Need for Revisiting the Concept of Reference Values
Authors: Henny Joseph , Petitclerc Claude , Fuentes-Arderiu Xavier , Petersen Per Hyltof , Queraltó Josep M. , Schiele Françoise , Siest Gérard 
Published: October 2004

Abstract
The reference values concept has been adopted by health care professionals, including clinical chemists, laboratory scientists, and clinicians and simultaneously by all the official organizations in charge of the establishment of legislation. But the estimation of reference limits, and the evaluation of biological variability need to be improved at the level of the procedures, which are currently too long and too expensive and not feasible easily for all laboratories. The procedures for obtaining reference values, if we follow the original documents, are complex, and that is the main reason that clinical chemists or diagnostic kit manufacturers have not used them systematically.
There is clearly a need that scientific societies and
international organizations propose practical recommendations:
1) Recommendations to describe methods linked to systematic error.

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How to transfer reference limits from one laboratory to another laboratory using different methods?

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Should we determine reference limits for each method?

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How can we differentiate bias due to the populations from these due to the method? Clear collaborations with manufacturers involved in kits and diagnostic systems are needed.

2) Practical recommendations linked to the reference population.

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How to transfer reference limits from one laboratory to another laboratory using different methods?

·
Should we determine reference limits for each method?

·
How can we differentiate bias due to the populations from these due to the method? Clear collaborations with manufacturers involved in kits and diagnostic systems are needed.

·
How to select a homogenous population? (Careful recommendations on the choice between healthy individuals, blood donors and individuals hospitalised for other diseases should be given.)

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How to estimate ethnic differences?

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How to define the exclusion and inclusion criteria according to quantity?

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How to deal with the question of reference limits for unstable periods, aging or old people particularly, when the difference between aging and disease is very difficult to define?

3) Practical recommendations on the statistical methods to be used.

·
How to transfer reference limits from one laboratory to another laboratory using different methods?

·
Should we determine reference limits for each method?

·
How can we differentiate bias due to the populations from these due to the method? Clear collaborations with manufacturers involved in kits and diagnostic systems are needed.

·
How to select a homogenous population? (Careful recommendations on the choice between healthy individuals, blood donors and individuals hospitalised for other diseases should be given.)

·
How to estimate ethnic differences?

·
How to define the exclusion and inclusion criteria according to quantity?

·
How to deal with the question of reference limits for unstable periods, aging or old people particularly, when the difference between aging and disease is very difficult to define?

·
How to make a good choice of the interquantile interval? Should we use and present only the centiles 2.5 or 97.5, or on the contrary should we give other centiles in addition, for example 5, 10, 75, 80, 85, 90?

4) Practical recommendations linked to the use of the concept of the reference values.

·
How to transfer reference limits from one laboratory to another laboratory using different methods?

·
Should we determine reference limits for each method?

·
How can we differentiate bias due to the populations from these due to the method? Clear collaborations with manufacturers involved in kits and diagnostic systems are needed.

·
How to select a homogenous population? (Careful recommendations on the choice between healthy individuals, blood donors and individuals hospitalised for other diseases should be given.)

·
How to estimate ethnic differences?

·
How to define the exclusion and inclusion criteria according to quantity?

·
How to deal with the question of reference limits for unstable periods, aging or old people particularly, when the difference between aging and disease is very difficult to define?

·
How to make a good choice of the interquantile interval? Should we use and present only the centiles 2.5 or 97.5, or on the contrary should we give other centiles in addition, for example 5, 10, 75, 80, 85, 90?

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How to make this concept more concrete and to have official definitions which are better understandable and not only abstract?

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How to demonstrate the value of using simultaneously reference limits and decision limits, and what does each of these limits bring to results interpretation?

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How to improve the presentation of the results? How to give more information on biological variability in the laboratory data, taking into account the scientific validity of their determination? Should we use new information techniques and new communication systems for reaching these objectives?

The responses to all these questions could only be provided if there is a concerted effort at the international level. Practical recommendations should be given, which would be very useful for a better understanding and use of reference values by laboratory scientists and clinicians.