What s new in newborn screening?

Transcription

1 PERSPECTIVE What s new in newborn screening? Bradford L Therrell Jr 1,2, Colleen Buechner 1,2, Michele A Lloyd-Puryear 3,4, Peter C van Dyck 3,5 & Marie Y Mann 3,6 Author for correspondence 1 National Newborn Screening & Genetics Resource Center, 1912 W Anderson Lane #210, Austin, TX 78757, USA Tel.: ; Fax: ; therrell@uthscsa.edu 2 University of Texas Health Science Center at San Antonio, Department of Pediatrics, 7703 Floyd Curl Drive, San Antonio, TX 78229, USA buechner@ uthscsa.edu 3 US Department of Health & Human Services, Health Resources & Services Administration, Maternal & Child Health Bureau, 5600 Fishers Lane, Rockville, MD 20857, USA Tel.: ; Fax: ; 4 mpuryear@hrsa.gov 5 pvandyck@hrsa.gov 6 mmann@hrsa.gov Keywords: dried blood spot, genetics, newborn, newborn screening, pediatrics, public health part of Newborn screening (NBS) serves as an important preventive public health program to assist families in obtaining early diagnoses, medical interventions and services for newborns affected with rare congenital conditions. Recent advances in screening techniques using tandem mass spectrometry have vastly increased the number of metabolic conditions that can be detected at birth and many NBS programs have expanded their screening panels accordingly, some now screening for more than 50 conditions. Ongoing program expansions and continuing advances in screening technology and medical care means that today, more than ever, clinicians must be fully informed about NBS. We review some of the issues impacting NBS in the USA as food for thought for clinicians faced with fulfilling their expanded role in NBS systems support. This article reviews the current status of NBS using experiences in the USA as an example of how current NBS systems are changing throughout the world. We provide information on recent publications of interest, significant policy and program issues and resources available to assist in coping with NBS advances. For clarification, we will refer to the classical form of NBS (i.e., laboratory analyses from dried blood spots) as newborn dried blood-spot screening (NDBS) and screening for congenital hearing deficiencies in newborns as newborn hearing screening (NHS). The abbreviation NBS will be used to denote the more comprehensive integrated system that can include both NDBS and NHS. Use of the term state programs refers to programs in the 50 US states and the District of Columbia (i.e., a total of 51 state programs nationally). It is now almost 50 years since Robert Guthrie initiated the pioneering research that eventually led to population-based newborn dried blood-spot screening (NDBS) [1]. He developed the now wellknown procedure of using blood absorbed onto filter paper to screen for phenylketonuria (PKU). His research and advocacy in the early 1960s were key to the general acceptance of NDBS as an essential preventive public health activity. Interestingly, suggestions about ways to implement universal newborn hearing screening (NHS) began at about the same time, but it was not until the late 1990s that it became accepted in medical practice [2]. As a result of research activities, technical advances, and health policy evolution through the years, comprehensive newborn screening (NBS) now routinely includes detection of over 50 congenital conditions, including NHS [3]. The ways in which NBS is implemented and the numbers of conditions screened vary throughout the world [4]. Recent country- and region-specific reviews highlight this variability [5 11]. It appears that the ways in which clinicians must function within NBS systems and react to system changes are not significantly different across programs. Despite the fact that the NBS process may occur at the same time in all jurisdictions (i.e., NDBS screening may occur at a few days of age in some jurisdictions or just after 24 h of age in others and the time for NHS screening also varies widely) and medical systems differ with respect to financing and care accessibility, the basic responsibilities for clinicians are essentially the same early and accurate diagnosis and medical management. Access to NBS and sustainable program financing includes legally required screening in some jurisdictions, most notably the states within the USA. In many jurisdictions outside of the USA, recommended (voluntary) NBS often accomplishes the same end result, particularly where NBS is considered to be a medical practice standard. We have targeted the screening activities in the USA as illustrative of general NBS activities and issues, with the understanding that the specifics of some USA discussion items may not apply in all international jurisdictions. As a practical matter, because there is not yet a national NBS policy in the USA, the state programs can usually be viewed functionally as similar to 51 separate national programs. Indeed, the number of births in individual states often equals or exceeds those of many nations around the world (Table 1) and NBS implementation/sustainability policy issues are often similar / Future Medicine Ltd ISSN Pediatric Health (2008) 2(4),

2 PERSPECTIVE Therrell Jr, Buechner, Lloyd-Puryear, van Dyck & Mann Table 1. Conditions required by US newborn screening programs. Jurisdiction Births * Conditions required in state newborn screening program Congenital hypothyroidism Phenylketonuria Galactosemia Sickle cell diseases Congenital adrenal hyperplasia Alabama 59,300 Biotinidase deficiency Alaska 10,365 Arizona 95,687 Arkansas 38,381 California 549,100 Colorado 69,205 Connecticut 42,133 Delaware 12,265 District of Columbia 14,311 Florida 226,415 Georgia 143,476 Hawaii 17,911 Idaho 22,522 Illinois 175,714 Indiana 87,843 Iowa 39,337 Kansas 40,737 Kentucky 54,590 Louisiana 60,461 Maine 13,975 Maryland 71,292 Massachusetts 77,820 Michigan 126,498 Minnesota 70,933 Mississippi 41,175 Missouri 79,523 Conditions indicated as required may not yet be available in some programs details of implementation status is available at [109]. * Birth statistics taken from National Center for Health Statistics Occurrent Births for Screening status as of May 15, Indicates full population screening mandate for MS/MS indicates mandate for all detectable conditions. Indicates less than full population mandate for MS/MS indicates that all detectable conditions are either not mandated or not included in the analytical interpretation. # Newborn screened only if mother not screened during pregnancy. MS/MS: Tandem mass spectrometry. 412 Pediatric Health (2008) 2(4) future science group

