Reference intervals of amino acid and acylcarnitine levels in full-term newborns. The effect of the timing of blood collection in newborns for extended neonatal screening

Cover Page


Cite item

Full Text

Open Access Open Access
Restricted Access Access granted
Restricted Access Subscription or Fee Access

Abstract

BACKGROUND: The timing of samples collection of blood for neonatal screening is a critical mean for the results accuracy. Changing the timing of samples of blood collection can affect the concentrations of amino acids and acylcarnitines, which requires clarifying the reference intervals to minimize false positive and false negative results.

AIM: To evaluate the effect of samples collection of blood time (on the 1 st –2 nd and 4 th –5 th days of life) on the concentrations of amino acids and acylcarnitines in dry blood spots of full-term newborns and verify the appropriate reference intervals for use in extended neonatal screening.

MATERIALS AND METHODS: A retrospective observational study was conducted, which included 83 087 newborn blood samples collected at the Morozov Children’s City Clinical Hospital in 2022–2023. Concentrations of 11 amino acids, 31 acylcarnitine and succinylacetone were determined by tandem mass spectrometry. Nonparametric methods with a significance level of p <0.05 were used to calculate the reference intervals and analyze the differences between the groups.

RESULTS: The analysis showed significant differences in concentrations for all 43 analytes between the groups (Day 1–2, n =61,996; Day 4–5, n =21,091). Concentrations of many amino acids were higher at later sampling periods, while methionine levels decreased. 99% reference intervals have been established for all analytes, which allows the threshold values to be adapted depending on the time of samples collection of blood.

CONCLUSION: The obtained data emphasize the need to adjust the reference intervals for amino acids and acylcarnitines depending on the timing of blood collection. This will ensure a more accurate diagnosis of hereditary diseases in newborns and increase the effectiveness of neonatal screening.

Full Text

Restricted Access

About the authors

Aleksei I. Geraskin

Morozov Children’s City Clinical Hospital; Peoples' Friendship University of Russia

Email: alexey-geraskin@mail.ru
ORCID iD: 0000-0003-1589-4564
SPIN-code: 8727-3045
Russian Federation, Moscow; Moscow

Yulia F. Shubina

Russian National Research Medical University named after N.I. Pirogov; Laboratory Diagnostic Center

Email: shubinaj@mail.ru
ORCID iD: 0000-0001-8661-3817
SPIN-code: 8887-6854

MD, Cand. Sci. (Medicine)

Russian Federation, Moscow; Moscow

Ivan R. Gaziev

Morozov Children’s City Clinical Hospital

Email: igaziev@morozdgkb.ru
ORCID iD: 0009-0006-8751-0434
SPIN-code: 6326-4337
Russian Federation, Moscow

Oleg E. Potekhin

Morozov Children’s City Clinical Hospital

Email: potehino@yandex.ru
ORCID iD: 0000-0001-6399-3247
SPIN-code: 1810-0370

MD, Cand. Sci. (Medicine)
Russian Federation, Moscow

Irina P. Vitkovskaya

Russian National Research Medical University named after N.I. Pirogov; Russian Research Institute of Health

Author for correspondence.
Email: vip-dzm@mail.ru
ORCID iD: 0000-0002-0740-1558
SPIN-code: 2970-0361

MD, Cand. Sci. (Medicine)

