Missed Cystic Fibrosis Newborn Screening Cases due to Immunoreactive Trypsinogen Levels below Program Cutoffs: A National Survey of Risk Factors.

Testing immunoreactive trypsinogen (IRT) is the first step in cystic fibrosis (CF) newborn screening. While high IRT is associated with CF, some cases are missed. This survey aimed to find factors associated with missed CF cases due to IRT levels below program cutoffs. Twenty-nine states responded to a U.S-wide survey and 13 supplied program-related data for low IRT false screen negative cases (CFFN) and CF true screen positive cases (CFTP) for analysis. Rates of missed CF cases and odds ratios were derived for each factor in CFFNs, and two CFFN subgroups, IRT above ("high") and below ("low") the CFFN median (39 ng/mL) compared to CFTPs for this entire sample set. Factors associated with "high" CFFN subgroup were Black race, higher IRT cutoff, fixed IRT cutoff, genotypes without two known CF-causing variants, and meconium ileus. Factors associated with "low" CFFN subgroup were older age at specimen collection, Saturday birth, hotter season of newborn dried blood spot collection, maximum ≥ 3 days laboratories could be closed, preterm birth, and formula feeding newborns. Lowering IRT cutoffs may reduce "high" IRT CFFNs. Addressing hospital and laboratory factors (like training staff in collection of blood spots, using insulated containers during transport and reducing consecutive days screening laboratories are closed) may reduce "low" IRT CFFNs.

William Harry Hannon-A Life Well Lived.

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Successful Implementation of Expanded Newborn Screening in the Philippines Using Tandem Mass Spectrometry.

Newborn bloodspot screening (NBS) began as a research project in the Philippines in 1996 and was mandated by law in 2004. The program initially included screening for five conditions, with a sixth added in 2012. As screening technology and medical knowledge have advanced, NBS programs in countries with developed economies have also expanded, not only in the number of newborns screened but also in the number of conditions included in the screening. Various approaches have been taken regarding selection of conditions to be screened. With limited resources, low- and middle-income countries face significant challenges in selecting conditions for screening and in implementing sustainable screening programs. Building on expansion experiences in the U.S. and data from California on Filipinos born and screened there, the Philippine NBS program has recently completed its expansion to include 29 screening conditions. This report focuses on those conditions detectable through tandem mass spectrometry. Expanded screening was implemented in a stepwise fashion across the seven newborn screening laboratories in the Philippines. A university-based biochemical genetics laboratory provides confirmatory testing. Follow-up care for confirmed cases is monitored and provided through the NBS continuity clinics across the archipelago. Pre-COVID-19 pandemic, the coverage was 91.6% but dropped to 80.4% by the end of 2020 due to closure of borders between cities, provinces, and islands.

Newborn Screening Long-Term Follow-Up Clinics (Continuity Clinics) in the Philippines during the COVID-19 Pandemic: Continuing Quality Patient Care.

The COVID-19 pandemic has challenged healthcare systems worldwide. In the Philippines, long-term care for patients with conditions identified through newborn screening (NBS) is coordinated through Newborn Screening Continuity Clinics (NBSCCs). These clinics are integral to achieving optimal outcomes by providing follow-up oversight and assistance for individuals identified through screening. Continuity of NBSCC care for NBS during the COVID-19 pandemic was both challenging and necessary and was accomplished through innovative strategies of dedicated personnel. Following the discontinuation of the community quarantine, a situation assessment survey was completed by each NBSCC to better understand the challenges encountered and their effect on patient care. Performance data from each NBSCC were reviewed both before and after an extended community quarantine (2018-2021) to evaluate the impact of NBSCC disaster contingency plans in overcoming the resultant challenges (transportation, supply chain, etc.). Thematic analysis of the survey showed three primary challenges: Operations, communications, and safety. In 2018 and 2019, successful patient contacts were 70.6% and 70.2%, respectively. During the pandemic, successful contacts were 74.9% in 2020 and 76.8% in 2021, demonstrating that the contact approaches taken by the NBSCCs were sufficient to maintain (and even improve) patient contacts. The number of unresponsive patients decreased during the pandemic likely due to decreased mobility and improved follow-up actions from the NBSCCs.

