SUPPLEMENT ARTICLE

Newborn Screening: Toward a Uniform ScreeningPanel and System—Executive SummaryMichael S. Watson, PhD, Marie Y. Mann, MD, MPH, Michele A. Lloyd-Puryear, MD, PhD, Piero Rinaldo, MD, PhD, R. Rodney Howell, MD,

American College of Medical Genetics Newborn Screening Expert Group

The authors have indicated they have no financial relationships relevant to this article to disclose.

ABSTRACT

The Maternal and Child Health Bureau commissioned the American College ofMedical Genetics to outline a process of standardization of outcomes and guide-lines for state newborn screening programs and to define responsibilities forcollecting and evaluating outcome data, including a recommended uniform panelof conditions to include in state newborn screening programs. The expert panelidentified 29 conditions for which screening should be mandated. An additional 25conditions were identified because they are part of the differential diagnosis of acondition in the core panel, they are clinically significant and revealed withscreening technology but lack an efficacious treatment, or they represent inciden-tal findings for which there is potential clinical significance. The process of iden-tification is described, and recommendations are provided.

www.pediatrics.org/cgi/doi/10.1542/peds.2005-2633I

doi:10.1542/peds.2005-2633I

KeyWordsnewborn, screening, genetics, publichealth, panel, congenital

AbbreviationsHRSA—Health Resources and ServicesAdministrationAAP—American Academy of PediatricsACMG—American College of MedicalGeneticsMS/MS—tandemmass spectrometry

Accepted for publication Dec 27, 2005

Address correspondence to Marie Y. Mann,MD, MPH, Genetic Service Branch, Maternaland Child Health Bureau, Health Resourcesand Service Administration, 5600 FishersLane, Rockville, MD 20857. E-mail:mmann@hrsa.gov

PEDIATRICS (ISSN Numbers: Print, 0031-4005;Online, 1098-4275); published in the publicdomain by the American Academy ofPediatrics

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IN THE UNITED States, newborn screening is a highlyvisible and important state-based public health pro-

gram that began �40 years ago. States and territoriesmandate newborn screening of all infants born withintheir jurisdiction for certain disorders that may not oth-erwise be detected before developmental disability ordeath occurs. Newborns with these disorders typicallyappear normal at birth. Appropriate compliance with themedical management prescribed can allow most affectednewborns to develop normally. As the model for publichealth-based population genetic screening, newbornscreening is recognized nationally as an essential pro-gram that aims to ensure the best outcomes for thenation’s newborn population.

There are no national newborn screening standards,aside from the Standard on Blood Collection on Filter Paperpublished by the National Committee for Clinical Labo-ratory Standards1 and guidance from the Council ofRegional Networks for Genetic Services, funded by theHealth Resources and Services Administration (HRSA),and limited advice is available from national advisorycommittees and national medical or public health pro-fessional organizations regarding newborn screeningpolicies and conditions to be included in screening man-dates. The level of state resources available (personnel,equipment, and service capacity); programs’ interpreta-tions of available evidence concerning given conditions(incidence, treatability, and impact); availability or ex-pense of new screening methods; and public advocacyby families, health care professionals, and state legisla-tors have often led to divergence among states regardingwhich conditions should be mandated for newbornscreening. This divergence has resulted in significantdisparities in screening services available to infants. In2000, the American Academy of Pediatrics (AAP) New-born Screening Task Force1 indicated that greater uni-formity among programs would benefit families, profes-sionals, and public health agencies.

The public health system faces many challenges asnewborn screening capabilities continue to evolve. Thehealth care service infrastructure is limited with respectto the interconnections among primary care profession-als and subspecialists, particularly in rural areas, a prob-lem complicated by the number and diversity of veryrare conditions identified in newborn screening pro-grams. There are geographic limitations in the availabil-ity of specific expertise for many of the rare conditions,and considerable needs exist throughout the health caresystem in the areas of training and education about thedisorders detected through newborn screening pro-grams. Furthermore, improvements in the newbornscreening system and expansion of the number of con-ditions for which screening is offered have costs, andthese costs and the associated benefits seem to accrueindependently of the public and private health care de-livery systems, which complicates their integration.

Many states provide the programs necessary to ensurethat screening and diagnosis occur, but they are limitedin their ability to ensure long-term management, includ-ing the provision of the necessary treatment and ser-vices. In addition, new technologies have brought 3major challenges to newborn screening: (1) expansion ofthe knowledge base regarding the causes and thereforethe treatment or potential treatment of genetic diseases;(2) rapid expansion of diverse technologies, such as mul-tiplex platforms, that may be used in screening; and (3)increased use of tiered testing strategies to enhance thepositive predictive value of an initial abnormal result.

The lack of newborn screening program uniformityfor infants, the changing dynamics of emerging technol-ogy, and the complexity of genetics necessitate assess-ment of the state of the art in newborn screening andviews on future directions such programs could take. In1999, the AAP Newborn Screening Task Force2 recom-mended that “HRSA should engage in a national processinvolving government, professionals, and consumers toadvance the recommendations of this Task Force andassist in the development and implementation of nation-ally recognized newborn screening system standards andpolicies.”

In response to this need, the Maternal and ChildHealth Bureau of HRSA commissioned the AmericanCollege of Medical Genetics (ACMG) to outline a processof standardization of outcomes and guidelines for statenewborn screening programs and to define responsibil-ities for collecting and evaluating outcome data, includ-ing a recommended uniform panel of conditions to in-clude in state newborn screening programs. It wasexpected that the analytical endeavor and subsequentrecommendations would be definitive and that the sub-sequent recommendations would be based on the bestscientific evidence and analysis of that evidence. ACMGwas asked specifically to develop recommendations toaddress (1) a uniform condition panel (including imple-mentation methods), (2) model policies and proceduresfor state newborn screening programs (with consider-ation of a national model), (3) model minimal standardsfor state newborn screening programs (with consider-ation of national oversight), (4) a model decision matrixfor consideration of state newborn screening programexpansion, and (5) consideration of the value of a na-tional process for quality assurance and oversight. Thisreport is a response to the HRSA/Maternal and ChildHealth Bureau request.

