Reliability of Neonatal Screening Results
2018; Multidisciplinary Digital Publishing Institute; Volume: 4; Issue: 3 Linguagem: Inglês
10.3390/ijns4030028
ISSN2409-515X
AutoresMária Knapková, Kate Hall, Gerard Loeber,
Tópico(s)Prenatal Screening and Diagnostics
Resumofirst_page settings Order Article Reprints Font Type: Arial Georgia Verdana Font Size: Aa Aa Aa Line Spacing: Column Width: Background: Open AccessMeeting Report Reliability of Neonatal Screening Results by Maria Knapkova 1, Kate Hall 2 and Gerard Loeber 3,* 1 Newborn Screening Center SK, Children's. Faculty Hospital. Banská Bystrica 97401, Slovakia 2 The Spinney, Sutton Coldfield, B75 5NQ, UK 3 ISNS office * Author to whom correspondence should be addressed. Int. J. Neonatal Screen. 2018, 4(3), 28; https://doi.org/10.3390/ijns4030028 Received: 20 July 2018 / Accepted: 6 September 2018 / Published: 6 September 2018 (This article belongs to the Special Issue Selected Papers from 11th ISNS European Regional Meeting) Download Download PDF Download PDF with Cover Download XML Download Epub Versions Notes 1. IntroductionThis special edition of the International Journal of Neonatal Screening comprises the abstracts of all oral presentations and posters from the biennial ISNS European regional meeting, to be held in Bratislava, Slovakia, 14–17 October 2018.While some neonatal screening programs around the globe have run for more than fifty years, scientific and technological advancements are rapidly enabling neonatal screening for ever more congenital conditions to become available. This potential to significantly expand the scope of neonatal screening reminds us that it is worthwhile reviewing experience acquired by earlier neonatal screening programs and asking if the screening result is reliable i.e., to what extent does the result provide a true answer to the question of whether the infant suffers from the condition sought?Factors involved in setting up a reliable screening system include establishing a clear definition of the disorder, determining which analytical parameters in body fluids are abnormal and can be analyzed with sufficient analytical precision to allow concentration or value ranges to be set to indicate a normal or a suspicious result with minimal overlap. Whether the infant's gender, ethnicity, gestational age at birth, age at sampling or nutritional status should be considered in interpreting the result is very important.The conference emphasizes the need to understand the reliability of screening results based on reflections on long-term experiences of screening for certain conditions such as congenital hypothyroidism. Time is also devoted to developments for two relatively new conditions, i.e., severe combined immunodeficiency (SCID) and spinal muscular dystrophy (SMA). Finally, the current neonatal screening situation in Europe is highlighted. 2. Invited Presentations I1. Some Notes on the History of Newborn Screening in Slovakia Svetozár Dluholucký Newborn Screening Center SK, Children's, Faculty Hospital, Banská Bystrica 97401, Slovakia Newborn Screening (NS) in Slovakia started in 1985, after a six-year pilot study, testing logistics and collaborating individual healthcare workplaces. Screening of congenital hypothyroidism (CH) was performed by a T4 RIA suite with a thyroid stimulating hormone (TSH) confirmation, later exchanged for TSH ILMA with T4 confirmation. Screening of PKU/HPA was associated at one center following the introduction of the phenylalanine dried blood spot (DBS) (1995) fluorometric assay. Further screening of congenital adrenal hyperplasia (CAH) by 17OHP ILMA was introduced by r. 2003, cystic fibrosis (CF) (IRT) screening in 2009. Screening of selected inherited metabolic diseases (IMD) MS/MS in 2012 and another 10 IMDs in pilot mode were added in 2013. At the moment, there are 23 failures in a single screening center in Slovakia. A specific feature of Slovak Screening is its coding system that allows the child identification by birthplace, the identification of escape from screening, and the number of examined children at the given time. The system allows to follow-up the screening population coverage, which is permanently almost 100%. Another specific point is that the second recall of suspected cases is provided at regional recall centers that assure further care in confirmed cases at the level of children's university hospitals. Continuous exchange of information between the screening center and recall centers allows monitoring of the actual incidence of malfunctions and possible correction of diagnosis. Since the introduction of NSF CF, it was necessary to start a follow-up of newborns according to ethnicity, as Roma children had a significantly higher cut-off value of both IRT1 and IRT2. This tracking allowed us to assess the ethnic incidence of all types of malfunctions. Since the start of NS in Slovakia, we have noted several good moments: The cumulative incidence of CH rises steadily over the years. While in 