Implementing a tracking system for confirmatory diagnostic results after positive newborn screening for cystic fibrosis—implications for process quality and patient care

The Heidelberg NBS Center performs NBS for about 140,000 children per year—mainly from south-west Germany—representing about 17% of children born annually in Germany. NBS and communication of abnormal NBS results is performed according to the Pediatrics Directive of the G-BA [5]. According to that, CF-NBS results are primarily transmitted to the sender of the sample as “positive” or “negative” without information about a possible homozygous or heterozygous CFTR mutation result. The sender of the sample is then responsible to inform the families about the NBS result and the recommended confirmatory testing. Thereafter, the families themselves—sometimes supported by the sender of the sample—have to contact a regional CF center for confirmatory testing and arrange an appointment for the sweat test. Since the diagnostic confirmation after positive CF-NBS should be carried out in institutions that are experienced in the diagnosis and treatment of CF, the German Cystic Fibrosis Society provides a website with all certified and non-certified CF centers in Germany for better orientation for NBS centers, maternity wards, and parents [12]. After completion of confirmatory testing, the center is requested to report the results to the NBS Center Heidelberg to allow classification of the case as “positive” or “false-positive.” In unresolved cases, the NBS center will try to request the missing information. However, as patients are not primarily assigned to a responsible regional center for confirmatory testing, the NBS Center Heidelberg faces considerable challenges in trying to resolve all screen-positive cases. The flow of information and confirmatory testing after abnormal CF-NBS in this setting is depicted in Fig. 1a.

In the federal state of Bavaria, a tracking center for all NBS cases has been successfully in operation since 1999, receiving all results from the two Bavarian NBS laboratories on a daily basis. In addition, there is a cross check with the residents’ registration offices. The Bavarian tracking center—by approval of federal state legislation—has access to the federal state’s birth registry and can therefore assure completeness of NBS. Families will be contacted by the tracking center if data matching with the birth registry shows absence of NBS to inquire if the family did actually not want to have NBS performed for their child or whether, e.g., the sample has been lost. In contrast to the other German federal states, parents in Bavaria have the opportunity to agree at the time of consent to NBS, that they will be directly informed about a positive CF-NBS result by a CF specialist from the nearest CF center [11]. This procedure, depicted in Fig. 1b, allows direct contact with the CF center to complete information on confirmation of unresolved cases. Usually, the CF center documents the results of confirmatory testing on a one-page form and sends the data to the tracking center with parental consent. If no information about confirmatory testing is sent to the Bavarian tracking center within 35 days, the CF center will be contacted by telephone. Of note, in this model, the parents still have the possibility to choose another CF center by themselves, although they are contacted primarily by one CF center. Therefore, also in this system, there is no violation of families’ free choice of medical center.

CF-NBS as part of the German NBS panel started at the Heidelberg NBS Center in October 2016. Before this time point, CF-NBS had already been performed in the context of a pilot study [8]. After 3 months, starting in January 2017, a systematic tracking strategy was implemented using written requests to the sender of the NBS sample for the results of confirmatory testing in unresolved cases. These requests were sent automatically 4 weeks and again 8 weeks after information about a positive CF-NBS result (compare Fig. 2).

Due to an unsatisfactory return rate of confirmatory results of only 43% also in this system, in February 2018, an additional active tracking system by telephone was added. For this system, a medical documentation officer (CL) was trained by the responsible physician for NBS (GG) to perform standardized telephone interviews with the sender of the initial NBS sample and, if required, also with the institution performing confirmatory testing after abnormal CF-NBS. This strategy was performed in addition to written requests if cases had remained unresolved 10 weeks after information of a positive CF-NBS result (compare Fig. 2). Tracking by telephone was carried out for new unresolved cases, but also retroactively for all previous cases that were still unresolved despite written requests.

Primary data for CF-NBS were prospectively documented and stored in the IT system of the NBS Center Heidelberg. Here, also the suspected diagnosis of CF was documented for cases with positive CF-NBS, and the final diagnosis (CF, CFSPID (CF screen positive, inconclusive diagnosis), or false positive) was noted after confirmatory results had been returned. Written requests were automatically generated in the NBS IT system in positive CF-NBS cases if a final diagnosis had not been reported and documented 4 weeks (first written request) and again 8 weeks (second written request) after first NBS report (compare Fig. 2). For additional tracking and documentation of NBS, all cases with abnormal NBS results (recalls) were transferred to an Access database. For the retrospective telephone tracking, all cases still unresolved were extracted to an Excel file for tracking to be performed and documented by the documentation officer. Accordingly, in the prospective telephone-tracking cohort, all cases still unresolved 10 weeks after first NBS report were extracted for telephone tracking. Information on the tracking progress and reported results were prospectively documented in Excel, Access database, and the NBS IT system.

