Critical comments to a recent EFLM recommendation for the review of reference intervals

Rainer Haeckel; Werner Wosniok; Farhad Arzideh; Jakob Zierk; Eberhard Gurr; Thomas Streichert

doi:10.1515/cclm-2016-1112

Article

Critical comments to a recent EFLM recommendation for the review of reference intervals

Rainer Haeckel , Werner Wosniok , Farhad Arzideh , Jakob Zierk , Eberhard Gurr and Thomas Streichert

Published/Copyright: February 2, 2017

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From the journal Clinical Chemistry and Laboratory Medicine (CCLM) Volume 55 Issue 3

Abstract

In a recent EFLM recommendation on reference intervals by Henny et al., the direct approach for determining reference intervals was proposed as the only presently accepted “gold” standard. Some essential drawbacks of the direct approach were not sufficiently emphasized, such as unacceptably wide confidence limits due to the limited number of observations claimed and the practical usability for only a limited age range. Indirect procedures avoid these disadvantages of the direct approach. Furthermore, indirect approaches are well suited for reference limits with large variations during lifetime and for common reference limits.

Keywords: direct (IFCC) approach; indirect approach; reference intervals

Author contributions: All the authors have accepted responsibility for the entire content of this submitted manuscript and approved submission.
Research funding: None declared.
Employment or leadership: None declared.
Honorarium: None declared.
Competing interests: The funding organization(s) played no role in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; or in the decision to submit the report for publication.

Appendix

Calculating the confidence limits of a given reference limit (RL) is most effectively done using the distribution of the reference values. Also, the 100%·(1–p) reference limits RL₁ and RL₂ themselves can be obtained from this distribution. They are defined as the p/2 and 1–p/2 quantiles of the reference value distribution with distribution function F:

RL1=F−1(p/2)

RL2=F−1(1−p/2)

For an underlying normal distribution with mean μ and standard deviation σ, the limits of a 95% reference interval (p=0.05) are μ±1.96 σ. In general, e.g. for the log-normal distribution, the RLs are calculated from the inverse distribution function F⁻¹ (the quantile function). This is available in standard software packages.

Confidence limits for a reference limit RL are calculated according to Serfling [31] using the standard deviation of the calculated RL given by

sRL=p(1−p)n⋅f(RL)

where 1–p is the confidence level of the confidence interval, n is the number of reference values that were used to determine the RL, and f(RL) is the probability density function f calculated at RL. Using this standard deviation, the 100%·(1–α) confidence interval is given by

CI=(RL−z1−α2sRL, RL+z1−α2sRL)

where z_1−α/2 is the 1−α/2 quantile of the standard normal distribution (for α=0.05: z_1−α/2=1.96). The preceding equation is an asymptotic one, but numerical simulation has shown its validity already for n much smaller than 120.

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Received: 2016-12-6

Accepted: 2017-1-2

Published Online: 2017-2-2

Published in Print: 2017-3-1

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Articles in the same Issue

https://doi.org/10.1515/cclm-2016-1112

Keywords for this article

direct (IFCC) approach; indirect approach; reference intervals