1985–1990 it was 1:5300, it was up to 1:1700 in 2017. The incidence of CH is higher in the Roma ethnicity (Index 1.3), its share in the rise of the secular incidence is not significant. The incidence of PKU/HPA has not changed over the years, there are no ethnic differences. Current MS/MS screening sensitively detects HPA cases in immature newborns, depending on nutrition. The incidence of CAH has a decreasing trend, probably due to a reduction in false positivity in the perinatal period (e.g., PICU patients). In Roma ethnicity the incidence of CAH is exceptional and its incidence is close to zero. Similarly to CAH, even in CF screening, although Roma have a 30% higher IRT, cystic fibrosis has been detected and confirmed in only one case of the Roma neonates. NS CF does not detect milder forms of cystic fibrosis. IMD screening using MS/MS revealed significant ethnic differences in incidence and spectrum of disorders. While the incidence of IMD in the majority population is 1:1880, in the Roma population even 1:121. The IMD spectrum in the majority population is dominated by PKU, medium-chain acyl-CoA dehydrogenase deficiency (MCAD), in the Roma population, it is MCAD, SCAD, CUD. In the large SCAD file, two new alleles of gene mutations were discovered, one of which had a potential lethal course (2 cases of SIDS), were found exclusively in Roma children. These findings are the subject of further studies. The ethnical approach to screening brings, in addition to focused care, new insights into this autochthonous minority and its origin. I2. NBS Is Pandora's Box; New Techniques Make Anything Possible Jim R. Bonham Sheffield Children's Hospital, Sheffield S10 2TH, UK There is little doubt that the advent of population-based newborn screening has benefitted many patients and families since its adoption in the 1960s. Indeed, a meeting held in Atlanta in 2012 to celebrate 50 years of newborn screening suggested that the lives of 12,000 babies per year are being saved or improved through this intervention in the US alone and the expansion in the number of conditions tested and the countries who choose to adopt these programs continues to increase throughout the world. When first described the detection of phenylketonuria depended upon a specific test to identify an increased concentration of phenylalanine in neonatal blood. The subsequent addition of screening for congenital hypothyroidism in the 1980s in many countries similarly depended upon a specifically designed test for a signature compound by a distinct technique. The introduction of enzyme linked immunoassays allowed generic approaches albeit with a single assay for each disorder. Electrospray injection tandem mass spectrometry in the 1990s changed this landscape by offering an approach to detect a range of up to 30 conditions using a single inexpensive test where a suitable key biochemical metabolite could be identified. More recently the introduction of DNA-based techniques such as T-cell receptor excision circle (TREC) analysis and next generation sequencing capable of using a dried blood spot sample provides the basis to extend the range of conditions to include those such as SCID and fragile X where no suitable biochemical marker exists. Biochemical, both metabolite and enzymic, and genetic testing combined with "big data" analysis to identify key environmental factors related to childhood well-being and development could go further to provide a comprehensive approach to improve the life chances of many children. Nevertheless, like Pandora's Box there can be serious and unforeseen side effects from the reasonable wish to identify and help those at risk. The weight attached to these "disutilities" when planning public health interventions varies depending upon those making the decisions. Typically, clinicians involved with treating those affected favor the early detection offered by screening whereas public health planners are somewhat more guarded, attempting to balance the risks for those who may be medicalized unnecessarily compared with the benefits to the small number who can be offered early treatment. An intelligent discussion of the decision around the introduction of new screening programs should perhaps not simply seek to establish the benefits of screening but also address how key disutilities may be ameliorated. These include technical considerations such as improved means of assigning screen positive results and secondary testing but also a qualitative understanding of how public engagement, pre-screening information and the careful delivery of screen positive results can lessen the negative impact of screening programs for the families affected. Closer attention to case definition at the outset with agreed and universally applied diagnostic protocols may do much to reduce uncertainty and facilitate meaningful outcome studies. Such clarity of definition and forward planning should perhaps be a pre-requisite of any new program development. By this means