DEVELOPING A UNIFORM SCREENING PANELAs indicated, the AAP task force was concerned partic-ularly about the lack of uniformity between the state-based newborn screening programs and the need for“nationally recognized newborn screening system stan-dards and policies.” There are few existing systems thatallow for the assessment of conditions to determine their

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appropriateness for newborn screening. In addition tothe original Wilson-Jungner criteria,3 some states (eg,Nebraska and Washington) have developed such evalu-ation criteria and systems; other countries (eg, Australiaand Belgium) have developed them as well. However,most use criteria that either are difficult to quantify or donot allow conditions to be comparatively ranked ade-quately. Most are inadequate with respect to the han-dling of conditions that have similar or overlapping dis-ease markers or may be detected through the use ofmultiplex technologies but may vary in their analyticaland clinical features.

METHODS

Expert Group Development and ProcessACMG convened a group, the Newborn Screening Ex-pert Group, that included participants with expertise invarious areas of subspecialty medicine and primary care,health policy, law, ethics, and public health, consumers,and several ad hoc work groups. As an initial step in theprocess, the expert group developed a set of guidingprinciples for its work. The establishment of these prin-cipals was followed by the development of criteria withwhich conditions were to be evaluated and the identifi-cation of the conditions to be evaluated. A steering com-mittee oversaw the work of this group. The 2 workgroups were formed to provide more in-depth analysisin 2 specific areas, that is the uniform panel and itscriteria and the diagnosis and follow-up system.

The expert group used a 2-tiered approach for assess-ing and ranking conditions. In the first tier, with thespecific evaluation criteria, conditions were analyzed byrecognized experts and other interested individuals todevelop a quantification of opinion. In the second tier,the quantification data were subjected to an analysis ofthe evidence base for each specific screening criterionscore. Basic principles developed to guide the decision-making process were factored with the 2 levels of anal-ysis to yield a set of core conditions. Further, additionalconditions that are clinically significant that can be re-vealed during establishment of the diagnosis due to re-lationships with screening analytes used to identify coreconditions or the technology used to screen were iden-tified and referred to as secondary condtions.

Establishing PrinciplesThe following basic principles were developed as aframework for defining the criteria with which to eval-uate conditions and to make recommendations. (1) Uni-versal newborn screening is an essential public healthresponsibility that is critical for improving the healthoutcomes of affected children. (2) Newborn screeningpolicy development should be driven primarily by theinterests of affected newborns, with secondary consider-ation being given to the interests of unaffected new-

borns, families, health professionals, and the public. (3)Newborn screening is more than testing. It is a coordi-nated comprehensive system consisting of education,screening, follow-up contact, diagnosis, treatment andmanagement, and program evaluation. (4) The medicalhome and the public and private components of thescreening programs should be in close communication,to ensure confirmation of test results and appropriatefollow-up evaluation and care of identified newborns.(5) Recommendations about the appropriateness of con-ditions for newborn screening should be based on eval-uation of scientific evidence and expert opinion. (6) Tobe included as a primary target condition in a newbornscreening program, a condition should meet the follow-ing minimal criteria: it can be identified at a time (24–48hours after birth) at which it would not ordinarily bedetected clinically; a test with appropriate sensitivity andspecificity is available for it; and there are demonstratedbenefits of early detection, timely intervention, and ef-ficacious treatment of the condition. (7) The primarytargets of newborn screening should be conditions thatmeet the criteria listed in principle 6. The newbornscreening program also should report any other resultsof potential clinical significance. (8) Centralized healthinformation data collection is needed for longitudinalassessment of disease-specific screening programs. (9)Total quality management should be applied to newbornscreening programs. (10) Newborn screening specimensare valuable health resources. Every program shouldhave policies in place to ensure confidential storage andappropriate use of specimens. (11) Public awareness,coupled with professional training and family education,is a significant program responsibility that must be partof the complete newborn screening system.

Choosing ConditionsThe conditions chosen for evaluation were included for�1 of several reasons, as follows. They are included inprivate, state, or national newborn screening programs.They are revealed coincidentally by some of the technol-ogies used in newborn screening. They were identifiedby members of the expert group as worthy of consider-ation. They were identified by disease-specific advocacyorganizations. They are included in the differential diag-nosis of screening results for another condition. In thecourse of information collection, all conditions weresubject to reconsideration. Eighty-four conditions werechosen for consideration.

Developing Evaluation Criteria and Their Comparative ValuesThe uniform panel working group developed the criteriawith which conditions were to be evaluated; these weremodified subsequently by the expert group. Criteriawere divided into 3 main categories that covered aspectsof the condition, that is, (1) clinical characteristics (eg,incidence, burden of disease if not treated, and pheno-

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type in the newborn); (2) analytical characteristics of thescreening test (eg, availability and features of the plat-form); and (3) diagnosis, treatment, and management ofthe condition in acute and chronic forms (this criterionincludes the availability of health professionals experi-enced in diagnosis, treatment, and management).

Within each of these categories, several componentcriteria were developed (resulting in a total of 19 crite-ria) for assignment of the comparative value or score.The scoring system recognizes the strengths and limita-tions found for each condition and summarizes them ina ranking system. Therefore, a low score in a particulararea does not necessarily mean that screening for thatcondition will never be conducted. In fact, low scorescould be overruled by scientific evidence of new ad-vances in testing and treatment and should be recog-nized as opportunities for targeted research endeavorsand subsequent reconsideration of the condition for in-clusion.