Successful Implementation of Newborn Screening for Hemoglobin Disorders in the Philippines.

The Philippine newborn bloodspot screening (NBS) program began in 1996 with 24 hospitals and was formalized by legislation in 2004. The NBS panel was recently expanded to include a number of additional hereditary congenital conditions. Expertise and experiences from other NBS programs already screening for hemoglobinopathies were essential to its successful integration into the ongoing dried bloodspot NBS program in the Philippines. Building on clinical experiences and population data from Filipinos born in California, USA, hemoglobinopathies (including thalassemias) were selected for inclusion in the expanded screening panel. Hemoglobinopathy NBS, using high performance liquid chromatography, was implemented in a stepwise manner into the seven regional NBS screening laboratories. A central university laboratory provides confirmatory testing using both capillary electrophoresis and molecular methodologies. NBS results indicating carriers are followed up with educational fact sheets, while results of presumptive disease are referred for confirmatory testing and follow-up with a hematologist. Long-term care is provided through newborn screening continuity clinics across the country. Hemoglobinopathy NBS is now included in the national insurance package and screening uptake continues to increase nationally, exceeding 90% of all newborns in 7400+ hospitals and birthing centers nationwide prior to the COVID-19 pandemic.

Philippine Performance Evaluation and Assessment Scheme (PPEAS): Experiences in Newborn Screening System Quality Improvement.

Newborn Bloodspot Screening (NBS) has existed for over 60 years, having been initiated by Guthrie in the U.S. In the Philippines, NBS was introduced in 1996 and later was supported by legislation. The NBS program now includes 29 conditions, covering 91.6% of the newborn population in 2019. Program growth and expansion necessitated development of a formal performance evaluation and assessment scheme (PEAS) for monitoring performance and for continuously improving quality. This study's objective was to present the development, implementation, and results to date of the Philippine Performance PEAS (PPEAS). Using the comprehensive listing of laboratory and non-laboratory elements in the model PEAS system in the U.S., PPEAS tools were developed for critical Philippine NBS system components: regional Department of Health (national health agency, Philippines) (DOH) offices (CHDs), NBS laboratories (NSCs), NBS specimen submitters (NSFs), and long-term case management centers (NBSCCs). Data generated from the various PPEAS have been periodically reviewed and analyzed for NBS system impact. PPEAS were developed to facilitate quality improvement at various levels of the Philippine NBS system. PPEAS identified successes, gaps, and challenges to be addressed by NSCs, NSFs, CHDs, and NBSCCs with the assistance of the Newborn Screening Reference Center and the Department of Health.

Empowering newborn screening programs in African countries through establishment of an international collaborative effort.

In an effort to explore new knowledge and to develop meaningful collaborations for improving child health, the First Pan African Workshop on Newborn Screening was convened in June 2019 in Rabat, Morocco. Participants included an informal network of newborn screening stakeholders from across Africa and global experts in newborn screening and sickle cell disease. Over 150 attendees, representing 20 countries, were present including 11 African countries. The agenda focused on newborn screening rationale, techniques, system development, implementation barriers, ongoing research, and collaborations both globally and across Africa. We provide an overview of the workshop and a description of the newborn screening activities in the 11 African countries represented at the workshop, with a focus on sickle cell disease.

Newborn screening in the developing countries.

