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Evaluation of specificity and sensitivity of IRT/IRT protocol in the cystic fibrosis newborn screening program: 6-year experience of three tertiary centers

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Abstract

We aimed to evaluate cutoff values of immunoreactive trypsinogen (IRT)/IRT and determine relationship between IRT values and clinical characteristics of children with cystic fibrosis (CF). This study is cross-sectional study. Data of children with positive newborn screening (NBS) between 2015 and 2021 were evaluated in three pediatric pulmonology centers. Age at admission, sex, gestational age, presence of history of meconium ileus, parental consanguinity, sibling with CF, and doll-like face appearance, first and second IRT values, sweat chloride test, fecal elastase, fecal fat, biochemistry results, and age at CF diagnosis were recorded. Sensitivity and specificity of IRT cutoff values were evaluated. Of 815 children with positive NBS, 58 (7.1%) children were diagnosed with CF. Median values of first and second IRT were 157.2 (103.7–247.6) and 113.0 (84.0–201.5) μg/L. IRT values used in current protocol, sensitivity was determined as 96.6%, specificity as 17.2% for first IRT, and 96.6% sensitivity, 20.5% specificity for second IRT. Positive predictive value (PPV) was determined as 7.1%. When cutoff value for first IRT was estimated as 116.7 μg/L, sensitivity was 69.0% and specificity was 69.6%, and when cutoff value was set to 88.7 μg/L for second IRT, sensitivity was 69.0% and specificity was 69.0%. Area under curve was 0.757 for first and 0.763 for second IRT (p < 0.001, p < 0.001, respectively). PPV was calculated as 4.3%.

    Conclusion: Although sensitivity of CF NBS is high in our country, its PPV is significantly lower than expected from CF NBS programs. False-positive NBS results could have been overcome by revising NBS strategy.

What is Known:

• Although immunoreactive trypsinogen elevation is a sensitive test used in cystic fibrosis newborn screening, its specificity is low.

• In countries although different algorithms are used, all strategies begin with the measurement of immunoreactive trypsinogen in dried blood spots.

What is New:

• In our study, it was shown that use of the IRT/IRT protocol for cystic fibrosis newborn screening is not sufficient for the cut-off values determined by the high number of patients.

• Newborn screening strategy should be reviewed to reduce false positive newborn screening results.

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Data availability

Data available on request from the authors.

Abbreviations

CF:

Cystic fibrosis

CFTR:

Cystic fibrosis transmembrane regulator protein

ECFS:

European Cystic Fibrosis Society

EGA:

Extended gene analysis

IRT:

Immunoreactive trypsinogen

IQR:

Interquartile range

NBS:

Newborn screening

PAP:

Pancreatic-associated protein

PPV:

Positive predictive value

UAC:

Area under the curve

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Authors and Affiliations

  1. Department of Pediatric Pulmonology, Faculty of Medicine, Gazi University, Ankara, Turkey

    Tugba Ramasli Gursoy, Pelin Asfuroglu, Tugba Sismanlar Eyuboglu & Ayse Tana Aslan

  2. Department of Pediatric Pulmonology, Necmettin Erbakan University Meram Faculty of Medicine, Konya, Turkey

    Asli Imran Yilmaz, Gokcen Unal & Sevgi Pekcan

  3. Department of Pediatrics, Necmettin Erbakan University Meram Faculty of Medicine, Konya, Turkey

    Büsra Sultan Kibar

  4. Department of Pediatric Pulmonology, Faculty of Medicine, Erciyes University, Kayseri, Turkey

    Melih Hangul & Mehmet Kose

  5. Department of Medical Education, Faculty of Medicine, Gazi University, Ankara, Turkey

    Isil Irem Budakoglu

  6. Department of Child and Adolescent Health, Public Health, General Directorate, Ankara, Turkey

    Deniz Acican

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  1. Tugba Ramasli Gursoy
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Contributions

All authors contributed to the study conception and design. Material preparation, data collection, and analysis were performed by Tugba Ramasli Gursoy, Pelin Asfuroglu, Tugba Sismanlar Eyuboglu, Ayse Tana Aslan, Asli Imran Yilmaz, Gokcen Unal, Büsra Sultan Kibar, Sevgi Pekcan, Melih Hangul, Mehmet Kose, Isil Irem Budakoglu, and Deniz Acican. The first draft of the manuscript was written by Tugba Ramasli Gursoy and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

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Correspondence to Ayse Tana Aslan.

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This study was performed in line with the principles of the Declaration of Helsinki. Approval was granted by the Ethics Committee of Gazi University Faculty of Medicine (Date 09.12.2019/No 249).

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Ramasli Gursoy, T., Asfuroglu, P., Sismanlar Eyuboglu, T. et al. Evaluation of specificity and sensitivity of IRT/IRT protocol in the cystic fibrosis newborn screening program: 6-year experience of three tertiary centers. Eur J Pediatr 182, 1067–1076 (2023). https://doi.org/10.1007/s00431-022-04766-4

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