The criteria that were developed to differentiate theappropriateness of conditions for newborn screening in-clude some that have a highly objective scientific basisand others that are associated with more subjective as-pects. To the extent possible, the expert group relied onthe scientific literature to provide the information onwhich the recommendations are based. However, somecriteria have significant subjective aspects that requirethe consideration of more than just scientific and expertopinion. For example, issues of cost were considered butwere not viewed as central in the analysis of the scien-tific literature. Cost is an example of a subjective crite-rion because it is a contextual concern and can be mea-sured only against the value of the outcome.

Collecting DataThe first tier of the analysis was accomplished throughthe development of a data collection instrument con-taining the evaluation screening criteria. A survey wasconducted to allow for the input of a wide range ofindividuals and organizations with interest in newbornscreening. The data collection instrument includedmethods not only to collect information from expertsbut also to quantify that expert opinion regarding fea-tures of the conditions under consideration for inclusionin a uniform condition panel.

Before wide distribution, the data collection instru-ment was pilot tested. Potentially ambiguous languagewas identified and clarified, and scores were adjustedmodestly to reflect the evolving priorities of the expertgroup. After modification, the data collection instrumentwas made widely available through passive efforts (eg,Listserv lists of interest groups such as the Genetic Alli-ance, Association of Public Health Laboratories, and As-sociation of State and Territorial Health Officials) andactive efforts (eg, direct approaches to experts on theconditions under evaluation and/or to support groups

for particular conditions under evaluation). In this way,it was possible to acknowledge broad views that were ofa more-subjective nature, such as the simplicity of thetreatment (parents and individuals with the disorder inquestion often differed significantly from experts whenscoring items such as simplicity of treatment). The re-sults led to a preliminary listing of conditions and theirplacement in 1 of 3 categories, that is, high scoring,moderately scoring but part of the differential diagnosisof a high-scoring condition, or low scoring and not ap-propriate for newborn screening at this time. The re-sponses of �3 recognized experts for each conditionwere compared with responses of all respondents re-garding that condition, and results were found to beconsistent.

Survey results were analyzed statistically. Respon-dents were characterized to ensure that they werebroadly representative of the population. With the rec-ognition that not all who responded have expertise orexperience in all aspects of newborn screening for aspecific condition, methods were used that allowed datato be aggregated for each criterion for each condition,rather than using the total score for a condition. A meanscore for each criterion for each condition was basedonly on the responses provided for the criterion. Re-spondents were allowed to insert a “U” if an answer wasunknown. The sum of the means was used for the totalscore assigned to a condition, because the sum of meanstends to acknowledge dissenting views more clearly thandoes the sum of medians.

It is recognized that this relatively open survey pro-cess limited the views of experts while considering theviews of those less knowledgeable about the individualconditions. However, analyses provided by scientific ex-perts showed that their views were in close agreementwith those of most respondents.

Establishing and Integrating the Evidence BaseIn the second tier of the assessment, the evidence basefor the conditions was established and an algorithmthrough which conditions were reassessed was devel-oped. Each condition was considered with respect to theavailable scientific evidence, such as systematic reviewsof reference lists (including Medline, PubMed, and oth-ers), books, Internet sources, professional guidelines,clinical evidence, and cost/economic evidence and mod-eling, for each criterion. The categorization was adjustedin accordance with the evidence. The analysis of theevidence base from the scientific literature included de-tails about the screening tests, the efficacy of treatments,and the adequacy of the knowledge base for the condi-tion. Disease-specific fact sheets were developed to de-scribe this evidence.

At least 2 recognized experts examined the evidenceon the fact sheet for all criterion scores for the conditionsand assigned a level of evidence for each criterion score,

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making the scoring system part of a fuller evidence-based analysis. Therefore, the evaluation of the evidencefor the scores in the second tier of analysis is part of abroader assessment of the scientific literature related tothe conditions, tests, and treatments. In addition to val-idating the evidence gleaned from the literature andother sources, the experts assigned a level of quality tothe studies from which the evidence was drawn. Adjust-ments based on the evidence were made primarily onthe basis of the accuracy of the information. When sig-nificant differences were found between the data col-lected through the survey and the evidence base, thedifferences were acknowledged and addressed in each ofthe fact sheets. Only rarely were adjustments required toalign the literature evidence with the views of the surveyrespondents.

RESULTSIn the first tier of assessment, nearly 300 individualsfrom the United States and other countries completedthe data collection instrument. Many respondents pro-vided information on multiple conditions, yielding in-formation on nearly 4000 individual disease-specific re-sponses. The data are displayed in Table 1 and Fig 1,where the sums of the means are displayed for all con-ditions. Medium-chain acyl-CoA dehydrogenase defi-ciency, congenital hypothyroidism, and phenylketonu-ria were the highest-scoring conditions in this evaluationsystem, followed by biotinidase deficiency, sickle cellanemia, and congenital adrenal hyperplasia. A numberof other conditions that scored in the upper third werealso found to have an efficacious treatment and suffi-cient natural history information to be considered ap-propriate for newborn screening. Most conditions in themiddle third of scores were also included in the differ-ential diagnosis of �1 of the higher-scoring conditions.Almost all conditions in the bottom third of scores eitherlacked a screening test that had been validated in ageneral newborn population or were deficient in meet-ing several of the assigned evaluation criteria. Because oflimited involvement of infectious disease experts, theexpert group chose to defer decision-making on infec-tious diseases.