PURPOSE OF REVIEW: We review newborn screening (NBS) publications from the developing countries to identify global progress in improving child health. RECENT FINDINGS: Many developing countries do not yet have national NBS. As infant mortality rates decline, NBS gains in public health priority. Local incidence and outcome data are used to persuade health officials to include screening in priority health spending. Congenital hypothyroidism is the most cost-effective screened condition in most countries. In sub-Saharan Africa, India and some parts of Asia, screening for hemoglobinopathies and glucose-6-dehydrogenase deficiency are also important. Expanded screening for metabolic conditions is most needed in areas of high consanguinity. Screening for hearing disorders and critical congenital heart defects is increasing globally. The largest birth cohorts are India and China, but only China has successful NBS. Reports from completed government research projects in India support initiation of NBS. SUMMARY: Government activities around NBS are increasing in India and there is increased emphasis on pilot programs for sickle cell NBS in sub-Saharan Africa. Genetic counseling training in Asia and Africa is increasing and will be helpful as part of NBS. To build successful screening programs, partnerships among health professionals, parents, policy makers and industry stakeholders are essential.

Newborn screening for hyperargininemia due to arginase 1 deficiency.

Hyperargininemia caused by Arginase 1 deficiency is a rare disorder of the urea cycle that can be diagnosed by elevation of arginine in newborn screening blood spots when analyzed by tandem mass spectrometry. Hyperargininemia is currently included as a secondary target on the U.S. Recommended Uniform Screening Panel, which directly influences state-based newborn screening. Because of the apparent low disease frequency and lack of case detection and treatment data, detailed attention has not been given to a model newborn screening algorithm including appropriate analytical cutoff values for disease indicators. In this paper we assess the frequency of hyperargininemia in the U.S. identified by newborn screening to date and document the current status and variability of hyperargininemia newborn screening across U.S. newborn screening programs. We also review other data that support improved screening efficacy by utilizing the arginine/ornithine ratio and other amino acid ratios as discriminators in the screening algorithm. Analysis of archived California screening data showed that an arginine cutoff of 50µM combined with an arginine/ornithine ratio of 1.4 would have resulted in a recall rate of 0.01%. Using an arginine cutoff of 60µM and an arginine/(phenylalanine x leucine) ratio of 1.4, reportedly used in one screening program, or the R4S Tool Runner, would have resulted in a recall rate of <0.005%. All 9 diagnosed patients would have been found for either protocol. Thus, use of appropriate ratios as part of the screening algorithm has the potential to increase both screening sensitivity and specificity. Improved newborn screening effectiveness should lead to better case detection and more rapid treatment to lower plasma arginine levels hence improving long term outcome of individuals with hyperargininemia.

A framework for assessing outcomes from newborn screening: on the road to measuring its promise.

UNLABELLED: Newborn screening (NBS) is intended to identify congenital conditions prior to the onset of symptoms in order to provide early intervention that leads to improved outcomes. NBS is a public health success, providing reduction in mortality and improved developmental outcomes for screened conditions. However, it is less clear to what extent newborn screening achieves the long-term goals relating to improved health, growth, development and function. We propose a framework for assessing outcomes for the health and well-being of children identified through NBS programs. The framework proposed here, and this manuscript, were approved for publication by the Secretary of Health and Human Services' Advisory Committee on Heritable Disorders in Newborns and Children (ACHDNC). This framework can be applied to each screened condition within the Recommended Uniform Screening Panel (RUSP), recognizing that the data elements and measures will vary by condition. As an example, we applied the framework to sickle cell disease and phenylketonuria (PKU), two diverse conditions with different outcome measures and potential sources of data. Widespread and consistent application of this framework across state NBS and child health systems is envisioned as useful to standardize approaches to assessment of outcomes and for continuous improvement of the NBS and child health systems. SIGNIFICANCE: Successful interventions for newborn screening conditions have been a driving force for public health newborn screening for over fifty years. Organizing interventions and outcome measures into a standard framework to systematically assess outcomes has not yet come into practice. This paper presents a customizable outcomes framework for organizing measures for newborn screening condition-specific health outcomes, and an approach to identifying sources and challenges to populating those measures.

Current status of newborn screening worldwide: 2015.

