Optimization of Phenylalanine Cut-Off Value in Newborn Screening Based on Blood Sampling Time

Abstract

Objective The aim of this study was to optimize the cut-off value of phenylalanine (Phe) for phenylketonuria (PKU) screening in Xinjiang Uygur Autonomous Region based on the time of blood sampling.

Study Design In this study, 110,806 neonates born in 91 obstetrics and gynecology hospitals of Xinjiang Uygur Autonomous Region between June 2017 and December 2019 were divided into two groups (i.e., groups 1 and 2) based on the sampling time. The concentration of Phe was determined using fluorimetric method. The optimization of the Phe cut-off value was conducted using the receiver operating characteristic curve from the treating set involving 80,354 neonates. Then, the diagnostic values of the optimized Phe cut-off value were evaluated using validation set involving 30,452 neonates, based on the comparison of sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) obtained from conventional cut-off value.

Results A range of cut-off values was used for preliminary Phe concentrations in the two groups to analyze the sensitivity, specificity, PPV, and NPV. The optimized cut-off value of Phe in group 1 was 2.0, while that in the group 2 was 2.21. A comparison was given to PPV, NPV, sensitivity, and specificity generated by the optimized cut-off value and the conventional cut-off value, which yielded similar sensitivity, specificity, and PPV, and less recalled number of samples.

Conclusion The optimization of cut-off value of Phe based on sampling time is feasible for PKU screening in Xinjiang Uygur Autonomous Region. In addition, the false positive rate was significantly reduced, which may save more efforts in sample recalling process.

Key Points

• The optimization of Phe cut-off value for Xinjiang Region.

• The optimized cut-off value reduced the recalling samples.

• Our cut-off value is feasible for PKU screening in Xinjiang.

Keywords

phenylketonuria - neonatal disease screening - sampling time - cut-off value - phenylalanine

Ethical Approval

Research involving human subjects complied with all relevant national regulations and institutional policies and is in accordance with the tenets of the Helsinki Declaration (as revised in 2013), and has been approved by the Ethics Committee of the First Affiliated Hospital of Xinjiang Medical University (approval no.: K202103–01).

Patient Consent

Informed consent was obtained from the parents of each participant.

Authors' Contributions

Z. L. and H. J. conceptualized and designed the study, analyzed data, and drafted the manuscript. M. Y., R. H., and N. H. collected the data and helped in data analysis. J. Z. revised the manuscript. All authors have accepted responsibility for the entire content of this manuscript and approved its submission.

Data Availability Statement

All data generated or analyzed during this study are included in this published article and its supplementary information files.

Publication History

Received: 27 June 2022

Accepted: 02 November 2022

Article published online:
30 December 2022

• References

• 1 van Spronsen FJ, Blau N, Harding C, Burlina A, Longo N, Bosch AM. Phenylketonuria. Nat Rev Dis Primers 2021; 7 (01) 36
• 2 Dietzen DJ, Rinaldo P, Whitley RJ. et al. National academy of clinical biochemistry laboratory medicine practice guidelines: follow-up testing for metabolic disease identified by expanded newborn screening using tandem mass spectrometry; executive summary. Clin Chem 2009; 55 (09) 1615-1626
• 3 van Wegberg AMJ, MacDonald A, Ahring K. et al. The complete European guidelines on phenylketonuria: diagnosis and treatment. Orphanet J Rare Dis 2017; 12 (01) 162
• 4 American College of Medical Genetics Newborn Screening Expert Group. Newborn screening: toward a uniform screening panel and system–executive summary. Pediatrics 2006; 117 (5 Pt 2): S296-S307
• 5 Al Hafid N, Christodoulou J. Phenylketonuria: a review of current and future treatments. Transl Pediatr 2015; 4 (04) 304-317
• 6 Shi XT, Cai J, Wang YY. et al. Newborn screening for inborn errors of metabolism in mainland China: 30 years of experience. JIMD Rep 2012; 6: 79-83
• 7 Chaiyasap P, Ittiwut C, Srichomthong C, Sangsin A, Suphapeetiporn K, Shotelersuk V. Massive parallel sequencing as a new diagnostic approach for phenylketonuria and tetrahydrobiopterin-deficiency in Thailand. BMC Med Genet 2017; 18 (01) 102
• 8 Arnopp JJ, Lorey FW, Currier RJ. et al. Results of screening for phenylketonuria using a lower cutoff value in early collected specimens. Screening 1995; 3 (04) 193-199
• 9 Wiley V, Webster D, Loeber G. Screening pathways through China, the Asia Pacific region, the World. Int J Neonatal Screen 2019; 5 (03) 26
• 10 Du Y, Wang W, Liu J. et al. National program for external quality assessment of Chinese newborn screening laboratories. Int J Neonatal Screen 2020; 6 (02) 38
• 11 Yu CW, He XY, Wan KX. et al. Improving quality management of newborn screening in southwest China. J Int Med Res 2021; 49 (04) 3000605211002999
• 12 Xiang L, Tao J, Deng K. et al. Phenylketonuria incidence in China between 2013 and 2017 based on data from the Chinese newborn screening information system: a descriptive study. BMJ Open 2019; 9 (08) e031474
• 13 Perko D, Repic Lampret B, Remec ZI. et al. Optimizing the phenylalanine cut-off value in a newborn screening program. Genes (Basel) 2022; 13 (03) 517
• 14 Pitt JJ. Newborn screening. Clin Biochem Rev 2010; 31 (02) 57-68
• 15 Lukacs Z, Santer R. Evaluation of electrospray-tandem mass spectrometry for the detection of phenylketonuria and other rare disorders. Mol Nutr Food Res 2006; 50 (4–5): 443-450
• 16 Mancilla VJ, Mann AE, Zhang Y, Allen MS. The adult phenylketonuria (PKU) gut microbiome. Microorganisms 2021; 9 (03) 530
• 17 Foreman PK, Margulis AV, Alexander K. et al. Birth prevalence of phenylalanine hydroxylase deficiency: a systematic literature review and meta-analysis. Orphanet J Rare Dis 2021; 16 (01) 253
• 18 Pode-Shakked B, Shemer-Meiri L, Harmelin A. et al. Man made disease: clinical manifestations of low phenylalanine levels in an inadequately treated phenylketonuria patient and mouse study. Mol Genet Metab 2013; 110 (suppl): S66-S70
• 19 Khan AR, Alothaim A, Alfares A. et al. Cut-off values in newborn screening for inborn errors of metabolism in Saudi Arabia. Ann Saudi Med 2022; 42 (02) 107-118
• 20 Gallop RJ, Crits-Christoph P, Muenz LR, Tu XM. Determination and interpretation of the optimal operating point for ROC curves derived through generalized linear models. Underst Stat 2003; 2 (04) 219-242
• 21 Giżewska M, MacDonald A, Bélanger-Quintana A. et al. Diagnostic and management practices for phenylketonuria in 19 countries of the South and Eastern European region: survey results. Eur J Pediatr 2016; 175 (02) 261-272
• 22 Hardelid P, Cortina-Borja M, Munro A. et al. The birth prevalence of PKU in populations of European, South Asian and sub-Saharan African ancestry living in South East England. Ann Hum Genet 2008; 72 (Pt 1): 65-71
• 23 Clemens PC, Neumann SJ, Wulke AP, Burmester JG. Newborn screening for hyperphenylalaninemia on day 5: is 240 mumol/liter the most appropriate cut-off level?. Prev Med 1990; 19 (01) 54-60