A score of 1200 on the data collection instrument wasfound to provide a logical point of separation between agroup of high-scoring conditions (1200–1799 of a pos-sible 2100) and another group of low-scoring (�1000)conditions. A group of conditions with intermediatescores (1000–1199) was identified, all of which werepart of the differential diagnosis of a high-scoring corecondition but without an efficacious treatment or with-out a well-understood natural history.

With the use of expert opinion and the validatedevidence base, each condition that had been assignedpreviously to a category on the basis of quantified scoreswas reconsidered on the basis of the scientific evidence

regarding an available screening test, an efficacioustreatment, an adequate understanding of the naturalhistory, whether the condition was part of the differen-tial diagnosis of another condition, and whether thescreening test results were related to a clinically signifi-cant condition. These categories were referred to as thecore panel, secondary targets (conditions that are part ofthe differential diagnosis of a core panel condition), andnot appropriate for newborn screening (either no new-born screening test is available or there is poor perfor-mance with respect to multiple other evaluation crite-ria).

DISCUSSIONThe basis for decision-making started with whether ascreening test is available, which was then overlaid withthe overall quantified expert opinion analysis gatheredwith the data collection information tool. The process ofquantifying this expert opinion was informed by litera-ture review and expert validation.

In the first tier of analysis, conditions with scores of�1200 met key criteria and were preliminarily consid-ered appropriate for inclusion in a core newborn screen-ing panel. Conditions scoring �1000 were not consid-ered appropriate for inclusion in the core newbornscreening panel at this time. As noted previously, theexpert group determined that laboratories should reportany result revealed coincidentally in the course of new-born screening that might be clinically significant. Ingeneral, the screening test has been optimized for thedetection of primary target conditions. Optimizing thetechnology for a primary target condition does not nec-essarily optimize the detection of all possible conditions.These conditions are often revealed through diagnostictesting because they are part of the differential diag-nosis of a core condition, as occurs with tandem massspectrometry (MS/MS)-identified cases, but they maybe apparent in the screening laboratory because of thetechnologies used in screening (eg, hemoglobinopathiesdetected with high-pressure liquid chromatography/isoelectric focusing). Therefore, the expert group desig-nated a category of secondary targets, which includedconditions for which results should be made available tohealth care professionals and/or families by the screen-ing laboratory or for which results are determined dur-ing the diagnostic phase of the screening program andprovided to families in the course of diagnosis and fol-low-up care. Most conditions placed in the secondarytarget category are part of the differential diagnosis of acondition in the core panel. Inclusion in the secondarytarget category allows for the collection of cases on anational level for additional investigation to understandthe disease process and for development of treatmentmodalities. Regardless of whether programs choose tointegrate all such conditions into their broader newbornscreening programs, it will be important for them to

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TABLE 1 Scores for All Conditions (Sorted in Descending Order of Sum of Mean Scores)

Condition Abbreviation Sum ofMean Scores

Percentile

Medium-chain acyl-CoA dehydrogenase deficiency MCAD 1799 1.00Congenital hypothyroidism CH 1718 0.99Phenylketonuria PKU 1663 0.98Neonatal hyperbilirubinemia (kernicterus) HPRBIL 1584 0.96Biotinidase deficiency BIOT 1566 0.95Sickle cell anemia (hemoglobin SS disease) Hb SS 1542 0.94Congenital adrenal hyperplasia (21-hydroxylase deficiency) CAH 1533 0.93Isovaleric acidemia IVA 1493 0.89Very long-chain acyl-CoA dehydrogenase deficiency VLCAD 1493 0.89Maple syrup disease MSUD 1493 0.89Classic galactosemia GALT 1473 0.88Hemoglobin S/�-thalassemia Hb S/�Th 1455 0.87Hemoglobin S/C disease Hb S/C 1453 0.86Long-chain L-3-hydroxyacyl-CoA dehydrogenase deficiency LCHAD 1445 0.84Glutaric acidemia type I GA I 1435 0.833-Hydroxy-3-methyglutaric aciduria HMG 1420 0.82Trifunctional protein deficiency TFP 1418 0.81Multiple carboxylase deficiency MCD 1386 0.80Benign hyperphenylalaninemia H-PHE 1365 0.78Methylmalonic acidemia (mutase deficiency) MUT 1358 0.77Homocystinuria (attributable to cystathionine �-synthase deficiency) HCY 1357 0.763-Methylcrotonyl-CoA carboxylase deficiency 3MCC 1355 0.75Hearing loss HEAR 1354 0.73Methylmalonic acidemia (Cbl A,B) Cbl A,B 1343 0.72Propionic acidemia PROP 1333 0.71Carnitine uptake defect CUD 1309 0.69Galactokinase deficiency GALK 1286 0.69Glucose-6-phosphate dehydrogenase deficiency G6PD 1286 0.67�-Ketothiolase deficiency BKT 1282 0.66Citrullinemia CIT 1266 0.65Argininosuccinic acidemia ASA 1263 0.64Tyrosinemia type I TYR I 1257 0.63Short-chain acyl-CoA dehydrogenase deficiency SCAD 1252 0.61Tyrosinemia type II TYR II 1249 0.60Glutaric acidemia type II GA2 1224 0.59Medium/short-chain L-3-hydroxyacyl-CoA dehydrogenase deficiency M/SCHAD 1223 0.58Cystic fibrosis CF 1200 0.57Variant hemoglobinopathies (including hemoglobin E) Var Hb 1199 0.55Human HIV infection HIV 1193 0.54Defects of biopterin cofactor biosynthesis BIOPT(BS) 1174 0.53Medium-chain ketoacyl-CoA thiolase deficiency MCKAT 1170 0.52Carnitine palmitoyltransferase II deficiency CPT II 1169 0.51Methylmalonic acidemia (Cbl C,D) Cbl C,D 1166 0.49Argininemia ARG 1151 0.48Tyrosinemia type III TYR III 1149 0.47Defects of biopterin cofactor regeneration BIOPT(REG) 1146 0.46Malonic acidemia MAL 1143 0.45Carnitine/acylcarnitine translocase deficiency CACT 1141 0.43Isobutyryl-CoA dehydrogenase deficiency IBG 1134 0.422-Methyl-3-hydroxybutyric aciduria 2M3HBA 1132 0.41Carnitine palmitoyltransferase I deficiency (liver) CPT IA 1131 0.402-Methylbutyryl-CoA dehydrogenase deficiency 2MBG 1124 0.39Hypermethioninemia MET 1121 0.37Dienoyl-CoA reductase deficiency DE RED 1119 0.36Galactose epimerase deficiency GALE 1066 0.353-Methylglutaconic aciduria 3MGA 1057 0.34Severe combined immunodeficiency SCID 1047 0.33Congenital toxoplasmosis TOXO 1041 0.31Familial hypercholesterolemia (heterozygote) FHC 1038 0.30Carnitine palmitoyltransferase I deficiency (muscle) CPT IB 1009 0.29Citrullinemia type II CIT II 1001 0.28