When consenting to performance of NBS, legal guardians were also asked to provide written informed consent for tracking in case of abnormal NBS results in their child. Evaluation of the effect of tracking was performed as part of quality assurance for the NBS laboratory Heidelberg. Ethical approval for evaluation of CF-NBS at the NBS Center Heidelberg in comparison with results from the Bavarian NBS was obtained from the institutional review board of the University Hospital Heidelberg in the context of a research project evaluating parents’ perspectives after positive CF-NBS (Number S-718/2017).

To assess the health economic aspects of implementing a tracking system for CF-NBS, a cost calculation was performed including required personnel and resources. As writing and handling of written requests in unresolved cases after positive NBS, tracking letters, telephone calls etc. are not performed by separate personnel for metabolic, endocrine disorders, or CF, this calculation was performed for a tracking concept for all target disorders of the German NBS panel at the time of evaluation [13]. Evaluation of required staff time was performed according to experience from the study period at the NBS Center Heidelberg. In addition, staff requirements were compared with personnel required in the tracking system at the Bavarian tracking center.

For CF-NBS, the Bavarian tracking center reports a rate of resolved cases after positive CF-NBS of 98% for the year 2016, 99% for 2017, and 100% for 2018.

When comparing the rate of resolved and unresolved cases over the three calendar years 2016, 2017, and 2018 at the Heidelberg NBS Center, an improvement in the rate of resolved cases could be documented over the course of time. For cases from the year 2016, telephone tracking led to an increase of resolved cases from 46 to 77% (Pearson’s chi-squared test with Yates’ continuity correction p = 0.37), for cases from the year 2017 from 43 to 84% (p = 0.002), and for cases from the year 2018 from 77 to 86% (p = 0.32). But compared with the values achieved in Bavaria, there is still a significant difference in every year (2016: p = 0.014; 2017: p = 0.0003; 2018: p = 0.0001; Pearson’s chi-squared test with Yates’ continuity correction) even after implementation of a tracking system including written requests and telephone tracking (Fig. 4).

A tracking concept for all target disorders of the German NBS panel at the time of evaluation (16 disorders: 2 endocrine, 13 metabolic disorders, CF) would require the following personnel. Two secretary staff members (each 50% part-time share to assure a substitute during vacation and illness) are required for identification of unresolved cases in the NBS IT system, verification of unresolved status after review of repeat dried blood samples in the laboratory system, and availability of returned reports of confirmatory testing. In cases with unresolved status after internal review—in ambiguous cases after consultation with the responsible physician of the NBS center—preparation and sending of written requests is performed by the secretary staff. A medical documentation officer (40% part-time share) is required for documentation of all returned results in a tracking database. In addition, telephone tracking is performed by both secretarial staff and documentation officer in cases remaining unresolved despite sending of written requests. This includes telephone calls with birth hospitals, pediatricians, and centers performing confirmatory testing for metabolic/endocrine disorders and CF. Contact with these centers is only possible under the prerequisite that information on the responsible center is available at the NBS center. A physician (75% part-time share) is required for medical evaluation of returned results and decision on the final diagnosis—e.g., confirmed, false positive, still unresolved—and requirement for further information and tracking. The physician is also responsible for all medical requests from senders, pediatricians, and centers performing confirmatory testing, as well as for advice on confirmatory testing and requests from families concerning medical aspects. The physician has final responsibility for validation of all cases after abnormal NBS. An IT specialist is required for programming the tracking database and transfer of results from the NBS IT system into the tracking structure. After programming and implementation of the required IT infrastructure, IT has to be available 5 days per week—the time share for the tracking system being about 10% of one person. In addition, a lump sum for general infrastructure is required and is estimated at 10,000 € (about US$11,080) per year. With respect to current cost of personnel (for details on cost calculation, compare Supplementary Table 1) and given the number of about 140,000 children screened at the Heidelberg NBS Center, this results in additional NBS cost for a systematic tracking system of 1.20€ (about US$1.40) per child including telephone tracking. This is comparable with the cost per child for tracking in Bavaria. The Bavarian tracking system requires 1.51€ per child for the follow-up system and 0.25€ for assurance of completeness, resulting in a total cost of 1.76€ per child (about US$2.0) in Bavaria.