Russian Federation, Moscow; Moscow

References

  1. CLSI. Dried Blood Spot Specimen Collection for Newborn Screening. 7 th ed. CLSI standard NBS01. Clinical and Laboratory Standards Institute; 2021.
  2. Cousineau J, Anctil S, Carceller A, Gonthier M, Delvin EE. Neonate capillary blood gas reference values. Clin Biochem. 2005;38(10):905–907. doi: 10.1016/j.clinbiochem.2005.07.006
  3. Therrell BL, Padilla CD, Loeber JG, et al. Current status of newborn screening worldwide: 2015. Semin Perinatol. 2015;39(3):171–187. doi: 10.1053/j.semperi.2015.03.002
  4. Horn PS, Pesce AJ. Reference intervals: An update. Clinica Chimica Acta. 2003;334(1–2):5–23. doi: 10.1016/s0009-8981(03)00133-5
  5. Mishra P, Pandey CM, Singh U, et al. Descriptive statistics and normality tests for statistical data. Ann Card Anaesth. 2019;22(1):67–72. doi: 10.1016/s0009-8981(03)00133-5
  6. Solberg HE, Lahti A. Detection of outliers in reference distributions: performance of Horn’s algorithm. Clin Chem. 2005;51(12):2326–2332. doi: 10.1373/clinchem.2005.058339
  7. CLSI. Defining, Establishing, and Verifying Reference Intervals in the Clinical Laboratory; Approved Guideline-Third Edition. Clinical and Laboratory Standards Institute; 2010.
  8. Ichihara K, Boyd JC. An appraisal of statistical procedures used in derivation of reference intervals. Clin Chem Lab Med. 2010;48(11):1537–1551. doi: 10.1515/CCLM.2010.319
  9. Hazra A, Gogtay N. Biostatistics Series Module 3: Comparing Groups: Numerical Variables. Indian J Dermatol. 2016;61(3):251–260. doi: 10.4103/0019-5154.182416
  10. Sharma B, Jain R. Right choice of a method for determination of cut-off values: A statistical tool for a diagnostic test. Asian J Med Sci. 2014;5(3):30–34. doi: 10.3126/ajms.v5i3.9296
  11. Wilcken B, Wiley V, Hammond J, Carpenter K. Screening Newborns for Inborn Errors of Metabolism by Tandem Mass Spectrometry. N Engl J Med. 2003;348(23):2304–2312. doi: 10.1056/NEJMoa025225
  12. Pechatnikova NL, Baydakova GV, Potekhin OY, et al. Reference values of amino acids and acylcarnitines in term and preterm neonates. Medical Genetics. 2023;22(1):12–21. doi: 10.25557/2073-7998.2023.01.12-21
  13. Xia L, Chen M, Liu M, et al. Nationwide Multicenter Reference Interval Study for 28 Common Biochemical Analytes in China. Medicine (Baltimore). 2016;95(9). doi: 10.1097/MD.0000000000002915
  14. Ichihara K, Itoh Y, Lam CW, et al. Sources of variation of commonly measured serum analytes in 6 Asian cities and consideration of common reference intervals. Clin Chem. 2008;54(2):356–365. doi: 10.1373/clinchem.2007.091843
  15. Céspedes N, Valencia A, Echeverry CA, et al. Reference values of amino acids, acylcarnitines and succinylacetone by tandem mass spectrometry for use in newborn screening in southwest Colombia. Colomb Med (Cali). 2017;48(3):113–119. doi: 10.25100/cm.v48i3.2180
  16. McHugh DMS, Cameron CA, Abdenur JE, et al. Clinical validation of cutoff target ranges in newborn screening of metabolic disorders by tandem mass spectrometry: a worldwide collaborative project. Genet Med. 2011;13(3):230–254. doi: 10.1097/GIM.0b013e31820d5e67
  17. Nemchinova NV, Bairova TA, Belskikh AV, Bugun OV, Rychkova LV. Assessment of reference intervals of acylcarnitines in newborns in Siberia. Acta Biomedica Scientifica. 2022;7(5-1):86–99. doi: 10.29413/ABS.2022-7.5-1.10
  18. Bermúdez A, Robayo D, Porras G, Acosta MA. Amino Acids and Acylcarnitines Reference Values for Neonatal Screening of Inborn Errors of Metabolism in Colombia by Tandem Mass Spectrometry. JIEMS. 2021;9:e20210012–e20210012. doi: 10.1590/2326-4594-JIEMS-2021-0012
  19. He F, Yang R, Huang X, et al. Reference Standards for Newborn Screening of Metabolic Disorders by Tandem Mass Spectrometry: A Nationwide Study on Millions of Chinese Neonatal Populations. Front Mol Biosci. 2021;8. doi: 10.3389/fmolb.2021.719866
  20. Al-Hosani H, Salah M, Saade D, Osman H, Al-Zahid J. United Arab Emirates National Newborn Screening Programme: an evaluation 1998-2000. East Mediterr Health J. 2003;9(3):324–332.
  21. Loeber JG, Burgard P, Cornel MC, et al. Newborn screening programmes in Europe; arguments and efforts regarding harmonization. Part 1. From blood spot to screening result. J Inherit Metab Dis. 2012;35(4):603–611. doi: 10.1007/s10545-012-9483-0
  22. Lindner M, Gramer G, Haege G, et al. Efficacy and outcome of expanded newborn screening for metabolic diseases--report of 10 years from South-West Germany. Orphanet J Rare Dis. 2011;6:44. doi: 10.1186/1750-1172-6-44
  23. Leonard JV, Morris AAM. Inborn errors of metabolism around time of birth. Lancet. 2000;356(9229):583–587. doi: 10.1016/s0140-6736(00)02591-5
  24. Leonard JV, Morris AAM. Diagnosis and early management of inborn errors of metabolism presenting around the time of birth. Acta Paediatr. 2006;95(1):6–14. doi: 10.1080/08035250500349413