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have the diagnostic confirmatory results for all suchcases, because the results have a direct impact on thecalculation of false-positive rates of screening for thecore panel conditions.

After conditions were preliminarily categorized onthe basis of their data collection instrument scores, theevidence base, as reflected in fact sheets developed foreach condition, was assessed. If a clinically significantcondition in the core panel did not have the scientificevidence to support the availability of an efficacioustreatment, then it was moved to the secondary targetcategory. Similarly, if it was determined that an under-standing of the natural history of the condition wasinsufficient to justify primary screening, then the condi-tion was moved to the secondary target category. Whentest results identified carriers of the conditions defini-tively, the handling of carrier information was movedinto the secondary target category.

Figure 2 demonstrates the decision-making algo-rithm. It is important to note that the algorithm pre-sumes an ongoing review of conditions to determinetheir continued or newly identified appropriateness fornewborn screening as new tests and treatments evolve.The data collection instrument used in this project pro-vides an assessment of only one aspect of a broaderdecision-making process required for establishing a new-born screening uniform panel. An ongoing analysis ofthe scientific evidence must be overlaid on the quanti-fied expert opinion.

Clearly, the first decision to screen is based on theavailability of a sensitive specific screening test that can

be performed in the 24- to 48-hour period after birth. Atotal of 29 conditions are considered appropriate fornewborn screening because they have a screening test,an efficacious treatment, and adequate knowledge ofnatural history (Table 2). The conditions best meeting allof the criteria established by the expert group are medi-um-chain acyl-CoA dehydrogenase, congenital hypo-thyroidism, and phenylketonuria. Among conditions as-signed to the core panel are 9 organic acidurias, 6 aminoacidurias, 5 disorders of fatty acid oxidation, 3 hemoglo-binopathies associated with a hemoglobin S allele, and 6other conditions. Twenty-three of the 29 conditions inthe core panel are identified with multiplex technologiessuch as MS/MS.

On the basis of the evidence, 6 of the 35 conditionsplaced initially in the core panel were moved into thesecondary target category, which expanded to 25 condi-tions that are part of the differential diagnosis of a corepanel condition. Knowledge of these secondary targets(ie, from newborn screening or follow-up test results)can be clinically important to the family. In addition tothe 54 conditions identified in Table 2, the expert groupidentified 27 conditions that were not considered appro-priate for newborn screening, either because they metfew evaluation criteria or because they lacked a screen-ing test.

There were limitations. Conditions with limited evi-dence reported in the scientific literature were moredifficult to evaluate with the data collection instrument.For example, some conditions have been reported for

TABLE 1 Continued

Condition Abbreviation Sum ofMean Scores

Percentile

Ornithine transcarbamylase deficiency OTC 942 0.27Guanidinoacetate methyltransferase deficiency GAMT 922 0.24Wilson disease WD 922 0.24Diabetes mellitus, insulin dependent IDDM 891 0.23Neuroblastoma NB 864 0.22Arginine:glycine amidinotransferase deficiency AGAT 861 0.20Turner syndrome TURNER 847 0.19Adenosine deaminase deficiency ADA 841 0.18Carbamoylphosphate synthetase deficiency CPS 833 0.17�1-Antitrypsin deficiency A1AT 819 0.16Congenital cytomegalovirus infection CMV 779 0.14Duchenne and Becker muscular dystrophy DMD 776 0.12Fragile X syndrome FX 776 0.12Congenital disorder of glycosylation type Ib CDG Ib 766 0.11Smith-Lemli-Opitz syndrome SLO 759 0.10Biliary atresia BIL 744 0.08Hurler-Scheie syndrome MPS-1H 707 0.07X-linked adrenoleukodystrophy ALD 705 0.06Fabry disease FABRY 661 0.05Creatine transport defect CR TRANS 646 0.04Lysosomal storage diseases LSD 638 0.02Pompe disease POMPE 613 0.01Krabbe disease KRABBE 447 0.00

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�10 families in the world. Many conditions were foundto occur in multiple forms, distinguished by age of onset,severity, or other features. Furthermore, unless a condi-tion was already included in newborn screening pro-grams, a potential for bias was apparent in the informa-tion related to some criteria. The power of the statisticalanalyses and the blending of 2 forms of evaluation alsopresented limitations. The data collection process in thefirst tier of the analysis was limited also by the significantvariability in the numbers of individuals responding forthe different conditions. Because of limitations in thescientific evidence for these rare diseases, there wassignificant reliance on the opinions of experts on theconditions. There were many conditions that scoredclose to other conditions, and it is unlikely that thestatistical power provided in these analyses was suffi-cient to discriminate accurately among the conditions ina ranking system. Nevertheless, groups of scores wereassessed, and natural separations between groups be-came apparent. In such circumstances, expert opinion,with reasoning that applied first principles of geneticmedicine to the evidence and to the quality of the data,determined the placement of the conditions in particularcategories.