3 What s new in newborn screening? PERSPECTIVE Table 1. Conditions required by US newborn screening programs (cont.). Jurisdiction Births * Conditions required in state newborn screening program Congenital hypothyroidism Phenylketonuria Galactosemia Sickle cell diseases Congenital adrenal hyperplasia Montana 11,551 Biotinidase deficiency Nebraska 26,350 Nevada 36,950 New Hampshire 13,968 New Jersey 110,800 New Mexico 28,291 New York 247,901 North Carolina 123,943 North Dakota 9621 Ohio 148,876 Oklahoma 50,656 Oregon 46,712 Pennsylvania 144,908 Rhode Island 13,481 South Carolina 55,321 South Dakota 11,957 Tennessee 87,072 Texas 387,856 Utah 52,555 Vermont 5932 Virginia 102,646 Washington 82,336 West Virginia 21,150 Wisconsin 69,769 Wyoming 6778 Totals 4,138, Conditions indicated as required may not yet be available in some programs details of implementation status is available at [109]. * Birth statistics taken from National Center for Health Statistics Occurrent Births for Screening status as of May 15, Indicates full population screening mandate for MS/MS indicates mandate for all detectable conditions. Indicates less than full population mandate for MS/MS indicates that all detectable conditions are either not mandated or not included in the analytical interpretation. # Newborn screened only if mother not screened during pregnancy. MS/MS: Tandem mass spectrometry. future science group 413

4 PERSPECTIVE Therrell Jr, Buechner, Lloyd-Puryear, van Dyck & Mann Table 1. Conditions required by US newborn screening programs (cont.). Jurisdiction Births * Conditions required in state newborn screening program Cystic fibrosis G6PD Deficiency Other amino acid disorders MS/MS detectable Toxoplasmosis HIV Other (Krabbe disease) Fatty acid oxidation disorders Alabama 59,300 Organic acid disorders Alaska 10,365 Arizona 95,687 Arkansas 38,381 California 549,100 Colorado 69,205 Connecticut 42,133 # Delaware 12,265 District of Columbia 14,311 Florida 226,415 Georgia 143,476 Hawaii 17,911 Idaho 22,522 Illinois 175,714 # Indiana 87,843 Iowa 39,337 Kansas 40,737 Kentucky 54,590 Louisiana 60,461 Maine 13,975 Maryland 71,292 Massachusetts 77,820 Michigan 126,498 Minnesota 70,933 Mississippi 41,175 Missouri 79,523 Conditions indicated as required may not yet be available in some programs details of implementation status is available at [109]. * Birth statistics taken from National Center for Health Statistics Occurrent Births for Screening status as of May 15, Indicates full population screening mandate for MS/MS indicates mandate for all detectable conditions. Indicates less than full population mandate for MS/MS indicates that all detectable conditions are either not mandated or not included in the analytical interpretation. # Newborn screened only if mother not screened during pregnancy. MS/MS: Tandem mass spectrometry. 414 Pediatric Health (2008) 2(4) future science group

5 What s new in newborn screening? PERSPECTIVE Table 1. Conditions required by US newborn screening programs (cont.). Jurisdiction Births * Conditions required in state newborn screening program Cystic fibrosis G6PD Deficiency Other amino acid disorders MS/MS detectable Toxoplasmosis HIV Other (Krabbe disease) Fatty acid oxidation disorders Montana 11,551 Organic acid disorders Nebraska 26,350 Nevada 36,950 New Hampshire 13,968 New Jersey 110,800 New Mexico 28,291 New York 247,901 North Carolina 123,943 North Dakota 9621 Ohio 148,876 Oklahoma 50,656 Oregon 46,712 Pennsylvania 144,908 Rhode Island 13,481 South Carolina 55,321 South Dakota 11,957 Tennessee 87,072 Texas 387,856 Utah 52,555 Vermont 5932 Virginia 102,646 Washington 82,336 West Virginia 21,150 Wisconsin 69,769 Wyoming 6778 Totals 4,138, Conditions indicated as required may not yet be available in some programs details of implementation status is available at [109]. * Birth statistics taken from National Center for Health Statistics Occurrent Births for Screening status as of May 15, Indicates full population screening mandate for MS/MS indicates mandate for all detectable conditions. Indicates less than full population mandate for MS/MS indicates that all detectable conditions are either not mandated or not included in the analytical interpretation. # Newborn screened only if mother not screened during pregnancy. MS/MS: Tandem mass spectrometry. future science group 415