Newborn screening describes various tests that can occur during the first few hours or days of a newborn's life and have the potential for preventing severe health problems, including death. Newborn screening has evolved from a simple blood or urine screening test to a more comprehensive and complex screening system capable of detecting over 50 different conditions. While a number of papers have described various newborn screening activities around the world, including a series of papers in 2007, a comprehensive review of ongoing activities since that time has not been published. In this report, we divide the world into 5 regions (North America, Europe, Middle East and North Africa, Latin America, and Asia Pacific), assessing the current NBS situation in each region and reviewing activities that have taken place in recent years. We have also provided an extensive reference listing and summary of NBS and health data in tabular form.

Newborn screening for sickle cell diseases in the United States: A review of data spanning 2 decades.

UNLABELLED: Sickle cell disease is a group of disorders, the majority of which are detected through state newborn screening programs. There is limited knowledge of disease prevalence in the U.S. POPULATION: We report 20 years of case finding and laboratory data for sickle cell disease and trait to assist in: planning for health services delivery; providing data for researchers; aiding in tracking health outcome trends; and assessing sickle gene prevalence in the newborn population. During the 20-year period, there were 39,422 confirmed cases of sickle cell disease among 76,527,627 newborn births screened (1:1941) and 1,107,875 laboratory reports of probable sickle trait among 73,951,175 newborn births screened (1:67). The highest sickle cell disease incidence during the 20 years was in the District of Columbia (1:437) followed by Mississippi (1:683) and South Carolina (1:771). For sickle cell trait, the highest incidences were in the District of Columbia (1:22), Mississippi (1:26), and South Carolina (1:31).

Inborn errors of metabolism identified via newborn screening: Ten-year incidence data and costs of nutritional interventions for research agenda planning.

Inborn errors of metabolism (IEM) are genetic disorders in which specific enzyme defects interfere with the normal metabolism of exogenous (dietary) or endogenous protein, carbohydrate, or fat. In the U.S., many IEM are detected through state newborn screening (NBS) programs. To inform research on IEM and provide necessary resources for researchers, we are providing: tabulation of ten-year state NBS data for selected IEM detected through NBS; costs of medical foods used in the management of IEM; and an assessment of corporate policies regarding provision of nutritional interventions at no or reduced cost to individuals with IEM. The calculated IEM incidences are based on analyses of ten-year data (2001-2011) from the National Newborn Screening Information System (NNSIS). Costs to feed an average person with an IEM were approximated by determining costs to feed an individual with an IEM, minus the annual expenditure for food for an individual without an IEM. Both the incidence and costs of nutritional intervention data will be useful in future research concerning the impact of IEM disorders on families, individuals and society.

Including the initial newborn screening bloodspot collection device serial number on birth certificates: basis and recommendations from the Secretary of Health and Human Services' Advisory Committee on Heritable Disorders in Newborns and Children.

PURPOSE: We provide background information/education for national recommendations to include initial newborn screening dried bloodspot serial numbers in electronic birth registrations. Mutual data linking would provide quality checks for each data source, determinations of percentages of newborns screened, and identification of locations where screening is lacking. METHODS: State newborn screening dried bloodspot programs were surveyed to determine the extent of newborn screening dried bloodspot and electronic birth registration linking and the states' level of interest in such linkages. These data were reviewed with federal and state policy makers and presented to the Secretary of Health and Human Services' Advisory Committee on Heritable Disorders in Newborns and Children for national policy recommendations. RESULTS: Only 40% of state newborn screening dried bloodspot programs reported comparing births with screens. All states use serially numbered newborn screening dried bloodspot collection cards, and electronic birth registrations exist in almost all states. Newborn screening dried bloodspot serial number data fields currently exist in only 24% of state electronic birth registrations. CONCLUSION: The Secretary of Health and Human Services' Advisory Committee on Heritable Disorders in Newborns and Children recommends the universal use of the newborn screening dried bloodspot serial number in a standardized format as part of state birth registration; consideration of including the initial newborn screening dried bloodspot serial number as a required data field; and, once established, using these data linkages to monitor completeness of newborn screening and to validate demographic information in both systems.

