Evaluation of the Performance of Newborn Screening for Tyrosinemia Type 1 in The Netherlands: Suggestions for Improvements Using Additional Biomarkers in Addition to Succinylacetone
Abstract
:1. Introduction
2. Materials and Methods
2.1. NBS Protocol for TT1 in The Netherlands
2.1.1. NeoBase
2.1.2. NeoBase 2
2.1.3. Data Registration Systems
2.2. Dataset and Study Outcomes
2.3. Performance of the Screening Protocol
2.4. Alternative Screening Protocols
3. Results
3.1. Performance of the Screening Protocol (See Table 1)
3.1.1. NeoBase
3.1.2. NeoBase 2
3.2. Alternative Screening Protocols
4. Discussion
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
Abbreviations
CDC | Centers for Disease Control and Prevention |
COV | Cut-off value |
DBS | Dried blood spot |
FIA-MS/MS | Flow-injection analysis tandem mass spectrometry |
FN | False negative |
FP | False positive |
HCC | Hepatocellular carcinoma |
NBS | Newborn screening |
NGS | Next-generation sequencing |
NPV | Negative predictive value |
Phe | Phenylalanine |
PKU | Phenylketonuria |
PPV | Positive predictive value |
QC | Quality control |
SA | Succinylacetone |
TP | True positive |
TT1 | Tyrosinemia type 1 |
tyr | Tyrosine |
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Period | 1 January 2018/ 31 December 2021 | 1 July 2009/ 31 December 2017 | 1 October 2008/ 30 June 2009 | 1 January 2007/ 28 February 2007 |
Analyzer | Waters Xevo TQD | Waters Quattro Micro/Premier | Waters Quattro Micro/Premier | Waters Quattro Micro |
Assay | Revvity NeoBase 2 non-derivatized kit | Revvity NeoBase non-derivatized kit | Revvity NeoBase non-derivatized kit | Revvity NeoGram non-derivatized kit |
COV | SA ≥ 0.60 µmol/L blood * | SA ≥ 1.2 µmol/L blood | SA ≥ 1.5 µmol/L blood | Tyr ≥ 500 µmol/L blood |
Screened newborns | 693,821 | 1,506,935 | 136,644 | 34,111 |
TN | 693,798 | 1,506,912 | 136,641 | 34,099 |
FN | 0 | 1 | 0 | 0 |
TP | 2 | 8 | 1 | 0 |
FP | 21 | 14 | 2 | 12 |
Referral rate | 0.0033% | 0.0015% | 0.0022% | 0.0352% |
Sensitivity | 100% | 89% | 100% | - |
Specificity | 99.997% | 99.999% | 99.999% | 99.965% |
PPV | 9% | 36% | 33% | 0% |
Prevalence | 1:346,910 | 1:167,437 | 1:68,322 $ | - |
Screening Assay | SA Cut-Off Value µmol/L | SA µmol/L | Converted SA # µmol/L | tyr µmol/L | phe µmol/L | tyr × SA # µmol2/L2 | tyr/SA # | SA #/tyr | SA #/phe | tyr/phe | phe/tyr | Original Screening Result | |
---|---|---|---|---|---|---|---|---|---|---|---|---|---|
1 | NeoBase | 1.50 | 4.93 | 2.84 | 829 | 81 | 2354 | 292 | 0.003 | 0.035 | 10.23 | 0.10 | Positive |
2 | NeoBase | 1.20 | 4.37 | 2.52 | 439 | 78 | 1106 | 174 | 0.006 | 0.032 | 5.63 | 0.18 | Positive |
3 | NeoBase | 1.20 | 1.08 | 0.64 | 288 | 68 | 184 | 450 | 0.002 | 0.009 | 4.24 | 0.24 | Negative |
4 | NeoBase | 1.20 | 6.70 | 3.85 | 833 | 137 | 3207 | 216 | 0.005 | 0.028 | 6.08 | 0.16 | Positive |
5 | NeoBase | 1.20 | 7.96 | 4.57 | 416 | 55 | 1901 | 91 | 0.011 | 0.083 | 7.56 | 0.13 | Positive |
6 | NeoBase | 1.20 | 5.13 | 2.95 | 493 | 47 | 1454 | 167 | 0.006 | 0.063 | 10.49 | 0.10 | Positive |
7 | NeoBase | 1.20 | 5.48 | 3.15 | 500 | 60 | 1575 | 159 | 0.006 | 0.053 | 8.33 | 0.12 | Positive |