6 PERSPECTIVE Therrell Jr, Buechner, Lloyd-Puryear, van Dyck & Mann General considerations in US newborn screening systems A US national NBS policy does not currently exist, but each state has a law that results in required screening. As part of the statutory requirements, the state public health authority has (at a minimum) oversight responsibility designed to ensure a properly run screening program (or programs, since in some states NDBS and NHS are separate programs) [12]. Laws and rules/regulations vary, sometimes specifying certain critical responsibilities, such as when a screening is to occur and who must ensure that it happens. In some cases, portions of program infrastructure may be contracted out rather than provided within the public health system. For example, some programs contract laboratory services to other states or private screening laboratories (Figure 1), and some contract part or all of patient tracking and follow-up, usually to academic or specialty centers. For this reason, the NBS system components (education, screening, follow-up, diagnosis, management/treatment and evaluation) must be carefully defined along with the responsibilities of each component, and systems operations must be seamlessly integrated for maximum efficiency and effectiveness [13 15]. As part of quality NBS activities, NDBS laboratories comply with certification requirements of the Clinical Laboratory Improvement Act (CLIA) [16]. Quality assurance of NBS nonlaboratory activities are generally self-defined and guided by best practices that ensure timely interventions that lead to positive medical outcomes [17]. In addition to professional organizations, such as the American Academy of Pediatrics (AAP) who have provided NBS guidance for their members over time, the Clinical Laboratory Standards Institute (CLSI) formerly known as the National Committee for Clinical Laboratory Standards (NCCLS) has played a pivotal role in developing national standards for NBS. For 20 years there has been a CLSI/NCCLS national standard for blood Figure 1. Various newborn screening laboratory models in use in the USA June DC Uses state public health laboratory Uses Oregon public health laboratory Contracts with seven private laboratories Contracts with Arizona public health laboratory Shared testing public health & MS/MS contract Uses Colorado public health laboratory Uses Iowa public health laboratory Contracts with commercial screening laboratory Uses Indiana Medical Center laboratory May use either of two approved laboratories Uses University of Massachusetts Medical Center laboratory May use the state public health laboratory or another laboratory Indicates location of regional laboratory MS/MS: Tandem mass spectrometry. 416 Pediatric Health (2008) 2(4) future science group

7 What s new in newborn screening? PERSPECTIVE collection on filter paper (LA4) [18], which defines many of the pre-analytic activities appropriate for quality NDBS. More recently, the CLSI has issued a guideline for NBS follow-up (I/L27-A) [19], which addresses follow-up issues applicable to both NDBS and NHS. Since premature and sick newborns present special screening challenges [20,21], a CLSI guideline (I/L31) defining NBS screening protocols in intensive care situations is currently in development. Committees preparing CLSI standards and guidelines include international representation to encourage global acceptance and procedural harmonization. Where specific NBS performance standards and guidelines do not exist, such as diagnostic procedures and clinical management, the best practices that lead to optimal health outcomes serve as surrogates. Most NBS programs have external advisory committees that serve as consultants, advisors and advocates [12,13,15]. Since NDBS and NHS advisory committees may be the primary mechanism by which a program obtains outside input, advisory committees are usually multidisciplinary. They include not only medical professionals, but also consumer advocates, ethicists and other NBS stakeholders. NBS program personnel serve to assist with committee activities but usually do not function as committee members. Advisory committees exist to provide a mechanism for stakeholder input and for vetting program decisions, which in turn serves to increase community acceptance of policy decisions. In cases where outside advocacy can assist with program changes, the advisory committee often serves in this role. In the USA, NDBS specimen collection and NHS usually occur at a birthing facility h after birth (before discharge from the facility), or as soon as possible if the infant is born outside of such a facility. In the case of newborns in intensive care units, a heelstick blood specimen is usually drawn before 7 days of age, in compliance with AAP recommendations that originated with newborn hypothyroidism screening [22]. NHS usually occurs during the same time period, in accordance with recommendations of the AAP Joint Committee on Infant Hearing (JCIH) [23,24]. In the case of hospital transfers, the transferring hospital is usually responsible for ensuring that a NDBS specimen has been collected or that the receiving hospital is aware of the need for collection of a blood specimen and completion of a hearing screen. Ideally, out-of-range (abnormal) NBS results trigger rapid patient follow-up that leads to timely confirmatory testing and initiation of appropriate clinical management. While NDBS programs have well-established short-term follow-up systems, usually in the state public health system, NHS short-term follow-up is often hospital based and follow-up data at the state level may not be well organized. In an effort to better utilize existing NDBS infrastructure and improve NHS follow-up, at least a third of state programs now include NHS result reports either as part of NDBS specimen collection card information or as part of the information collected on electronic birth certificates. By centralizing screening data, the opportunity for better followup and administrative management/oversight of NHS exists [25]. It is preferable for prospective parents to receive information about NBS before the birthing event [26 28], but many still receive this information as part of their maternity information materials upon admission to the hospital or postpartum. The responsibility to explain NBS often resides with nurses in the newborn nursery who may also collect the NDBS specimen and/or provide hearing screening. In the hospital setting, NDBS specimens may be collected by a laboratory phlebotomist while a midwife may obtain specimens on newborns born in other settings. The NDBS specimen collection process is defined by the state NDBS program, and is usually based on the current CLSI standard (LA4- A5). In some cases, an additional specimen may be collected at the parents request for other purposes (e.g., additional screening, baby book, etc.). NHS, on the other hand, may be performed by a trained NHS technician [29,30] and may include either an evoked otoacoustic emission or an auditory brainstem response test (or a combination of the two). In some states, a certification program may exist, which prescribes the NHS protocol, while in others the protocol may be defined by individual hospitals. Dried blood-spot specimens for biochemical screening are sent either by mail or courier to a state designated screening laboratory, which may be either the state public health laboratory, a contracted laboratory (either private, public or nonprofit) or a combination of the two. Several models of laboratory service exist (Figure 1) and each has been found to provide acceptable screening laboratory services in its own unique setting. While state public health laboratories provide the majority of screening services, some state future science group 417