PROGRAM EVALUATION, COST-EFFECTIVENESS, ANDFUTURE NEEDS OF THE NEWBORN SCREENING SYSTEM

The Newborn Screening SystemBecause the appropriate functioning of the system iscritical to realizing improved outcomes, the componentsof a screening system were examined by the expertgroup during the project. (Information was obtainedfrom program reports submitted to the National New-born Screening and Genetics Resource Center and isbased on information available as of October 2003.) Thegoal of the evaluation was to determine the extent towhich states have addressed the many aspects of com-ponents of this system and to recommend performancestandards to improve the quality of the system. Theability to ensure appropriate diagnosis and managementis considered to be primarily a system responsibility.Limitations and significant variability were identified inthe components of prenatal education, screening, fol-low-up services, diagnosis, treatment, and programmanagement. For example, financing across state andcounty lines is constrained by state-based Medicaidrules; service delivery is fragmented on a categorical ordisease basis; there is insufficient support to bridge geo-

FIGURE 1Scoring according to test availability. This scoring separates conditions that have an acceptable, validated, population-based screening test from those that do not. Abbreviations forconditions are as listed in Table 1.

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FIGURE 2Condition evaluation and decision-making algorithm. NBS indicates newborn screening.

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graphic barriers; it is difficult to identify experiencedhealth care professionals for complex care (eg, centers ofexcellence for genital reconstructive surgery for congen-ital adrenal hyperplasia or confirmation of metabolicdiagnoses); there is misinterpretation of privacy regula-tions (eg, the Health Information Portability and Account-ability Act); there is underuse and lack of uniformity ofinformation technology; collaborative management andcare are often constrained by systems of reimbursementfor services; state sovereignty sometimes dictates indi-vidual approaches; and there is variability in financing ofscreening programs.4

There are national and state roles in addressing theselimitations, and states must retain their significant rolesand responsibilities. They have clear authority with re-gard to oversight and evaluation, as well as enforcement.There is a need to integrate the various systems of healthcare coverage and payment through flexible compre-hensive financing of services. Service coordination atstate and local levels must be considered, as well asprogram integration with the State Children’s HealthInsurance Program, early intervention programs, Title Vprograms, and similar services.

It is apparent, however, that all state programs couldbenefit from a more-robust national role in newbornscreening. Because so many of the conditions screenedfor among newborns or under consideration for screen-ing are rare, most states that undertake evaluations ofthe scientific basis for screening of conditions must relyon the same, relatively small group of patients identifiedthroughout the world. There is a potential national rolein providing scientific evaluation of conditions and de-

fining core condition panels. This would allow states toapply the best science to their own considerations whendetermining their roles in expanded screening.

Practice guidelines also could be developed at a na-tional level by interested organizations. The expertgroup identified a clear gap between the informationavailable and the information needed by primary careprofessionals to facilitate an immediate response in theevent of a screen-positive case. In response, the expertgroup developed an action sheet for each core conditionand secondary target, to facilitate immediate responseson the part of primary care professionals with respect tothe expected steps in diagnosis and follow-up care.

There are also potentially expanded national roles inoversight, data collection, and program evaluation, aswell as development of educational materials to supportnewborn screening. Depending on the overall incidenceof particular conditions, regional collaborative groupssuch as those funded by HRSA could coordinate access tohealth care professionals, serve as coordinators and re-positories for data collection, provide long-term fol-low-up capability when resources and expertise are lim-ited, facilitate transition (and access) from pediatric toadult care, and provide education.

The distribution of primary, secondary, and tertiaryservices is based largely on the incidence of a conditionand the complexity of its short- and long-term diagnosisand management. For more common conditions witheasier diagnosis and follow-up management, there islikely to be sufficient local health care expertise forpatient care. As incidence decreases and complexity in-creases, particularly for rare metabolic diseases, servicesbecome more difficult to access. Developing resources toensure that health care professionals are available lo-cally, regionally, and nationally will be important toensuring access to high-quality services.

Cost-Effectiveness AnalysisA basic cost-effectiveness assessment project was per-formed to inform the decision-making process. The as-sessment focused primarily on a scientific analysis ofconditions and the features that should be consideredwhen deciding whether they should be included in anewborn screening program, because costs often are thebasis on which such decisions are made.

Costs and benefits related to screening for particularconditions or groups of conditions were evaluated aftermapping them over major disease outcomes (eg, lifeexpectancy, cerebral palsy/stroke, seizures, develop-mental delay, hearing loss, and vision loss). Costs wereobtained from the literature, and benefits were deter-mined from expected outcomes with and without earlytreatment or intervention. The results of these analysesindicated that most newborn screening programs im-prove outcomes and reduce overall costs. Furthermore,technologies such as MS/MS or high-pressure liquid

TABLE 2 Core Panel and Secondary Targets in Newborn ScreeningPanel

OA FAO AA Hemoglobinopathies Other

Core panelIVA MCAD PKU Hb SSa CHGA I VLCAD MSUD Hb S/�Tha BIOTHMG LCHAD HCYa Hb S/Ca CAHa

MCD TFP CIT GALTMUTa CUD ASA HEAR3MCCa TYR Ia CFCbl A,Ba

PROPBKT

Secondary targetsCbl C,Da SCAD H-PHE Var Hba GALKa

MAL GA2 TYR II GALEIBG M/SCHAD BIOPT(BS)2M3HBA MCKAT ARG2MBG CPT II TYR III3MGA CACT BIOPT(REG)

CPT IA METDE RED CIT II

OA indicates disorders of organic acidmetabolism; FAO, disorders of fatty acidmetabolism; AA,disorders of amino acid metabolism. Abbreviations used for conditions are listed in Table 1.a Conditions for which specific discussions of unique issues are found in the text.