we may be able to assess the longer-term effects from lifting the lid on Pandora's Box and understand more clearly how to limit some of the harms resulting from screening while preserving the benefits that are so important to patients and families. I3. Does It Count? Defining Disorders Veronica Wiley NSW Newborn Screening Program, Sydney Children's Hospital Network, Wentworthville, NSW 2145, Australia Assessing the efficacy of a population screening program requires evaluation of the entire system including the pre-analytical, analytical and post-analytical aspects. While this has been common practice for over 50 years since the World Health Organization commissioned Wilson and Jungner to develop "Principles and Practice of Screening for Disease" [1], there remains a lack of national and international agreement on what should be included in newborn screening programs and what should be counted. Many of the conditions under current consideration as a pilot program of either a country, or at least region within a country, (for example: lysosomal storage disorders and neuromuscular disorders) have diverse clinical symptoms ranging from acute neonatal presentation to those with presentation late in childhood or adulthood, if at all. However, this is not really a new phenomenon with most disorders included in newborn population screening having mild or late-onset forms including phenylketonuria, hypothyroidism, cystic fibrosis and congenital adrenal hyperplasia. Carefully defining what is being sought is necessary to appropriately assess effectiveness. What constitutes a positive result must be defined for the determination of sensitivity (affected persons with a positive result/all affected); specificity (healthy persons with a negative result/all non-affected); and positive predictive value (proportion with a positive result that are affected). In Australasia, the newborn screening committee with clinical and scientific representatives from professional societies advising on aspects of newborn bloodspot screening including the Human Genetics Society of Australasia (HGSA), and the Australasian College of Physicians have developed definitions of disorders for data gathering and to ensure comparability of data. The definitions currently available on the HGSA website recognized that for all cases there needs to be diagnostic evidence and that case finding remains a continuing process and not a one-time project.Wilson, J.M.G.; Jungner, G. Principles and Practice of Screening for Disease. Public Health Papers 1968. Available online: http://apps.who.int/iris/bitstream/10665/208882/1/WHO_PA_66.7_eng.pdf (accessed on 15 June 2018).HGSA (Human Genetics Society of Australasia) Policies. https://www.hgsa.org.au/resources/hgsa-policies-and-position-statements (accessed on 15 June 2018). 2.4. Long-Term Outcome Studies, the (Often) Neglected Part of Newborn Screening Programs Stefan Kölker Division of Pediatric Neurology and Metabolic Medicine, Center for Pediatric and Adolescent Medicine, University Hospital Heidelberg, Heidelberg 69120, Germany Newborn screening (NBS) programs are intended to identify newborns with treatable conditions and to enable the implementation of a therapy before patients suffer irreversible damage. Their goal is thus to improve health outcomes and quality of life of affected individuals. For many diseases, however, the impact of NBS has remained unclear for various reasons. Long-term observational studies are valid tools to overcome these uncertainties and to elucidate whether NBS programs achieve their goal. This is discussed for glutaric aciduria type 1 (GA1), isovaleric aciduria (IVA), (isolated) methylmalonic acidurias (MMA) and propionic aciduria (PA). While GA1 and IVA have been included into an increasing number of NBS programs worldwide, there is still reservation towards inclusion of MMA and PA. When NBS pilot studies for GA1 were initiated two decades ago, evidence was weak that this condition was treatable at all. Meanwhile, studies in different countries confirmed that the neurologic outcome was significantly improved by NBS. However, the patient benefit critically relied on the therapeutic quality: both non-adherence to recommended emergency treatment and low lysine diet clearly increased the risk of striatal damage. Regardless of NBS and therapy, however, chronic kidney disease develops over time in some patients, while loss of GCDH activity was associated with progressing white matter abnormalities of unclear clinical relevance. In contrast to GA1, the benefit for IVA patients is less clear. In comparison to other organic acidurias IVA is exceptional considering its milder neurologic phenotype and the fact that NBS also identifies individuals with mild IVA, a benign disease variant. Although NBS seems to reduce neonatal mortality and to improve neurologic outcome, this positive effect was not confirmed by a recent European study after exclusion of individuals with mild IVA. To avoid overestimation