8 PERSPECTIVE Therrell Jr, Buechner, Lloyd-Puryear, van Dyck & Mann programs find it effective to utilize the services of private or nonprofit laboratories. Many of the smaller population states utilize the services of regional public health or university laboratories. Regionalization of some NDBS genetics specialty services for follow-up also exists [31]. NDBS laboratory regionalization has been shown to improve testing quality through increased case access and case identification, and cost savings are realized through economies of scale. Proficiency testing for all NDBS laboratories is provided by the NBS Quality Assurance Program (NSQAP) at the US CDC (program details are available at [101]). This program is voluntary, but all state NDBS programs utilize the services to satisfy their licensure requirements for proficiency testing. The NSQAP now serves over 325 NDBS laboratories in 53 countries worldwide [16]. Newborn screening follow-up is a shared responsibility among the NBS program, parents and appropriate healthcare professionals. Longterm follow-up and case management and followup are also essential shared activities aimed at optimizing health outcomes and evaluating program effectiveness [15]. Quality indicators for these and all aspects of the NBS system have been defined in a Performance Evaluation and Assessment Scheme (PEAS), developed by national working groups as part of a Health Resources and Services Administration (HRSA)-funded initiative of the US National NBS and Genetics Resource Center (NNSGRC) [102]. This self-evaluation tool provides a basis for NBS quality improvement by helping programs to define missing or deficient system elements [32]. Screening policies & screened conditions We have previously noted that NBS in the USA has evolved in the absence of a national policy. Hence, state policy makers have struggled with defining which conditions to include in screening mandates and how screening-system components should be implemented and financed. In many cases, public opinion/advocacy and litigation have impacted policy decisions, and many medical practice issues have not been clearly addressed. There continues to be variation nationally in the screening requirements in each state program [12]; however, recent actions by federal agencies and the Secretary of Health and Human Services Advisory Committee on Heritable Diseases and Genetic Disorders in Newborns and Children (ACHDGDNC) have provided some encouragement for improved harmonization [103]. Historically, NBS policy decisions have been guided by the 1960s criteria developed as part of a WHO initiative on population screening [3]. Responding to advances in science, medicine, technology and research, and recognizing the need for a centralized focal point for NBS information, HRSA/Maternal and Child Health Bureau (MCHB) initiated two national NBS projects in One project established the NNSGRC through a cooperative agreement with the University of Texas Health Science Center at San Antonio, TX, USA. The other (through a contract with the AAP) initiated a review of the status of NBS in the USA with recommendations for improvement. Presently, the NNSGRC initiative continues as a focal point for national NBS information and assistance, including national data collection and expert review/advice for state program improvement [16]. The AAP contract resulted in a published national NBS blueprint for the future that more clearly defined the activities, needs and government (federal and state) responsibilities [33]. Responding to suggestions in the AAP report, HRSA/MCHB subsequently contracted with the American College of Medical Genetics (ACMG) to address the specific issues of: Developing a decision-making matrix that could be used by state programs to systematically expand (or contract) screening mandates; Recommending a core panel of NBS conditions that should be included in all state mandates [34]. As a result, the ACMG-convened NBS expert group developed a comparative scoring system for evaluating conditions that might be candidates for inclusion in state program mandates. Based on the scoring system, the group recommended a core panel of screening conditions [35]. A total of 84 conditions were evaluated. Of these, 29 core conditions (including 28 NDBS conditions and NHS) and 25 secondary targets (conditions that might be identified incidental to detecting the core conditions, but lacking a score high enough to rank them as a core condition), were recommended as a uniform NBS panel that should be required in all state NBS programs (Table 2) [36,37]. Even though screening for certain infectious diseases (toxoplasmosis and HIV) occurs in some programs, infectious diseases were not evaluated, owing to a lack of expertise in the working group and a lack of appropriate comparative information. Conditions not included in the core 29 were generally conditions for which additional research was felt necessary either to develop a 418 Pediatric Health (2008) 2(4) future science group