8 | NeoBase | 1.20 | 1.90 | 1.11 | 900 | 64 | 999 | 811 | 0.001 | 0.017 | 14.06 | 0.07 | Positive |
9 | NeoBase | 1.20 | 16.93 | 9.70 | 236 | 56 | 2289 | 24 | 0.041 | 0.173 | 4.21 | 0.24 | Positive |
10 | NeoBase | 1.20 | 5.32 | 3.06 | 569 | 75 | 1741 | 186 | 0.005 | 0.041 | 7.59 | 0.13 | Positive |
11 | NeoBase 2 | 0.60 | 0.99 | N/A | 112 | 43 | 111 | 113 | 0.009 | 0.023 | 2.60 | 0.38 | Positive |
12 | NeoBase 2 | 0.60 | 2.92 | N/A | 422 | 30 | 1232 | 145 | 0.007 | 0.097 | 14.07 | 0.07 | Positive |
13 | NeoBase 2 | 0.60 | 2.03 | N/A | 465 | 87 | 944 | 229 | 0.004 | 0.023 | 5.34 | 0.19 | Positive |
Protocols and Cut-Off Values | TN | FN | TP | FP | Referral Rate (%) | Sensitivity (%) | Specificity (%) | PPV (%) | NPV (%) |
---|---|---|---|---|---|---|---|---|---|
Current protocol SA ≥ 0.60 µmol/L | 653,396 | 0 | 13 | 127 | 0.0214 | 100 | 99.981 | 9 | 100 |
Alternative L SA ≥ 0.60 µmol/L Tyr ≥ 100 µmol/L Tyr × SA ≥ 100 µmol2/L2 Tyr/Phe ≥ 2.5 | 653,515 | 0 | 13 | 8 | 0.0032 | 100 | 99.999 | 62 | 100 |
Alternative N SA ≥ 0.60 µmol/L Tyr ≥ 100 µmol/L Tyr × SA ≥ 110 µmol2/L2 Phe/Tyr ≤ 0.5 | 653,516 | 0 | 13 | 7 | 0.0031 | 100 | 99.999 | 65 | 100 |
Alternative O SA ≥ 0.60 µmol/L Tyr ≥ 100 µmol/L Tyr × SA ≥ 110 µmol2/L2 Tyr/Phe ≥ 2.5 | 653,518 | 0 | 13 | 5 | 0.0028 | 100 | 99.999 | 72 | 100 |
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Share and Cite
Bouva, M.J.; Kuypers, A.M.; Kemper, E.A.; Maase, R.E.; Bosch, A.M.; van Spronsen, F.J.; Heijboer, A.C.; Heiner-Fokkema, M.R.; Heil, S.G.; Boelen, A. Evaluation of the Performance of Newborn Screening for Tyrosinemia Type 1 in The Netherlands: Suggestions for Improvements Using Additional Biomarkers in Addition to Succinylacetone. Int. J. Neonatal Screen. 2025, 11, 35. https://doi.org/10.3390/ijns11020035
Bouva MJ, Kuypers AM, Kemper EA, Maase RE, Bosch AM, van Spronsen FJ, Heijboer AC, Heiner-Fokkema MR, Heil SG, Boelen A. Evaluation of the Performance of Newborn Screening for Tyrosinemia Type 1 in The Netherlands: Suggestions for Improvements Using Additional Biomarkers in Addition to Succinylacetone. International Journal of Neonatal Screening. 2025; 11(2):35. https://doi.org/10.3390/ijns11020035
Chicago/Turabian StyleBouva, Marelle J., Allysa M. Kuypers, Evelien A. Kemper, Rose E. Maase, Annet M. Bosch, Francjan J. van Spronsen, Annemieke C. Heijboer, M. Rebecca Heiner-Fokkema, Sandra G. Heil, and Anita Boelen. 2025. "Evaluation of the Performance of Newborn Screening for Tyrosinemia Type 1 in The Netherlands: Suggestions for Improvements Using Additional Biomarkers in Addition to Succinylacetone" International Journal of Neonatal Screening 11, no. 2: 35. https://doi.org/10.3390/ijns11020035
APA StyleBouva, M. J., Kuypers, A. M., Kemper, E. A., Maase, R. E., Bosch, A. M., van Spronsen, F. J., Heijboer, A. C., Heiner-Fokkema, M. R., Heil, S. G., & Boelen, A. (2025). Evaluation of the Performance of Newborn Screening for Tyrosinemia Type 1 in The Netherlands: Suggestions for Improvements Using Additional Biomarkers in Addition to Succinylacetone. International Journal of Neonatal Screening, 11(2), 35. https://doi.org/10.3390/ijns11020035