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chromatography save money because of their multiplex-ing capabilities and low screening false-positive rates.The identification of potentially affected individuals atsuch an early age leads to many years over which thebenefits accrue and aggregate over costs.

CONCLUSIONSSignificant variability in the conditions for which new-borns are screened led to this project to assess the scien-tific and medical evidence and the views of variousindividuals and interest groups associated with the con-ditions being considered. Throughout this undertaking,scientific literature and expert opinion formed the basisfor information collection and assessment. The expertpanel considered a range of information, from disease-specific information to the full breadth of the newbornscreening system, in evaluating 84 conditions. There wasan effort to overlay the evidence, where available, onexpert opinion. The process of quantifying this expertopinion was informed by literature review and expertvalidation. It is important to acknowledge that there waslimited scientific evidence available on the rare disordersconsidered by the expert panel. Furthermore, becausethere was limited activity in the area of coordinated datacollection and analysis, it seemed unlikely that robustscientific evidence would be available in the near future.Therefore, reliance on experts and their ability to applyfirst principles5,6 was required.

Guiding principals for newborn screening and criteriawere established for evaluating conditions. The condi-tions being considered were assigned initially, throughexpert analysis, to 1 of 3 categories, depending on howthey met the screening criteria. The categories were corepanel, secondary targets (conditions that are part of thedifferential diagnosis of a core panel condition), and notappropriate for newborn screening (either no newbornscreening test is available or there is poor performancewith respect to multiple other evaluation criteria). Eachcondition was then evaluated to determine the extent towhich the scientific evidence supports the availability ofa test and a treatment, whether the natural history of thecondition is well understood, and whether the informa-tion provided by testing indicates the possible presenceof the condition or of a carrier state.

The expert panel identified 29 conditions for whichscreening should be mandated. An additional 25 condi-tions were identified because they are part of the differ-ential diagnosis of a condition in the core panel, they areclinically significant and revealed with screening tech-nology but lack an efficacious treatment (eg, some iden-tified with MS/MS technology), or they represent inci-dental findings for which there is potential clinicalsignificance (hemoglobinopathies). The expert groupthought it was important that such findings be commu-nicated to the health care service community and tofamilies. In addition, the view that the technologies used

in newborn screening should be maximized is inherentin the recommendation that all clinically significant in-formation discovered through newborn screeningshould be provided to the relevant health care profes-sionals and/or the family. The expert group recommendsthat state newborn screening programs mandate screen-ing for all core panel conditions defined in this article;mandate reporting of all secondary target conditionsdefined herein and reporting of any abnormal resultsthat may be associated with clinically significant condi-tions, including definitive identification of carrier status;maximize the use of multiplex technologies; and con-sider that the range of benefits realized through new-born screening includes treatments that go beyond aninfant’s death or morbidity.

The full breadth of the newborn screening system wasassessed, including a brief review of its cost-effective-ness. Numerous barriers to implementation of an opti-mal screening and follow-up program were identified.Recommended actions to overcome these barriers in-clude establishment of a national role in the scientificevaluation of conditions and the technologies withwhich they are screened, standardization of case defini-tions and reporting procedures, enhanced oversight ofhospital-based screening activities, long-term data col-lection and surveillance, and consideration of the finan-cial needs of programs.

The recommendations are as follows. (1) Programsshould continue to improve the components of the sys-tem beyond the initial screening, communicate results,and ensure that affected newborns enter short-term fol-low-up care. (2) Reporting procedures should be stan-dardized. (3) Reports of confirmatory results should beobtained. (4) There should be improved oversight (eg,Joint Commission on Accreditation of Hospital Organi-zations) of hospital-based screening activities, to im-prove tracking of screen-positive cases. (5) There shouldbe more uniformity in the definition of the performancestandards (eg, repeat test versus second test) monitoredand reported by programs. (6) The quality assuranceprograms involving the diagnostic and follow-up systemshould be enhanced. (7) National oversight and author-ity, with appropriate resources, should be provided. (8)Systems should be in place for collection of data aboutindividuals identified as screen-positive in newbornscreening programs.

ACKNOWLEDGMENTSThis work was conducted under a subcontract from theAmerican College of Medical Genetics (agreement 240-01-0038), with funding from the Maternal and ChildHealth Bureau.

The Newborn Screening Expert Group was as follows:Newborn Screening Steering Committee: Jose Cordero,MD, MPH, Centers for Disease Control and Prevention;E. Steven Edwards, MD, Past President, AAP; R. Rodney