9 What s new in newborn screening? PERSPECTIVE Table 2. Core conditions and secondary targets included in the American College of Medical Genetics report. 29 core conditions 25 secondary targets MS/MS-detectable organic acid disorders Isovaleric acidemia Methylmalonic acidemia (Cbl C, D) Glutaric acidemia type I Malonic acidemia 3-hydroxy 3-methyl glutaric aciduria Isobutyryl-CoA dehydrogenase deficiency Methylmalonic acidemia (mutase deficiency) 2-methyl 3-hydroxy butyric aciduria 3-methylcrotonyl-CoA carboxylase deficiency 2-methylbutyryl-CoA dehydrogenase deficiency Methylmalonic acidemia (Cbl A, B) 3-methylglutaconic aciduria Multiple carboxylase deficiency (holocarboxylase synthetase deficiency) Propionic acidemia β-ketothiolase deficiency MS/MS-detectable fatty acid oxidation disorders Medium-chain acyl-coa dehydrogenase deficiency Short-chain acyl-coa dehydrogenase deficiency Very long-chain acyl-coa dehydrogenase deficiency Medium/short-chain L-3-hydroxy acyl-coa dehydrogenase deficiency Long-chain L-3-hydroxy acyl-coa dehydrogenase deficiency Medium-chain ketoacyl-coa thiolase deficiency Trifunctional protein deficiency Carnitine palmitoyltransferase II deficiency Carnitine uptake defect Carnitine acylcarnitine translocase deficiency Carnitine palmitoyltranferase I deficiency (liver) Glutaric acidemia type II (multiple acyl-coa dehydrogenase deficiency) 2, 4-dienoyl-CoA reductase deficiency MS/MS-detectable amino acid disorders Phenylketonuria Benign hyperphenylalaninemia Maple syrup urine disease Tyrosinemia type II Homocystinuria Tyrosinemia type III Citrullinemia type I Defects of biopterin cofactor biosynthesis Argininosuccinic aciduria Defects of biopterin cofactor regeneration Tyrosinemia type I Argininemia Hypermethioninemia Citrullinemia type II Hemoglobinopathies Sickle cell anemia (SS-disease) Variant hemoglobinopathies Sickle-C disease S-β thalassemia Other Transferase-deficient galactosemia (classical) Galactokinase deficiency Primary congenital hypothyroidism Galactoepimerase deficiency 21-hydroxylase-deficient congenital adrenal hyperplasia Biotinidase deficiency Hearing screening Cystic fibrosis MS/MS: Tandem mass spectrometry. Data taken from [35,36]. satisfactory NBS test or to develop better clinical outcomes information. Thus, studies of conditions outside of the core 29 constitute a de facto research agenda. Publication of the final ACMG report and its acceptance by the ACHDGDNC has provided national guidance for state NBS programs. While controversial regarding the methods used [37 39], future science group 419

10 PERSPECTIVE Therrell Jr, Buechner, Lloyd-Puryear, van Dyck & Mann the ACMG report, coupled with the actions of parent advocacy organizations, individual parents and private-sector screening companies, has impacted NBS programs across the country. As a result, all state programs have expanded their required screening panels to some degree, and most have expanded significantly to require the core 29 conditions [40]. Many programs require screening for some or all of the 25 secondary targets, and some programs include conditions not yet classified as secondary or core (Table 1) [5]. Since the analytical markers for the core conditions may also be markers for secondary target conditions, some secondary targets may be identified and reported even though screening for them is not required. The ACHDGDNC has recently adopted a process for nominating conditions to be included in the core panel. A description of the nomination process and the appropriate nominating forms are electronically available on the HRSA s website [104]. Once a condition is nominated, the scientific information submitted must undergo a rigorous impartial review prior to its consideration by the ACHDGDNC [41]. Among the conditions into which extensive NDBS research is ongoing are the lysosomal storage diseases (LSDs). Development of enzyme-replacement therapy and stem cell transplantation has led to demonstrated health benefits for patients, and earlier detection offers the opportunity for even better outcomes. Research into NDBS laboratory methodologies and consumer advocacy led to the addition of Krabbe disease to the required New York screening panel at the end of 2006 [5]. The Illinois Legislature passed legislation in 2007 that adds screening for five LSDs (Krabbe, Pompe, Gaucher, Fabry and Niemann Pick) within 6 months after four conditions are met: Registration of the necessary screening reagents with the US FDA; Availability of the necessary reagents from the CDC; The availability of a quality-assurance testing methodology for the screening processes; Acquisition and installment of the equipment necessary to implement the expanded screening tests (legislation available at [105]). Research into NDBS for additional LSDs and associated NDBS reagent production is ongoing [42 45]. Studies of possible NDBS methodologies for screening for other congenital conditions, such as severe combined immune deficiency (SCID) [46 50], Duchenne muscular dystrophy [51 52], fragile X syndrome [53], Type 1 diabetes [54,55] and others [56], are also currently being performed, although not without controversy (particularly concerning ethical considerations of such full population screening). Of these, NDBS for SCID is perhaps the least controversial. SCID has been successfully treated with stem cells and treatment works best if initiated within a few months of birth. Therefore, early detection is critical. Recent research has shown that the measurement of T-cell receptor excision circles from excised DNA samples is successful in screening for affected individuals [40]. However, developing a cost-effective, high-throughput screen has proven difficult [43]. Other screening methods, including immunoassays for T-cell-specific proteins and measurements of lymphocyte number, are being studied, and it is likely that a reliable NBS test will be developed soon [44]. Screening for SCID began in WI, USA, in January of 2008 and the results will be continually assessed in order to refine and evaluate the success of the program. SCID has also been proposed to the ACHDGDNC to be added to the core panel of recommended tests and the application is currently under evaluation. Barriers to population-based screening for some of the conditions under consideration include limited treatment options or inadequate treatment/management infrastructure, ambiguous screening test results and lack of reliable information on disease severity when detected in newborns. As there are risks involved in some disease treatments, such as bone marrow transplantation for Krabbe disease, parents and clinicians may face difficult decisions if the potential severity of the disorder is unclear from the screening results [57]. Some of the candidate NBS conditions currently have few treatment options. Even so, parents of affected children note that detecting these conditions through NBS can provide early diagnostic information that would help avoid the diagnostic odyssey or repeated medical visits and tests in search of a diagnosis that may take months or years to obtain. In addition, early diagnosis as a result of NBS could provide useful information for future pregnancy considerations. Current state screening practices All states have specific statutes that either directly require or indirectly allow for requiring universal NDBS under a broader public health mandate, and most also require universal screening for NHS [12]. Since there is neither a national NDBS nor a national NHS policy, the numbers of NBS 420 Pediatric Health (2008) 2(4) future science group