of NBS-related benefits, the case mixes of NBS and pre-screening cohorts must be carefully balanced. MMA and PA are not implemented in the majority of NBS programs since the specificity of C3-based NBS is low and patients with neonatal disease onset may not benefit from NBS. A recent European study showed that about 60–65% of MMA and PA patients remained asymptomatic during the first week of life. Cobalamin-nonresponsive MMA patients identified by NBS were less likely to develop motor abnormalities, while screened PA patients had a lower risk for cardiac manifestation with age than those not screened. With the availability of two or multiple tier NBS technologies these results may encourage to reconsider the inclusion of MMA and PA into NBS programs. These examples show that observational studies are a powerful tool to elucidate the long-term benefits of patients identified by NBS and to optimize and harmonize therapy and management. I5. Neonatal Screening for Congenital Hypothyroidism: 50 Years of Changing Definitions Toni Torresani 8132 Egg, Switzerland Neonatal Screening is a public health initiative, which has been implemented for more than 50 years. Unfortunately, quite often the fact that a neonatal screening test simply indicates that a baby might have a condition, is overlooked. Furthermore, when different programs compare their performances, the different conditions for sample collection, transport and analysis are not taken into consideration. Whether a neonatal screening result can be classified as within or outside limit, is not only dependent from the above-mentioned conditions, but also from several clinical conditions such as maturity, time of sample collection, general health condition of the baby and sometimes also from the mother. The above-mentioned factors have contributed to a change in the definition of the aims of neonatal screening for congenital hypothyroidism. Numerous contributions and publications have appeared in recent years covering this topic. A selected overview of the relevant literature will be presented and discussed. I6. Detection of Congenital Adrenal Hyperplasia: Is There a Need to Screen All Babies Twice? Patrice K. Held 1,*, Stuart K. Shapira 2, Cynthia F. Hinton 2, Elizabeth Jones 3, W. Harry Hannon 4 and Jelili Ojodu 3 1 Wisconsin State Laboratory of Hygiene, University of Wisconsin, Madison, WI 53706, USA 2 National Center on Birth Defects and Developmental Disabilities, Centers for Disease Control and Prevention, Atlanta, GA 30341, USA 3 Newborn Screening and Genetics Program, Association of Public Health Laboratories, Silver Spring, MD 20910, USA 4 Division of Laboratory Sciences, Centers for Disease Control and Prevention (retired), Atlanta, GA 30341, USA * Corresponding author There is no clear consensus among state newborn screening programs on whether routine second screening of newborns identifies clinically relevant cases of congenital adrenal hyperplasia. This retrospective study evaluated laboratory practices, along with biochemical and medical characteristics of congenital adrenal hyperplasia (CAH) cases (1) detected on the first newborn screen in one-screen compared to two-screen states, and (2) detected on the first versus the second screen in the two-screen states, to determine the effectiveness of a second screen. A total of 374 confirmed cases of CAH from 2 one-screen states and 5 two-screen states were included in this study. Demographic data and diagnostic information on each reported case were collected and analyzed. Additionally, laboratory data, including screening methodologies and algorithms, were evaluated. The one-screen states reported 99 cases of CAH out of 1,740,586 (1 in 17,500) newborns screened: 88 (89%) identified on first screen and 5 (5%) identified on targeted second screen. The two-screen states reported 275 cases of CAH out of 2,629,627 (1 in 9500) newborns screened: 165 (60%) identified on first screen and 99 (36%) identified on second screen. Using a multivariate model, the only significant predictor of whether a case was identified on the first or second screen in the two-screen states was the type of CAH. Compared with classical salt-wasting CAH, classical simple virilizing and non-classical CAH cases were less likely to be detected on the first versus the second screen. The routine second newborn screen is important for identifying children with CAH, particularly simple virilizing and non-classical forms, which might otherwise not be captured through a single screen. Mol Genet Metab. 