Newborn Screening: Toward a Uniform Screening Panel and System—Executive Summary

Expert Group Development and Process

ACMG convened a group, the Newborn Screening Expert Group, that included participants with expertise in various 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 the process, the expert group developed a set of guiding principles for its work. The establishment of these principals was followed by the development of criteria with which conditions were to be evaluated and the identification of the conditions to be evaluated. A steering committee oversaw the work of this group. The 2 work groups were formed to provide more in-depth analysis in 2 specific areas, that is the uniform panel and its criteria and the diagnosis and follow-up system.

The expert group used a 2-tiered approach for assessing and ranking conditions. In the first tier, with the specific evaluation criteria, conditions were analyzed by recognized experts and other interested individuals to develop a quantification of opinion. In the second tier, the quantification data were subjected to an analysis of the evidence base for each specific screening criterion score. Basic principles developed to guide the decision-making process were factored with the 2 levels of analysis to yield a set of core conditions. Further, additional conditions that are clinically significant that can be revealed during establishment of the diagnosis due to relationships with screening analytes used to identify core conditions or the technology used to screen were identified and referred to as secondary condtions.

Establishing Principles

The following basic principles were developed as a framework for defining the criteria with which to evaluate conditions and to make recommendations. (1) Universal newborn screening is an essential public health responsibility that is critical for improving the health outcomes of affected children. (2) Newborn screening policy development should be driven primarily by the interests of affected newborns, with secondary consideration being given to the interests of unaffected newborns, families, health professionals, and the public. (3) Newborn screening is more than testing. It is a coordinated comprehensive system consisting of education, screening, follow-up contact, diagnosis, treatment and management, and program evaluation. (4) The medical home and the public and private components of the screening programs should be in close communication, to ensure confirmation of test results and appropriate follow-up evaluation and care of identified newborns. (5) Recommendations about the appropriateness of conditions for newborn screening should be based on evaluation of scientific evidence and expert opinion. (6) To be included as a primary target condition in a newborn screening program, a condition should meet the following minimal criteria: it can be identified at a time (24–48 hours after birth) at which it would not ordinarily be detected clinically; a test with appropriate sensitivity and specificity is available for it; and there are demonstrated benefits of early detection, timely intervention, and efficacious treatment of the condition. (7) The primary targets of newborn screening should be conditions that meet the criteria listed in principle 6. The newborn screening program also should report any other results of potential clinical significance. (8) Centralized health information data collection is needed for longitudinal assessment of disease-specific screening programs. (9) Total quality management should be applied to newborn screening programs. (10) Newborn screening specimens are valuable health resources. Every program should have policies in place to ensure confidential storage and appropriate use of specimens. (11) Public awareness, coupled with professional training and family education, is a significant program responsibility that must be part of the complete newborn screening system.

Choosing Conditions

The conditions chosen for evaluation were included for ≥1 of several reasons, as follows. They are included in private, state, or national newborn screening programs. They are revealed coincidentally by some of the technologies used in newborn screening. They were identified by members of the expert group as worthy of consideration. They were identified by disease-specific advocacy organizations. They are included in the differential diagnosis of screening results for another condition. In the course of information collection, all conditions were subject to reconsideration. Eighty-four conditions were chosen for consideration.

Developing Evaluation Criteria and Their Comparative Values

The uniform panel working group developed the criteria with which conditions were to be evaluated; these were modified subsequently by the expert group. Criteria were divided into 3 main categories that covered aspects of the condition, that is, (1) clinical characteristics (eg, incidence, burden of disease if not treated, and phenotype in the newborn); (2) analytical characteristics of the screening test (eg, availability and features of the platform); and (3) diagnosis, treatment, and management of the condition in acute and chronic forms (this criterion includes the availability of health professionals experienced in diagnosis, treatment, and management).

Within each of these categories, several component criteria were developed (resulting in a total of 19 criteria) for assignment of the comparative value or score. The scoring system recognizes the strengths and limitations found for each condition and summarizes them in a ranking system. Therefore, a low score in a particular area does not necessarily mean that screening for that condition will never be conducted. In fact, low scores could be overruled by scientific evidence of new advances in testing and treatment and should be recognized as opportunities for targeted research endeavors and subsequent reconsideration of the condition for inclusion.