Design and evaluation of a decision aid for inviting parents to participate in a fragile X newborn screening pilot study.

The major objectives of this project were to develop and evaluate a brochure to help parents make an informed decision about participation in a fragile X newborn screening study. We used an iterative development process that drew on principles of Informed Decision Making (IDM), stakeholder input, design expertise, and expert evaluation. A simulation study with 118 women examined response to the brochure. An independent review rated the brochure high on informational content, guidance, and values. Mothers took an average of 6.5 min to read it and scored an average of 91.1 % correct on a knowledge test. Most women rated the brochure as high quality and trustworthy. When asked to make a hypothetical decision about study participation, 61.9 % would agree to screening. Structural equation modeling showed that agreement to screening and decisional confidence were associated with perceived quality and trust in the brochure. Minority and white mothers did not differ in perceptions of quality or trust. We demonstrate the application of IDM in developing a study brochure. The brochure was highly rated by experts and consumers, met high standards for IDM, and achieved stated goals in a simulation study. The IDM provides a model for consent in research disclosing complicated genetic information of uncertain value.

Immunoreactive Trypsinogen (IRT) as a Biomarker for Cystic Fibrosis: challenges in newborn dried blood spot screening.

On May 23-24, 2011, a workshop entitled "Immunoreactive Trypsinogen (IRT) as a Biomarker for Cystic Fibrosis: Technical Issues and Challenges" was held in Annapolis, Maryland. The two-day workshop was co-hosted by the National Newborn Screening and Genetics Resource Center, Austin, Texas, and the Association of Public Health Laboratories, Silver Spring, Maryland, in collaboration with the Health Resources and Services Administration and the Centers for Disease Control and Prevention. Participants included nearly 40 representatives from U.S. state public health and commercial laboratories performing newborn dried blood spot screening tests for cystic fibrosis (CF), the federal government, academic research institutions, and commercial vendors of products used in newborn screening. Representatives from selected European CF newborn screening programs were also present. The workshop focused on identifying key IRT testing issues and mechanisms for achieving their resolution and laboratory harmonization in order to reduce, or eliminate completely, the late identified CF cases following a negative newborn screen. Informative findings are reported, their impacts on improving IRT screening are described, and their implications are discussed.

Consolidating newborn screening efforts in the Asia Pacific region : Networking and shared education.

Many of the countries in the Asia Pacific Region, particularly those with depressed and developing economies, are just initiating newborn screening programs for selected metabolic and other congenital disorders. The cultural, geographic, language, and economic differences that exist throughout the region add to the challenges of developing sustainable newborn screening systems. There are currently more developing programs than developed programs within the region. Newborn screening activities in the Asia Pacific Region are particularly important since births there account for approximately half of the world's births. To date, there have been two workshops to facilitate formation of the Asia Pacific Newborn Screening Collaboratives. The 1st Workshop on Consolidating Newborn Screening Efforts in the Asia Pacific Region occurred in Cebu, Philippines, on March 30-April 1, 2008, as a satellite meeting to the 7th Asia Pacific Conference on Human Genetics. The second workshop was held on June 4-5, 2010, in Manila, Philippines. Workshop participants included key policy-makers, service providers, researchers, and consumer advocates from 11 countries with 50% or less newborn screening coverage. Expert lectures included experiences in the United States and the Netherlands, international quality assurance activities and ongoing and potential research activities. Additional meeting support was provided by the U.S. National Institutes of Health, the Centers for Disease Control and Prevention, the U.S. National Newborn Screening and Genetics Resource Center, the International Society for Neonatal Screening, and the March of Dimes. As part of both meeting activities, participants shared individual experiences in program implementation with formal updates of screening information for each country. This report reviews the activities and country reports from two Workshops on Consolidating Newborn Screening Efforts in the Asia Pacific Region with emphasis on the second workshop. It also updates the literature on screening activities and implementation/expansion challenges in the participating countries.