2015 November; 116(3): 133–138. I7. Precision Newborn Screening Driven by Results Adjustments for Multiple Covariates Piero Rinaldo Biochemical Genetics Laboratory, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN 55905, USA Virtually all medical specialties are challenged by utilization management and precision medicine forces, so public health and specifically the performance of newborn screening are unlikely to be exempted from the same scrutiny. Newborn screening (NBS) is based upon laboratory tests performed on a growing proportion of ~130 million children born worldwide every year. Poor performance on a mass scale distresses a multitude of patients, and exposes both families and providers to an increasing risk of psychosocial harm while incurring in unnecessary expenses. Our multidisciplinary team is focused on the creation of high-throughput post-analytical interpretive tools to improve NBS performance. Our goal is to achieve a near-zero false positive rate (FPR), which is the proposed definition of precision newborn screening. Collaborative Laboratory Integrated Reports (CLIR 2.09; https://clir.mayo.edu) is a second-generation web application that maintains an interactive database of laboratory results from multiple sites. The CLIR tools are applicable to either the diagnosis of one condition or to the differential diagnosis between two conditions with overlapping phenotypes (affected vs. heterozygote; true positives vs. false positives). CLIR's defining characteristics are the replacement of analyte cut-off values with condition-specific degree of overlap between cumulative reference and disease ranges, and the integration of primary markers with all informative permutations of ratios. Ratios calculated between markers not directly related at the biochemical level are particularly helpful to correct for pre-analytical factors and potential analytical bias. An additional and unique feature of CLIR is the replacement of conventional reference intervals with continuous, covariate-adjusted (age, birth weight, sex) moving percentiles. Harmonization by location is also routinely possible. Access to CLIR is freely available to qualified users worldwide willing to share reference data and profiles of positive cases in advance of being given access to the website. The goal of collaboration and data sharing is to sustain a constantly evolving, and improving, clinical validation. The type of statistical modeling that takes place within CLIR requires big data, and indeed a willingness to evaluate the concept that reference intervals could be defined by "recycling" and harmonizing vast amounts (>>1 M) of normal screening test results from a multitude of sources. As an example, over a two-year period (N = 116,469) we have achieved an FPR of 0.0009% and a positive predictive value (PPV) of 87% for NBS of three lysosomal disorders. FPR reduction for non-MS/MS conditions between 50% and 80% is also achievable. I8. Newborn Screening for Severe Combined Immunodeficiency (SCID) Bobby Gaspar Professor of Pediatrics and Immunology, UCL Great Ormond Street Institute of Child Health, 30 Guilford Street, London WC1N 1EH, UK Severe combined immunodeficiency (SCID) is the most severe form of inherited primary immunodeficiency and is a pediatric emergency. Delay in recognizing and detecting SCID can have fatal consequences and reduces the chances of a successful hematopoietic stem cell transplant (HSCT). Screening for SCID at birth would prevent children from dying before HSCT can be attempted and would increase the success of HSCT. There is strong evidence to show that SCID fulfills the internationally-established criteria for a condition to be screened for at birth. There is also a test (the T-cell receptor excision circle (TREC) assay) that is now being successfully used in an increasing number of US states to screen for SCID in routine newborn Guthrie samples. Concerted lobbying efforts have highlighted the need for newborn screening (NBS) for SCID, and its implementation is being discussed in Europe both at EU and individual country level, but as yet there is no global mandate to screen for this rare and frequently lethal condition. This session will summarize the current evidence for, and the success of SCID NBS, together with a review of the practical aspects of SCID testing and the arguments in favor of adding SCID to the conditions screened for at birth. I9. Newborn Screening for Severe Combined Immunodeficiencies–IPOPI Perspective Leire Solis Health Policy and Advocacy Manager, International Patient Organization for Primary Immunodeficiencies (IPOPI), Estoril 2765-187, Portugal Newborn screening for rare diseases has been a successful method of speeding up diagnosis and treatment of diseases. In case of diseases in need of a timely diagnosis and early access to treatment, such as severe combined immunodeficiencies, newborn screening is of paramount importance and should be seen as a pediatric emergency. Screening newborns to identify whether they could have SCID is possible and is already ongoing in some countries and regions of the world. It is already happening and helping patients access, once the diagnosis is confirmed, their life-saving curative treatment. From a patient perspective and given the availability of curative treatments (HSCT and gene therapies), every country should take the necessary steps to ensure that the lives of children with SCID can be saved. The