The criteria that were developed to differentiate the appropriateness of conditions for newborn screening include some that have a highly objective scientific basis and others that are associated with more subjective aspects. To the extent possible, the expert group relied on the scientific literature to provide the information on which the recommendations are based. However, some criteria have significant subjective aspects that require the consideration of more than just scientific and expert opinion. For example, issues of cost were considered but were not viewed as central in the analysis of the scientific literature. Cost is an example of a subjective criterion because it is a contextual concern and can be measured only against the value of the outcome.

Collecting Data

The first tier of the analysis was accomplished through the development of a data collection instrument containing the evaluation screening criteria. A survey was conducted to allow for the input of a wide range of individuals and organizations with interest in newborn screening. The data collection instrument included methods not only to collect information from experts but also to quantify that expert opinion regarding features of the conditions under consideration for inclusion in a uniform condition panel.

Before wide distribution, the data collection instrument was pilot tested. Potentially ambiguous language was identified and clarified, and scores were adjusted modestly to reflect the evolving priorities of the expert group. After modification, the data collection instrument was made widely available through passive efforts (eg, Listserv lists of interest groups such as the Genetic Alliance, Association of Public Health Laboratories, and Association of State and Territorial Health Officials) and active efforts (eg, direct approaches to experts on the conditions under evaluation and/or to support groups for particular conditions under evaluation). In this way, it was possible to acknowledge broad views that were of a more-subjective nature, such as the simplicity of the treatment (parents and individuals with the disorder in question often differed significantly from experts when scoring items such as simplicity of treatment). The results led to a preliminary listing of conditions and their placement in 1 of 3 categories, that is, high scoring, moderately scoring but part of the differential diagnosis of a high-scoring condition, or low scoring and not appropriate for newborn screening at this time. The responses of ≥3 recognized experts for each condition were compared with responses of all respondents regarding that condition, and results were found to be consistent.

Survey results were analyzed statistically. Respondents were characterized to ensure that they were broadly representative of the population. With the recognition that not all who responded have expertise or experience in all aspects of newborn screening for a specific condition, methods were used that allowed data to be aggregated for each criterion for each condition, rather than using the total score for a condition. A mean score for each criterion for each condition was based only on the responses provided for the criterion. Respondents were allowed to insert a “U” if an answer was unknown. The sum of the means was used for the total score assigned to a condition, because the sum of means tends to acknowledge dissenting views more clearly than does the sum of medians.

It is recognized that this relatively open survey process limited the views of experts while considering the views of those less knowledgeable about the individual conditions. However, analyses provided by scientific experts showed that their views were in close agreement with those of most respondents.

Establishing and Integrating the Evidence Base

In the second tier of the assessment, the evidence base for the conditions was established and an algorithm through which conditions were reassessed was developed. Each condition was considered with respect to the available scientific evidence, such as systematic reviews of reference lists (including Medline, PubMed, and others), books, Internet sources, professional guidelines, clinical evidence, and cost/economic evidence and modeling, for each criterion. The categorization was adjusted in accordance with the evidence. The analysis of the evidence base from the scientific literature included details about the screening tests, the efficacy of treatments, and the adequacy of the knowledge base for the condition. Disease-specific fact sheets were developed to describe this evidence.

At least 2 recognized experts examined the evidence on the fact sheet for all criterion scores for the conditions and assigned a level of evidence for each criterion score, making the scoring system part of a fuller evidence-based analysis. Therefore, the evaluation of the evidence for the scores in the second tier of analysis is part of a broader assessment of the scientific literature related to the conditions, tests, and treatments. In addition to validating the evidence gleaned from the literature and other sources, the experts assigned a level of quality to the studies from which the evidence was drawn. Adjustments based on the evidence were made primarily on the basis of the accuracy of the information. When significant differences were found between the data collected through the survey and the evidence base, the differences were acknowledged and addressed in each of the fact sheets. Only rarely were adjustments required to align the literature evidence with the views of the survey respondents.

