This study of screening and diagnostic costs is 1 aspect of the global question on the cost effectiveness of CF NBS, whereas the care costs are still being investigated with utilization data that should allow us to reach conclusions about overall cost effectiveness. This comprehensive assessment of costs for diagnosis adds to the literature through novel inclusion of all procedures such as (1) the costs of procuring the second blood specimen in IRT/IRT; (2) costs for genetic counseling with IRT/DNA; (3) the outcomes associated with “loss to follow-up” and other flaws in the designs of both screening systems; (4) costs associated with missed diagnoses; (5) the overall costs of the screening program to various segments, such as the costs to families, insurers, and screening laboratories; and (6) creating more robust results by allowing the components of the model to have variability and showing a range of outcome values. Overall, results from the simulations demonstrated that the IRT/IRT system offers substantial cost savings as compared with IRT/DNA but has the potential to miss or delay diagnosis for up to 50% of all infants given a diagnosis of CF through screening annually as compared with 15% for the IRT/DNA system. As such, the IRT/DNA system cost per diagnosis is 14% lower than the IRT/IRT cost per diagnosis. Thus, the decision trees provide a visual process to examine costs at each stage of the screening program and could be used to help in a systematic evaluation of the effectiveness of laboratory costs.
Because early diagnosis of CF, before 1 to 2 months of age,14,39
is the key reason for screening, it is crucially important for NBS programs to consider both expected outcomes40–46
and costs. Three publications from the United States have assessed the costs of the IRT/DNA method and the individual cost of IRT,10,11,16
but none of these studies included the cost of health effects or offered a comparison with other screening methods. The authors of another publication from the United Kingdom assessed the cost-effectiveness of IRT/DNA compared with no screening but did not offer a comparison with other screening methodologies.14
Finally, the authors of 1 comprehensive study from the Netherlands conducted a thorough assessment of the cost-effectiveness of 4 screening methodologies but did not account for problems with loss to follow-up in either system, nor did they offer a critique of the overall system designs with a discussion of possible solutions to correct flaws in each system.12
In addition, the Netherlands study did not take into account the possible cost consequences of lowering the initial IRT cutoff levels in the IRT/IRT system to avoid false negatives.6,26
There are some limitations to our study and also some other “hidden” costs in both screening methods that are currently difficult to define with precision. It should be pointed out that some sweat tests need to be repeated because of insufficient quantities of sweat; in fact, up to 10% can be assumed,47
which adds $4029 (at $237 per sweat test) plus $1700 (at $103 per sweat test) for family travel and work costs assuming a cohort of 100
000 newborns. In addition, many states that employ IRT/IRT screening are now using expanded genetic analysis either as part of the screening process for evaluating premature infants or in conjunction with the diagnostic sweat test. A survey of 4 commercial laboratories revealed that charges for CFTR
multimutation analyses range from $550 to $800, and gene sequencing is $2485 to $3546 per test.
Another limitation is that we relied heavily on Wisconsin data to have completely accessible costs and outcomes for the models, but their general applicability in the United States has been described48
recently. On the other hand, certain expenses such as salaries for personnel will vary in other regions and thus the simulations described herein may require revisions (eg, in the United Kingdom where the newborn blood specimens are obtained at home, which causes greater health care personnel costs but lower family expenses).
Two major system failures were identified as contributors to missed and delayed diagnoses: (1) protocol definition failures and (2) follow-up system failures. Protocol definition failures, the first type of system failure accounting for the largest proportions of potential missed diagnoses, resulted most commonly from the definitions of an abnormal IRT screen in each protocol. In the design of our IRT/IRT assessment, standard cutoffs of 105 ng/mL and 70 ng/mL were set as the abnormal values for the first and second screen, respectively, but data suggest that this can lead to a potential missed diagnosis rate estimated as high as ~30% of the total number of newborns with CF given a diagnosis annually through screening.6
Thus IRT cutoff values have been lowered continuously during the past decade and have varied among the states from 58 to 130 ng/mL for the first IRT and 50 to 90 ng/mL for the second IRT. The IRT/DNA system uses a much lower cutoff level for identifying abnormal IRT screens, thereby lowering the percentage of infants with CF with a missed diagnosis. Therefore, lowering the cutoff level of the abnormal IRT screens in the IRT/IRT system may offer 1 solution to this prominent system failure but will also lead to an unintended consequence of increasing costs. If the IRT/IRT system were to adopt the same cutoff levels as the IRT/DNA system, 4000 infants out of the 100
000 fictional screened newborns would require a second blood specimen.
The follow-up component is the second type of system where failures can occur. Among the 2 screening methods compared in this study, IRT/IRT clearly experiences the greatest number of potential missed diagnoses in the follow-up system and the largest proportion of these were lost at the point of obtaining the second dried blood specimen. In the IRT/DNA method, very few newborns with CF are categorized as a loss to follow-up because replacing the second dried blood specimen with a mutation analysis conducted on the initial dried blood specimen does not allow for loss to follow-up at this stage.
Therefore, the results from this study have demonstrated that the system design of the IRT/IRT and IRT/DNA screening programs offer different sets of advantages and disadvantages. The design of the IRT/DNA screening protocol minimizes system failures and out-of-pocket costs to families. The IRT/IRT screening protocol minimizes costs to state laboratories and insurance but is associated with more potential system failures. Redesigning the IRT/IRT system by increasing the sensitivity of the initial IRT test (ie, lowering the initial cutoff for abnormal) and decreasing loss to follow-up will improve early detection and treatment of infants with CF but will substantially increase the societal cost of the screening program.