first crucial step to do this is to screen all newborns for SCID. IPOPI, as the International Patient Organization for Primary Immunodeficiencies, has been supporting initiatives and programs aimed at achieving the implementation of SCID newborn screening. We are working at European level and supporting national campaigns of some of our members to ensure a timely implementation. From IPOPI's perspective, only by establishing a partnership between healthcare professionals, screening experts and patients, can advocacy campaigns be successful in making SCID newborn screening a reality that will help avoiding the loss of many babies' lives. I10. Newborn Screening for SCID in New Zealand Webster D., de Hora M., Dryland P., Sinclair J., Hsiao K. and Brothers S. National Testing Center, Auckland AK1, New Zealand Adding disorders to the New Zealand newborn screening program follows a well-documented process and this was followed for the addition of SCID including a cost utility study which showed the Quality Adjusted Life Year (QALY) cost similar to other healthcare interventions and screening started in December 2017. Although the Policy Framework lists introduction of new screening tests as a primary use of the dried blood spot sample the Ministry of Health National Screening Unit (NSU) did not approve use of anonymized samples for assay set up and validation and a protocol was agreed whereby following the Ministerial announcement that screening would start a limited number of named samples could be used with any suspicious results reviewed using the final assay protocol and families contacted if appropriate (fortunately none found). An implementation group with membership from the NSU, laboratory and the pediatric immunology team was formed and selected the Perkin-Elmer Enlite Neonatal TREC kit due to a tight timeframe for implementation. Information for families and others was developed and along with other resources is publicly available. Technical issues identified have been kit fragility with increased temperature in shipping; microtiter plate sealing and PCR instruments. Due to the small but geographically dispersed population there have been some difficulties getting the appropriate diagnostic samples to the central testing laboratory in a timely way. The suggested kit cut-offs on screening data would have given a high recall rate so these have been, and are, under review. The agreed follow-up pathway of clinical referral when disease is likely has produced the expected number of positive results (6 in about 30,000) of whom none have the condition. Policy framework https://www.nsu.govt.nz/system/files/page/newborn_metabolic_screening_programme_policy_framework_june_2011.pdf. SCID FAQs and cost utility study etc. https://www.nsu.govt.nz/health-professionals/newborn-metabolic-screening-programme/screening-severe-combined-immune. Information resources https://www.nsu.govt.nz/pregnancy-newborn-screening/newborn-metabolic-screening-programme-heel-prick-test/information. I11. Newborn Screening for SCID-The Dutch Approach Peter Schielen 1, Maartje Blom 1, Eugenie Dekkers 2, Robbert Bredius 3, Mirjam van der Burg 4 and on behalf of the SONNET Study Group 1 Reference Laboratory for Neonatal Screening, Center for Health Protection Research, Dutch Institute of Public Health and the Environment (RIVM), 37210 BA Bilthoven, The Netherlands 2 Center for Population Screening, RIVM, 3720BA Bilthoven, The Netherlands 3 Department of Pediatrics, Leiden University Medical Center, 2333ZA Leiden, The Netherlands 4 Department of Pediatrics, Laboratory for Immunology, Leiden University Medical Center, 2333ZA Leiden, The Netherlands In July 2015 the Dutch Minister of Health sanctioned an advice of the Dutch Health Council to expand the newborn screening program with screening for 17 diseases, with special reference to one disease in particular; severe combined immunodeficiency (SCID). While for all other diseases, the Center for Population Screening of the National Institute for Public Health and the Environment (RIVM-CVB) was invited to perform a feasibility study, for SCID screening RIVM-CVB was asked to enable a prospective pilot screening to identify and overcome all challenges of the introduction of SCID screening in the routine screening program. Thus, a project group was composed with representatives of all relevant fields of expertise, including clinical genetics, clinical chemistry, medical ethics, immunological pediatrics and the screening process and policy. This group composed a study proposal to screen 70,000 neonates, nested in the routine screening program. The proposal consisted of four work packages, covering (1) all organizational aspects of the pilot screening (literally from the heel of the neonate to screening result), (2) the actual pilot screening of 70,000 neonates, including the evaluation of the screening policy, (3) a concise cost-effectiveness analysis and (4) et
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