Supplementary files

Supplementary Files
Action
1. JATS XML
Download
2. Медианы, межквартильные интервалы, границы 99% референсных интервалов
Download (24KB)
Indexing metadata
3. Fig. 1. Graphs of the distribution density and box plot of leucine values by groups according to the time of blood collection. Comparison of groups by Mann–Whitney test: p <0.01 (difference is significant).

Download (119KB)
Indexing metadata
4. Fig. 2. Graphs of the distribution density and box plot of methionine values by groups according to the time of blood collection. Comparison of groups by Mann–Whitney test: p <0.01 (difference is significant).

Download (122KB)
Indexing metadata
5. Fig. 3. Graphs of the distribution density and box plot of arginine values by groups according to the time of blood collection. Comparison of groups by Mann–Whitney test: p <0.01 (difference is significant).

Download (122KB)
Indexing metadata
6. Fig. 4. Graphs of the distribution density and box plot of glycine values by groups according to the time of blood collection. Comparison of groups by Mann–Whitney test: p <0.01 (difference is significant).

Download (121KB)
Indexing metadata
7. Fig. 5. Graphs of the distribution density and box plot of propionylcarnitine (С3) values by groups according to the time of blood collection. Comparison of groups by Mann–Whitney test: p <0.01 (difference is significant).

Download (113KB)
Indexing metadata
8. Fig. 6. Graphs of the distribution density and box plot of tetradecenoyl carnitine (С14:1) values by groups according to the time of blood collection. Comparison of groups by Mann–Whitney test: p <0.01 (difference is significant).

Download (112KB)
Indexing metadata
9. Fig. 7. Graphs of the distribution density and box plot of isovalerylcarnitine (С5) values by groups according to the time of blood collection. Comparison of groups by Mann–Whitney test: p <0.01 (difference is significant).

Download (119KB)
Indexing metadata
10. Fig. 8. Graphs of the distribution density and box plot of succinylacetone values by groups according to the time of blood collection. Comparison of groups by Mann–Whitney test: p <0.01 (difference is significant).

Download (126KB)
Indexing metadata

Copyright (c) 2024 Geraskin A.I., Shubina Y.F., Gaziev I.R., Potekhin O.E., Vitkovskaya I.P.

Creative Commons License
This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.
СМИ зарегистрировано Федеральной службой по надзору в сфере связи, информационных технологий и массовых коммуникаций (Роскомнадзор).
Регистрационный номер и дата принятия решения о регистрации СМИ:  ПИ № ФС 77 - 86785 от 05.02.2024 (ранее — ПИ № ФС 77 - 59057 от 22.08.2014).