11 What s new in newborn screening? PERSPECTIVE conditions required and the manner in which screening is implemented varies by state [12,15]. State legislatures ultimately control broad NBS administrative issues (e.g., legal requirements, program financing and oversight responsibility). State public health departments are usually given the legal responsibility for developing operational details of the screening systems, including associated public health programs. While state legislatures determine the extent to which government funds can be used for system support, state public health departments define and operationalize system financing [58,59]. Since NHS programs and systems are less uniform than NDBS programs across the country, a discussion of NHS protocols and program administrative details is best addressed on a program by program basis and will not be attempted here. Instead, we will focus on NDBS programs and systems, which are more amenable to a general descriptive discussion. All but six public health NDBS programs use fee income to offset at least part of the expenses for maintaining the screening system [12,58,59]. Of the remaining six, at least four have been given authority to begin charging a fee in the near future. The amount of fees varies depending on the extent to which other public health funds are available for NDBS support (a current fee listing is available at [106]). In no case is a newborn refused screening because of a lack of ability to pay for screening services, although issues such as insurance may impact whether or not a routine second screen is obtained [60]. While most private insurers cover the cost of initial NBS, payment for follow-up services is often problematic. In some states, insurers are required to pay for metabolic formulas and metabolic foods, but there is little uniformity in such insurance requirements across the country. As a result, clinicians must at times be involved in insurance reimbursement issues on behalf of their patients [61]. And, while NBS is an allowed Medicaid expense, the manner in which it is covered and the amount of reimbursement is a statespecific issue with significant variability across the country. The lack of Current Procedural Terminology (CPT ) codes for NDBS at the national level has been cited as a confounding factor in financing the program [59]. The method for fee collection in state NDBS programs also varies widely. Some programs bill birthing facilities directly following completion of the screening laboratory tests, while others bill in advance as filter paper collection kits are ordered. Programs that require two specimens usually include the cost of both in the initial testing or kit fee, but some have a fee system that bills physicians who may be providing the second or subsequent screens. The components of NBS fees are not standardized. Some fees include nonlaboratory components, such as follow-up, education and public relations, while others are limited to laboratory costs alone. Some programs receive direct Medicaid fund transfers, while others consider Medicaid reimbursement to be a hospital/physician issue [58,59]. Few include any treatment or medical management expenses [61]. Details of specimen collection and its subsequent transmittal to the screening laboratory are defined by state screening protocols, many of which are available in printed manuals sent to specimen submitters or on program websites (an interactive national map with program links is available at [107]). The collection of an initial NDBS specimen routinely occurs prior to hospital discharge, usually after 24 h of age. A limited number of programs require specimen collection after the age of 48 h, and one allows specimen collection after 12 h of age. Only three programs, WY, DC and MD, require consent for the required NBS panel. In most other states, there is an option to opt out for religious reasons [12]. Age requirements for specimen collection historically reflect a concern that specimens collected too early may result in insufficient levels of certain analytes that depend on age-related physiologic processes. Over the years, technological improvements in test kits have overcome many of the age concerns so that earlier specimen collection is now more accepted. Several state programs have a consent/dissent process where supplemental testing may be available in addition to the required screening panel [62]. Some programs require the collection of a second NDBS specimen at 1 2 weeks of age in an attempt to improve screening efficiency [3,12]. Reports of additional case detections in these programs have generally focused on endocrinopathies [63 66]. Metabolic case reports as a result of second screen findings have been limited. Since the overall number of newborns receiving second screens is approximately 25% nationally, the Laboratory Standards and Procedures Subcommittee of the ACHDGDNC has initiated a study to more formally assess the impact of second screens. Included in the study are programs with alternative screening protocols focused on limited supplemental testing in certain defined instances, such as those newborns in neonatal intensive care units. future science group 421

