The basis for decision-making started with whether a screening test is available, which was then overlaid by the overall quantified expert opinion analysis gathered via the data collection information tool. The process of quantifying this expert opinion was then informed by literature review and expert validation.
In the first tier of analysis, conditions with scores above 1,200 met key criteria and were preliminarily considered appropriate for inclusion in a core newborn screening panel. Conditions scoring below 1,000 were not considered appropriate for inclusion in the core newborn screening panel at this time. As noted previously, the expert group determined that the laboratory should report any result coincidentally revealed in the course of newborn screening that might be clinically significant. In general, the screening test has been optimized for the detection of primary target conditions. Optimizing the technology for a primary target condition does not necessarily optimize the detection of all possible conditions. These conditions are often revealed through diagnostic testing since they are part of the differential diagnosis of a core condition as occurs with MS/MS identified cases but may be apparent in the screening laboratory due to the technologies employed in screening (e.g., hemoglobinopathies by high pressure liquid chromatography (HPLC)/isoelectric focusing (IEF)). Hence, the expert group designated a category of “secondary targets” to include conditions for which the results should be made available to health care professionals and/or families by the screening laboratory or that are determined during the diagnostic phase of the screening program and provided to families in the course of diagnosis and follow-up. Most conditions placed in the secondary target category are part of the differential diagnosis of a condition in the core panel. Inclusion in the secondary target category allows for the collection of cases on a national level for further investigation to understand the disease process, and for the development of treatment modalities. Regardless of whether programs choose to integrate all such conditions into their broader newborn screening programs, it will be important for them to have the diagnostic confirmatory results for all such cases, since they have a direct impact on the calculation of false-positive rates of screening for the core panel conditions.
After conditions were preliminarily categorized based on their data collection instrument scores, the evidence base, as reflected in fact sheets developed for each condition, was assessed. If a clinically significant condition in the core panel did not have the scientific evidence to support the availability of an efficacious treatment, it moved to the secondary target category. Similarly, if it was determined that an understanding of the natural history of the condition was insufficient to justify primary screening, the condition was moved to the secondary target category. When test results definitively identified carriers of the conditions, the handling of carrier information was moved into the secondary target category.
The following flow diagram () demonstrates the decision-making algorithm. It is important to note that the algorithm presumes an ongoing review of conditions to determine their continued or newly identified appropriateness for newborn screening as new tests and treatment evolve. The data collection instrument used in this project provides an assessment of only one aspect of a broader decision-making process required for establishing a newborn screening uniform panel. An ongoing analysis of the scientific evidence must be overlaid on the quantified expert opinion.
Condition evaluation and decision-making algorithm.
Clearly, the first decision to screen is based on the availability of a sensitive and specific screening test that can be done in the 24- to 48-hour interval after birth. There are a total of 29 conditions considered appropriate for newborn screening because they have a screening test, an efficacious treatment, and there is adequate knowledge of natural history (see ). The conditions best meeting all of the criteria established by the expert group are MCAD, CH and PKU. Among conditions assigned to the core panel are nine organic acidurias; six amino acidurias; five disorders of fatty oxidation; three hemoglobinopathies associated with an Hb S allele; and six other conditions. Twenty-three of the 29 conditions in the core panel are identified with multiplex technologies such as MS/MS.
Newborn screening panel: core panel and secondary targets
On the basis of the evidence, 6 of the 35 conditions placed initially in the core panel were moved into the secondary target category, which expanded to 25 conditions that are part of the differential diagnosis of a core panel condition. Knowledge of these secondary targets (i.e., in a newborn screening test result or in follow-up) can be clinically important to the family.
In addition to the 54 conditions identified in , the expert group identified 27 other conditions that were not considered appropriate for newborn screening, either because they met few evaluation criteria or because they lacked a screening test.
Conditions with limited evidence reported in the scientific literature were more difficult to evaluate using the data collection instrument. For example, some conditions have been reported in 10 or fewer families in the world. Many conditions were found to occur in multiple forms distinguished by age-of-onset, severity or other features. Further, unless a condition was already included in newborn screening programs, a potential for bias was apparent in the information related to some criteria. The power of the statistical analyses and the blending of two forms of evaluation also presented limitations. The data collection process in the first tier of the analysis was limited also by the significant variability in the numbers of individuals responding for the different conditions. Due to limitations in the scientific evidence of these rare diseases, there was significant reliance on the opinions of experts in the conditions. There were many conditions that scored close to other conditions and it is unlikely that the statistical power provided in these analyses was sufficient to truly discriminate among them in a ranking system. Nevertheless, groups of scores were assessed and natural separations between groups became apparent. In such circumstances, expert opinion with reasoning that applied first principles of genetic medicine to the evidence and to the quality underlying the data determined the placement of the conditions into particular categories.