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Howell, MD, ACMG, University of Miami School ofMedicine; Jennifer L. Howse, PhD, President, March ofDimes Birth Defects Organization; Michele A. Lloyd-Puryear, MD, PhD, HRSA; Marie Y. Mann, MD, MPH(project officer), HRSA; Tricia Mullaley, BA, GeneticAlliance; Peter van Dyck, MD, MPH, Maternal and ChildHealth Bureau; HRSA; Michael S. Watson, PhD (projectdirector), ACMG; Newborn Screening Expert Group: R.Rodney Howell, MD (chair), ACMG, University ofMiami School of Medicine; William Becker, DO, Associ-ation of Public Health Laboratories, Ohio State Depart-ment of Health, Ohio State University; Coleen Boyle,PhD (ex officio), Centers for Disease Control and Pre-vention; George C. Cunningham, MD, MPH, GeneticsDisease Branch, California Department of Health Ser-vices; Michael R. DeBaun, MD, MPH, Washington Uni-versity School of Medicine; Stephen M. Downs, MD,Indiana University School of Medicine; Edward Gold-man, JD, University of Michigan Hospitals and HealthSystem; Stephen I. Goodman, MD, University of Colo-rado Health Sciences Center; Fernando Guerra, MD,MPH, San Antonio Metropolitan Health District; W.Harry Hannon, PhD (ex officio), Centers for DiseaseControl and Prevention; James Hanson, MD (ex officio),National Institute of Child Health and Human Develop-ment, National Institutes of Health; Cecilia Larson, MD,New England Newborn Screening Program; Michele A.Lloyd-Puryear, MD, PhD (ex officio), HRSA; Marie Y.Mann, MD, MPH (ex officio) (project officer), HRSA;Scott McLean, MD, LTC, MC (ex officio), United StatesArmy; Gurvaneet Randhawa, MD, MPH (ex officio),Agency for Healthcare Research and Quality; PieroRinaldo, MD, PhD, Mayo Clinic College of Medicine;Derek Robertson, MBA, JD, health care consultant/fam-ily representative; Mark Rothstein, JD, University ofLouisville; Robert D. Steiner, MD, Oregon Health andScience University; Sonia Suter, MS, JD, George Wash-ington University Law School; Bradford Therrell, PhD,National Newborn Screening and Genetics ResourceCenter, University of Texas Health Science Center atSan Antonio; Thomas Tonniges, MD, AAP; WandaYazzie, RN, MPH, New Mexico Department of Health;Michael S. Watson, PhD (project director), ACMG; New-born Screening Conditions and Criteria Work Group:Piero Rinaldo, MD, PhD (chair), Mayo Clinic College ofMedicine; Donald Bailey, PhD (family representative),University of North Carolina at Chapel Hill; Celia I.Kaye, PhD, MD, University of Texas Health ScienceCenter at San Antonio; Alex R. Kemper, MD, MPH,University of Michigan Health System; Michele A.Lloyd-Puryear, MD, PhD, HRSA; Marie Y. Mann, MD,MPH (project officer), HRSA; Kenneth Pass, PhD, Asso-ciation of Public Health Laboratories, New York StateDepartment of Health; Jennifer M. Puck, MD, NationalHuman Genome Research Institute, National Institutesof Health; Bradford Therrell, PhD, National Newborn

Screening and Genetics Resource Center, University ofTexas Health Science Center at San Antonio; Michael S.Watson, PhD (project director), ACMG; NewbornScreening External Review Group: Franklin Desposito,MD, University of Medicine and Dentistry of New Jer-sey; Gary Hoffman, BS, Wisconsin State Laboratory ofHygiene; Kathy Stagni, BS, Organic Acidemia Associa-tion; Arnold Strauss, MD, Vanderbilt University Schoolof Medicine; Tracy Trotter, MD, private pediatric prac-tice; Anne M. Willey, PhD, JD, Association of PublicHealth Laboratories, New York State Department ofHealth; Newborn Screening Diagnosis and Follow-upWork Group: Harvey L. Levy, MD (chair), Children’sHospital Boston, Harvard Medical School; James R. Eck-man, MD, Emory University School of Medicine;Michele A. Lloyd-Puryear, MD, PhD, HRSA; Fred Lorey,PhD, California Department of Health Services; Marie Y.Mann, MD, MPH (project officer), HRSA; Deborah L.Marsden, MBBS, Children’s Hospital Boston, HarvardMedical School; Julie Miller, BS, Nebraska Departmentof Health; Danielle Laraque, MD, Mount Sinai School ofMedicine; Kelly R. Leight, JD (family representative),CARES Foundation; Derek Robertson, MBA, JD, healthcare consultant/family representative; Bradford Therrell,PhD, National Newborn Screening and Genetics Re-source Center, University of Texas Health Science Centerat San Antonio; Michael S. Watson, PhD (project direc-tor), ACMG; Barbara Yawn, MD, American Academy ofFamily Physicians; Newborn Screening Health Informa-tion Portability and Accountability Act Work GroupEdward B. Goldman, JD (chair), University of Michi-gan Hospitals and Health System; Coleen Boyle, PhD,Centers for Disease Control and Prevention; Beverly Do-zier, PhD, Department of Health and Human Services;Lynn D. Fleisher, PhD, JD, Sidley, Austin, Brown, andWood; Mark Rothstein, JD, University of Louisville; SoniaSuter, MS, JD, George Washington University Law School.

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2. American Academy of Pediatrics, Newborn Screening Task Force.Serving the family from birth to the medical home: newbornscreening: a blueprint for the future. Pediatrics. 2000;106:389–427

3. National Academy of Sciences. Genetic Screening: Programs, Prin-ciples, and Research. Washington, DC: National Academy ofSciences; 1975

4. US Congress, Office of Technology Assessment. Data and meth-ods used in OTA’s cost-effectiveness analysis of strategies fornewborn screening. In: Healthy Children: Investing in the Future.Washington, DC: US Government Printing Office; 1988:236–241. Publication OTA-H-345. Available at: www.wws.princeton.edu/ota/ns20/alpha_f.html

5. McCabe ERB. Principle of newborn screening for metabolicdisease. Perinatol Neonatol. 1982;6:63–73

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DOI: 10.1542/peds.2005-2633I2006;117;S296Pediatrics 

Rodney HowellMichael S. Watson, Marie Y. Mann, Michele A. Lloyd-Puryear, Piero Rinaldo and R.

SummaryExecutive−−Newborn Screening: Toward a Uniform Screening Panel and System

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SummaryExecutive−−Newborn Screening: Toward a Uniform Screening Panel and System

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