12 PERSPECTIVE Therrell Jr, Buechner, Lloyd-Puryear, van Dyck & Mann The idealized goal of NBS, in general, is to identify and assist all at-risk newborns and their families so that early diagnosis and intervention can occur. As a result, sensitivity and specificity of NBS tests are continually under evaluation. With the exception of some of the diagnostic technologies used in the screening environment (e.g. tandem mass spectrometry [MS/MS], isoelectric focusing, HPLC and DNA), most NDBS methodologies have low positive predictive rates and require additional testing to differentiate true cases. While diagnostic capability is a consideration, other test characteristics are also important for screening, including speed of analyis and ability to detect a particular analyte in a unique specimen matrix, such as dried blood on filter paper. In NDBS, the basic nature of the screening specimens and screening laboratory protocols, and the biology of the target condition in the newborn period, precludes 100% case ascertainment without some out-of-range results that require recall for further testing. Realistically, the goal of all NBS is to identify as many at-risk newborns as possible needing additional (diagnostic) tests without excessive recall. As screening tests are by definition not diagnostic, there may be significant differences in the ability of individual screening tests to detect affected newborns. Program policies may further define the manner in which recall occurs (e.g., recall not to exceed 1% of all newborns screened). Whether screening laboratories utilize diagnostic or nondiagnostic methodologies, adjusting expected ranges of results based on case-ascertainment data is an essential part of improving the overall screening process. Screening cutoffs must be continually evaluated and adjusted to reduce unnecessary patient recall. In the case of the rarer conditions, combining case-finding data from multiple programs may assist in defining screening cutoffs; this is currently the case in an ongoing study with MS/MS case finding [67]. Improved analytical efficiency is sometimes possible by considering additional factors, such as birth weight or age at time of specimen collection [68]. Occasionally, screening efficiency can be improved by adding a second-tier test (an additional test performed on screening specimens initially found to be out of the expected range) to the screening protocol [32]. As an example, US NDBS programs screening for congenital hypothyroidism using thyroxin (T4) as the initial screening test routinely employ thyrotropin (TSH) testing as a second tier on a certain portion of out-of-range initial screens [22]. DNA testing is sometimes used as a second-tier test for sickle cell disease [69] and is often a second-tier test for cystic fibrosis screening [70]. The current interest in second-tier testing centers around improving the screening efficiency for congenital adrenal hyperplasia with second-tier liquid chromatography MS/MS steroid profiling [71,72] and for tyrosinemia type 1 using second-tier succinylacetone testing [73,74]. Second-tier tests have also been piloted for methylmalonic acidemia, homocystinuria and maple syrup urine disease [75]. The goal of NBS follow-up is timely confirmatory testing, diagnosis and clinical management so that optimal long-term outcomes can be realized. Short-term NBS follow-up protocols define appropriate actions for rapid follow-up of out-ofrange screens and unsatisfactory screening specimens to the point of diagnosis and initiation of appropriate clinical management. The CLSI follow-up guideline identifies the elements of efficient and effective follow-up and provides guidance for closed-loop tracking systems [19]. It loosely defines long-term follow-up as the processes occurring after diagnosis that ensure monitoring of screening effectiveness, possibly including ensuring the availability of interventions and services throughout the life cycle. The ACHDGDNC has defined long-term follow-up to include the assurance and provision of quality chronic disease management, condition-specific treatment and age-appropriate preventive care throughout the lifespan of affected individuals [76]. Clarification of the roles and responsibilities in long-term follow-up are currently being addressed by the ACHDGDNC Subcommittee on Long-Term Follow-Up and Treatment. Birthing facilities are responsible for maintaining records that document completion of the NBS process. In particular, NDBS records should show that for every newborn: a specimen was collected, a result was obtained and appropriate follow-up actions were completed. In cases where unsatisfactory or out-of-range NDBS results occur, documentation of efforts to assist with rescreening or other confirmatory processes should exist. Specimen submitters have a responsibility to transmit accurate information about the newborn s primary healthcare provider (PCP) so that NDBS patient tracking is not delayed by inaccurate or missing information on the specimen collection card [19]. Responsibilities for providing NDBS results to PCPs vary according to the state program s rules and policies. Results may be transmitted to the PCP by the birthing facility, 422 Pediatric Health (2008) 2(4) future science group

13 What s new in newborn screening? PERSPECTIVE the state NBS program or both. In either case, PCPs should take appropriate steps to see that they receive timely NDBS reports [77]. As development and utilization of electronic health records proceeds, efforts to facilitate the integration of NBS results are underway [78,79]. Discussions about inclusion of NBS (both NDBS and/or NHS) information currently focus on universal coding schemes for screening results. Since NDBS identifies increased risk(s) for the presence of congenital conditions, interpretations of qualitative or quantitative laboratory findings may be reported for some screening analyses instead of, or in addition to, a numeric result. As an example, qualitative isoelectric focusing screening results for sickle cell disease usually do not include percentages of the various hemoglobins observed. Or, screening laboratories sometimes may use percentile rankings for endocrine screening tests rather than using analyte concentrations. The complexity of reporting a NBS result that arises from nonstandardized screening protocols and analytic methods will require creativity and flexibility in developing useful resulttransfer standards. These standards will likely not be as straightforward as in a diagnostic setting. Whether quantitative values for screening results or their interpretations are reported (or some combination of the two), standardized language (coding) will be necessary for electronic information technology to be efficiently utilized in NBS. Newborn screening education Expanded NBS means diagnosing an expanded panel of conditions (both rare and common), and the complexities of these diagnoses accentuate the need for additional education for most pediatric health professionals. As an educational aid for determining immediate next steps, the ACMG, with HRSA/MCHB funding, has utilized specialists with first-hand knowledge of each of the 29 core conditions to create online action/information (ACT) sheets for healthcare professionals. These ACT sheets provide just-in-time information and associated references so that PCPs can immediately begin the next steps for confirming out-of-range NBS results. Accessible through the ACMG or NNSGRC websites [108], the ACMG ACT sheets are designed to be used as is or as models for state program educational information. The creation of additional ACT sheets for the secondary targets is currently underway. Since prenatal education of parents is also recognized as a critical need in the NBS system, HRSA/MCHB funded the development of model prenatal education materials for both parents and health professionals [80,81]. Focus groups of parents and physicians identified their prenatal educational needs to health educational professionals, who developed brief informative materials that address the seven issues that parents most want to know about NBS. Model brochures resulting from this effort and others are available online to provide state programs with example basic knowledge materials at appropriate literacy levels [109]. Some programs have also prepared information for parents in other languages, but their literacy levels have generally not been assessed. The education subcommittee of the ACHDGDNC is currently evaluating the need for materials in different languages and for different cultural groups. The AAP has also addressed NBS educational issues. Their NBS fact sheets were first published in 1989 [82], and provided basic information about the most popular screening conditions at the time. These fact sheets have been periodically updated as new screening information has accumulated. The most recent version [83] provides updates on biotinidase deficiency, congenital adrenal hyperplasia, congenital hearing loss, congenital hypothyroidism, cystic fibrosis, galactosemia, homocystinuria, maple syrup urine disease, mediumchain acyl-coa dehydrogenase deficiency, PKU, sickle cell disease, other hemoglobinopathies and tryrosinemia. In the companion introduction to the fact sheets [15], related topics, including NBS as a public health system, informed consent, MS/MS, DNA analysis in NBS, status of NBS in the USA and the effect of sample timing, preterm birth, diet, transfusion and total parenteral nutrition on NBS results are discussed. The extent to which information about NBS has been emphasized by professional organizations, such as the AAP, emphasizes the extreme importance that this preventive health program now plays in improving the health and wellbeing of all newborns. The necessity for linkages between NBS activities and the medical home further emphasizes the need for good communication between PCPs, families and birthing facilities so as to not waste time in providing for follow-up on out-of-range or unsatisfactory NDBS or NHS results. A new AAP policy statement provides further recommendations for pediatricians and medical homes regarding their growing role and responsibilities in expanded NBS [40]. This statement: future science group 423

