionally been conducted without parental permission and have grown dramatically in the last decade. Whether these programmes serve patients' best interests has recently become a point of controversy. Privacy advocates, concerned that newborn screening infringes upon individual liberties, are demanding fundamental changes to these programmes. These include parental permission and limiting the research on the blood samples obtained, an agenda at odds with the viewpoints of newborn screening advocates. This essay presents the history of newborn screening in the USA, with attention to factors that have contributed to concerns about these programmes. The essay suggests that the rapid increase in the number of disorders screened for and the addition of research without either public knowledge or informed consent were critical to the development of resistance to mandatory newborn screening and research. Future newborn screening initiatives should include public education and comment to ensure continued support.

[Results and lessons after 10 years of universal neonatal hearing screening in the Champagne-Ardenne region of France]. / Dépistage systématique de la surdité à la naissance : résultats et enseignements au terme de 10 ans de pratique en Champagne-Ardenne.

In France, universal newborn hearing screening has been mandatory since April23rd, 2012, but it began in the Champagne-Ardenne region on January 15th 2004. More than 99 % of 160 196 newborns have since been systematically screened in this region. Bilateral hearing impairment was thus identified in 116 infants when they were around 3.5 months old. Earlier diagnosis improves the outcome of deafness, which is only diagnosed around age 20 months without screening. The authors report their experience and the lessons learnt.

Inborn errors of metabolism and expanded newborn screening: review and update.

Inborn errors of metabolism (IEM) are a phenotypically and genetically heterogeneous group of disorders caused by a defect in a metabolic pathway, leading to malfunctioning metabolism and/or the accumulation of toxic intermediate metabolites. To date, more than 1000 different IEM have been identified. While individually rare, the cumulative incidence has been shown to be upwards of 1 in 800. Clinical presentations are protean, complicating diagnostic pathways. IEM are present in all ethnic groups and across every age. Some IEM are amenable to treatment, with promising outcomes. However, high clinical suspicion alone is not sufficient to reduce morbidities and mortalities. In the last decade, due to the advent of tandem mass spectrometry, expanded newborn screening (NBS) has become a mandatory public health strategy in most developed and developing countries. The technology allows inexpensive simultaneous detection of more than 30 different metabolic disorders in one single blood spot specimen at a cost of about USD 10 per baby, with commendable analytical accuracy and precision. The sensitivity and specificity of this method can be up to 99% and 99.995%, respectively, for most amino acid disorders, organic acidemias, and fatty acid oxidation defects. Cost-effectiveness studies have confirmed that the savings achieved through the use of expanded NBS programs are significantly greater than the costs of implementation. The adverse effects of false positive results are negligible in view of the economic health benefits generated by expanded NBS and these could be minimized through increased education, better communication, and improved technologies. Local screening agencies should be given the autonomy to develop their screening programs in order to keep pace with international advancements. The development of biochemical genetics is closely linked with expanded NBS. With ongoing advancements in nanotechnology and molecular genomics, the field of biochemical genetics is still expanding rapidly. The potential of tandem mass spectrometry is extending to cover more disorders. Indeed, the use of genetic markers in T-cell receptor excision circles for severe combined immunodeficiency is one promising example. NBS represents the highest volume of genetic testing. It is more than a test and it warrants systematic healthcare service delivery across the pre-analytical, analytical, and post-analytical phases. There should be a comprehensive reporting system entailing genetic counselling as well as short-term and long-term follow-up. It is essential to integrate existing clinical IEM services with the expanded NBS program to enable close communication between the laboratory, clinicians, and allied health parties. In this review, we will discuss the history of IEM, its clinical presentations in children and adult patients, and its incidence among different ethnicities; the history and recent expansion of NBS, its cost-effectiveness, associated pros and cons, and the ethical issues that can arise; the analytical aspects of tandem mass spectrometry and post-analytical perspectives regarding result interpretation.

Technical report: Ethical and policy issues in genetic testing and screening of children.

The genetic testing and genetic screening of children are commonplace. Decisions about whether to offer genetic testing and screening should be driven by the best interest of the child. The growing literature on the psychosocial and clinical effects of such testing and screening can help inform best practices. This technical report provides ethical justification and empirical data in support of the proposed policy recommendations regarding such practices in a myriad of settings.

We're off to see the genome.

We discuss some societal and legal ramifications of the human genetics revolution. Our reflections were stimulated by discussions among scientists, citizens and legal experts at a large public symposium. We outline key issues regarding oversight of genetic research on human subjects, banking of DNA data by governments and corporations, the potential impact of behavioural genetics and effects upon racial and racist thinking. We contend that, in some cases, well-intentioned but naive efforts to protect the rights of individuals and groups may hurt everyone by blocking the progress of useful research.

Revisiting the Wilson-Jungner criteria: how can supplemental criteria guide public health in the era of genetic screening?

PURPOSE: Advances in technology have made newborn screening for more than 50 inborn errors of metabolism possible using a dried blood sample. A framework is proposed that public health practitioners may use when considering candidate disorders for newborn screening panels. METHODS: The framework expands on the 10 Wilson-Jungner criteria with the addition of 11 criteria specific to newborn screening. A calculation, the "pNBS Decision Score," is used to quantify results and rank candidate disorders. RESULTS: The pNBS Decision Scores that were calculated for phenylketonuria (OMIM# 261600), cystic fibrosis (OMIM# 219700), Pompe disease (OMIM# 232300), and severe combined immunodeficiency (OMIM# 102700) support their inclusion as newborn screening disorders. The pNBS Decision Score suggests that Krabbe disease (OMIM# 245200) is not a candidate disorder for inclusion at this time. CONCLUSION: The proposed framework adds to the ability of policy makers to quantify an essential portion of the process for adding disorders to newborn screening panels. Other factors such as ethical, legal, and social issues, clinical utility, and advocacy are also part of the policy process. The framework is not intended to replace existing nomination processes but rather to enhance those processes by encouraging iterative review of newborn screening-specific criteria. The use of the framework will provide consistency across a portion of the decision process. The public health community should take the opportunity to revisit the screening determinants of the Wilson-Jungner criteria from a 21st century perspective. The results suggest that this framework provides the public health practitioner with a consistent process for making an evidence-based decision.