The Newborn Screening System

Because the appropriate functioning of the system is critical to realizing improved outcomes, the components of a screening system were examined by the expert group during the project. (Information was obtained from program reports submitted to the National Newborn Screening and Genetics Resource Center and is based on information available as of October 2003.) The goal of the evaluation was to determine the extent to which states have addressed the many aspects of components of this system and to recommend performance standards to improve the quality of the system. The ability to ensure appropriate diagnosis and management is considered to be primarily a system responsibility. Limitations and significant variability were identified in the components of prenatal education, screening, follow-up services, diagnosis, treatment, and program management. For example, financing across state and county lines is constrained by state-based Medicaid rules; service delivery is fragmented on a categorical or disease basis; there is insufficient support to bridge geographic barriers; it is difficult to identify experienced health care professionals for complex care (eg, centers of excellence for genital reconstructive surgery for congenital adrenal hyperplasia or confirmation of metabolic diagnoses); there is misinterpretation of privacy regulations (eg, the Health Information Portability and Accountability Act); there is underuse and lack of uniformity of information technology; collaborative management and care are often constrained by systems of reimbursement for services; state sovereignty sometimes dictates individual approaches; and there is variability in financing of screening programs.⁴

There are national and state roles in addressing these limitations, and states must retain their significant roles and responsibilities. They have clear authority with regard to oversight and evaluation, as well as enforcement. There is a need to integrate the various systems of health care coverage and payment through flexible comprehensive financing of services. Service coordination at state and local levels must be considered, as well as program integration with the State Children's Health Insurance Program, early intervention programs, Title V programs, and similar services.

It is apparent, however, that all state programs could benefit from a more-robust national role in newborn screening. Because so many of the conditions screened for among newborns or under consideration for screening are rare, most states that undertake evaluations of the scientific basis for screening of conditions must rely on the same, relatively small group of patients identified throughout the world. There is a potential national role in providing scientific evaluation of conditions and defining core condition panels. This would allow states to apply the best science to their own considerations when determining their roles in expanded screening.

Practice guidelines also could be developed at a national level by interested organizations. The expert group identified a clear gap between the information available and the information needed by primary care professionals to facilitate an immediate response in the event of a screen-positive case. In response, the expert group developed an action sheet for each core condition and secondary target, to facilitate immediate responses on the part of primary care professionals with respect to the expected steps in diagnosis and follow-up care.

There are also potentially expanded national roles in oversight, data collection, and program evaluation, as well as development of educational materials to support newborn screening. Depending on the overall incidence of particular conditions, regional collaborative groups such as those funded by HRSA could coordinate access to health care professionals, serve as coordinators and repositories for data collection, provide long-term follow-up capability when resources and expertise are limited, facilitate transition (and access) from pediatric to adult care, and provide education.

The distribution of primary, secondary, and tertiary services is based largely on the incidence of a condition and the complexity of its short- and long-term diagnosis and management. For more common conditions with easier diagnosis and follow-up management, there is likely to be sufficient local health care expertise for patient care. As incidence decreases and complexity increases, particularly for rare metabolic diseases, services become more difficult to access. Developing resources to ensure that health care professionals are available locally, regionally, and nationally will be important to ensuring access to high-quality services.

Cost-Effectiveness Analysis

A basic cost-effectiveness assessment project was performed to inform the decision-making process. The assessment focused primarily on a scientific analysis of conditions and the features that should be considered when deciding whether they should be included in a newborn screening program, because costs often are the basis on which such decisions are made.

Costs and benefits related to screening for particular conditions or groups of conditions were evaluated after mapping them over major disease outcomes (eg, life expectancy, cerebral palsy/stroke, seizures, developmental delay, hearing loss, and vision loss). Costs were obtained from the literature, and benefits were determined from expected outcomes with and without early treatment or intervention. The results of these analyses indicated that most newborn screening programs improve outcomes and reduce overall costs. Furthermore, technologies such as MS/MS or high-pressure liquid chromatography save money because of their multiplexing capabilities and low screening false-positive rates. The identification of potentially affected individuals at such an early age leads to many years over which the benefits accrue and aggregate over costs.