Optimal - The Blog

January 8, 2023

Shortcomings of Standard Reference Ranges

An overview of the determination and shortcomings of standard reference ranges.

Laboratory reference ranges, also known as "reference intervals," are used to determine what is normal for a particular group of people. They are calculated using specimen samples from a group of people thought to be healthy and free of certain conditions or diseases. These ranges differ from clinical decision limits, which are specific to each case (Jones 2018).

Functional Blood Chemistry focuses on trends outside of an optimal range and a comprehensive picture of a person's overall health, lifestyle, nutritional status, and history. Just because something is considered "normal" or "average" doesn't mean it is healthy (Ceriotti 2008). It's helpful to use optimal ranges to identify small changes in a person's biology that could lead to problems in the future.

In general, standard reference intervals: (Merck, Katayev 2010, Lamers 2019, Costello 2016)

  • Represent normal distribution of results but not necessarily normal physiological function
  • Reflect a wide range of values for 95% of individuals presumed to be healthy
  • Do not necessarily correlate with clinical outcomes
  • Can vary from lab to lab due to differences in testing equipment, technique, geographic area, etc.
  • Reflect population averages in the vicinity of the testing laboratory, and reflect the increasing prevalence of disease and dysfunction in that local population
  • Only detect overt pathology once the “damage is done”
  • Fail to highlight or reveal subclinical imbalances or metabolic issues
  • “Lab test results in some people with disease fall within the reference range, especially in the early stages of a disease” (American Association of Clinical Chemistry)
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Ceriotti, Ferruccio, and Joseph Henny. “"Are my Laboratory Results Normal?" Considerations to be Made Concerning Reference Intervals and Decision Limits.” EJIFCC vol. 19,2 106-14. 16 Oct. 2008

Costello, Rebecca B et al. “Perspective: The Case for an Evidence-Based Reference Interval for Serum Magnesium: The Time Has Come.” Advances in nutrition (Bethesda, Md.) vol. 7,6 977-993. 15 Nov. 2016, doi:10.3945/an.116.012765  

Jones, Graham R D et al. “Indirect methods for reference interval determination - review and recommendations.” Clinical chemistry and laboratory medicine vol. 57,1 (2018): 20-29. doi:10.1515/cclm-2018-0073

Katayev, Alex et al. “Establishing reference intervals for clinical laboratory test results: is there a better way?.” American journal of clinical pathology vol. 133,2 (2010): 180-6. doi:10.1309/AJCPN5BMTSF1CDYP   

Lamers, Yvonne. “Approaches to improving micronutrient status assessment at the population level.” The Proceedings of the Nutrition Society vol. 78,2 (2019): 170-176. doi:10.1017/S0029665118002781   

Merck Manual Professional Version. Normal Laboratory Values. 

NIH. What are blood tests.? 

Pagana, Kathleen Deska, et al. Mosby's Diagnostic and Laboratory Test Reference. 15th ed., Mosby, 2021.

Testing.com, formerly American Association for Clinical Chemists Lab Tests Online. Reference Ranges and What They Mean

Tag(s): Biomarkers

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