14 PERSPECTIVE Therrell Jr, Buechner, Lloyd-Puryear, van Dyck & Mann Delineates the responsibilities of pediatric health professionals (both primary-care and pediatric medical subspecialists) within the NBS system; Introduces two algorithms that, together, outline a clear and efficient pathway through the process of fulfilling those responsibilities; Outlines resources that will support pediatric health professionals in addressing their responsibilities. In addition, it addresses steps that individual pediatric health professionals and practices must take in preparing for their system responsibilities. This report further emphasizes the importance for pediatric health professionals to understand NBS, their responsibility within the system, the responsibilities of others and how they can actively participate in the NBS system in order to provide the best care for newborns in their practices. Newborn screening system evaluation Evaluation is an important component of NBS quality assurance. It is necessary to know if the component parts of the NBS system are functioning properly and if the goals of early detection and medical management are achieving the proper outcomes. A recent report outlines the history and current status of NDBS system evaluation efforts in the USA [16]. While laboratory proficiency is perhaps the most obvious evaluation activity, and a formal voluntary national program exists through the CDC, evaluations of other aspects of the screening system are equally important. The HRSA/MCHB initiative to develop PEAS (see introduction) has led to a comprehensive list of indicators that may be used for program selfevaluation and improvement. This four-part evaluation instrument (cross-cutting, preanalytic, analytic and postanalytic), comprehensively lists system components and performance indicators to provide administrative guidance for system improvement plans that should ultimately lead to increased program uniformity nationally. Comprehensive program review by external experts provides another means of program quality assessment available to US NBS programs. Initiated in 1988 as a program-improvement activity of HRSA/MCHB, this review process has now been accessed by over 30 state programs. A small multidisciplinary team of NBS experts with extensive program experience is provided on request by the NNSGRC. Their review process includes on-site visits with state-program staff and other interested stakeholders to address selfidentified issues targeted for program improvement/refinement. Following interviews, information sharing and visits with local stakeholders, a summary exit interview and written report serve to document the review team s recommendations. Team members remain available for consultative assistance following the program review [16]. Conclusion Newborn screening is a system consisting of six major components: education, screening, followup, diagnosis, treatment or management and evaluation [3,14,15]. Owing to the complexity of interactions within the screening system and the expansive array of screened conditions, it is no longer acceptable to refer to NDBS as PKU screening, as many US healthcare workers continue to do. NBS programs are truly comprehensive and inappropriate descriptive terminology increases the danger of inappropriate patient care. There are many anecdotal reports of instances where screening results for a condition other than PKU were communicated as PKU test results resulting in subsequent inappropriate medical actions. While there are no published reports addressing that adverse medical outcomes have occurred as a result, the potential still exists. Clinicians should actively work to eliminate incorrect and inaccurate NBS program nicknames. Likewise, failure to timely and adequately follow-up NDBS results has been reported to result in adverse consequences, including unnecessary surgery, dehydration, pneumonia and at least one death [84,85]. The lack of a NDBS result should never be interpreted as a sign that increased risk for screened conditions is absent. Rather, a missing result should be interpreted as a need for additional screening follow-up. The NBS knowledge gap in the clinical community is well documented [27,86,87] and clinicians must avail themselves of opportunities to increase their knowledge. Knowledge gathering should not only include medical implications of NBS results, but also information about how NBS programs operate and how screening policies are made. Active involvement by clinicians in the decision-making process can add an often overlooked dimension to discussions about program expansion and refinement. In addition, clinicians have an obligation to convey accurate information to their patients. Parents have come to expect meaningful discussions about the NBS experience from obstetricians, pediatricians and family physicians. Clinicians need 424 Pediatric Health (2008) 2(4) future science group