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Licensed Unlicensed Requires Authentication Published by De Gruyter December 3, 2021

Blood sampling frequency as a proxy for comorbidity indices when identifying patient samples for review of reference intervals

Simon Lykkeboe EMAIL logo , Stine Linding Andersen , Claus Gyrup Nielsen , Peter Vestergaard and Peter Astrup Christensen



Indirect data mining methods have been proposed for review of published reference intervals (RIs), but methods for identifying patients with a low likelihood of disease are needed. Many indirect methods extract test results on patients with a low frequency blood sampling history to identify putative healthy individuals. Although it is implied there has been no attempt to validate if patients with a low frequency blood sampling history are healthy and if test results from these patients are suitable for RI review.


Danish nationwide health registers were linked with a blood sample database, recording a population of 316,337 adults over a ten-year period. Comorbidity indexes were defined from registrations of hospital diagnoses and redeemed prescriptions of drugs. Test results from patients identified as having a low disease burden were used for review of RIs from the Nordic Reference Interval Project (NORIP).


Blood sampling frequency correlated with comorbidity Indexes and the proportion of patients without disease conditions were enriched among patients with a low number of blood samples. RIs based on test results from patients with only 1–3 blood samples per decade were for many analytes identical compared to NORIP RIs. Some analytes showed expected incongruences and gave conclusive insights into how well RIs from a more than 10 years old multi-center study (NORIP) performed on current pre-analytical and analytical methods.


Blood sampling frequency enhance the selection of healthy individuals for reviewing reference intervals, providing a simple method solely based on laboratory data without the addition of clinical information.

Corresponding author: Simon Lykkeboe, MSc, Department of Clinical Biochemistry, Aalborg University Hospital, Hobrovej 18-22, 9000 Aalborg, Denmark, Phone: +45 97 66 48 68, E-mail:

  1. Research funding: None declared.

  2. Author contributions: All authors have accepted responsibility for the entire content of this manuscript and approved its submission.

  3. Competing interests: Authors state no conflict of interest.

  4. Informed consent: Not applicable.

  5. Ethical approval: The study was a technical and quality investigation in accordance with the guidelines of the Northern Denmark Regional Science and Ethics Committee.


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Received: 2021-09-07
Accepted: 2021-11-21
Published Online: 2021-12-03
Published in Print: 2022-01-27

© 2021 Walter de Gruyter GmbH, Berlin/Boston

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