Folate reference interval estimation in the Dutch general population

Michel J Vos*, L Joost van Pelt, Maarten B Kok, D A Janneke Dijck-Brouwer, M Rebecca Heiner-Fokkema, Lambert D Dikkeschei, Jenny E Kootstra-Ros

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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Background: Folate functions as an enzyme co-factor within the one-carbon metabolic pathway, providing key metabolites required for DNA synthesis and methylation. Hence, insufficient intake of folate can negatively affect health. As correct interpretation of folate status is dependent on a well-established reference interval, we set out to perform a new estimation following the restandardization of the Roche folate assay against the international folate standard.

Materials and methods: The folate reference interval was estimated using samples obtained from the Dutch population-based Lifelines cohort. The reference interval was estimated using two methods: a nonparametric estimation combined with bootstrap resampling and by fitting the data to a gamma distribution. The lower reference limit was verified in a patient cohort by combined measurement of folate and homocysteine.

Results: Dependent on the method used for estimation and in- or exclusion of individuals younger than 21 years of age, the lower reference limit ranged from 6.8 to 7.3 nmol/L and the upper reference limit ranged from 26 to 38.5 nmol/L. Applying a lower reference limit of 7.3 nmol/L resulted in the following percentage of folate deficiencies over a period of 12 months: general practitioner 15.5% (IQR 4.0%), general hospital 12.8% (IQR 5.3%), academic hospital 9.6% (IQR 4.3%).

Conclusions: We estimated the folate reference interval in the Dutch general population which is not affected by a folic acid fortification program and verified the obtained lower reference limit by homocysteine measurements. Based on our results, we propose a folate reference interval independent of age of 7.3-38.5 nmol/L

Original languageEnglish
Article number00127
Number of pages6
JournalPractical Laboratory Medicine
Publication statusPublished - Aug-2019


  • Folate
  • Folic acid
  • One-carbon metabolism
  • Homocysteine
  • Reference interval

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