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Letters |
Medical Affairs: Critical Care, Chiron Diagnostics, 220 Pelham St., Methuen, MA 01844\. {res} Dr. Brown responds:
Dept. of Anesthesia, Massachusetts General Hosp., 32 Fruit St., Boston, MA 02114
To the Editor:
Brown et al. (1) reported on the different analytical approaches used to characterize and quantify "the smallest analyte concentration an immunoassay can measure." While in agreement with the excellent science of the report, I take issue with certain aspects of some of the basic terminology and definitions used.
Given that a definition is a "statement of meaning" (2)(3), and a term is "a spoken or written representation of a concept" (2)(3), the title seems to put the cart before the definitive horse, in that the term being "defined" by the report is actually the "minimal detectable concentration (MDC)," by which the authors mean "the smallest analyte concentration an immunoassay can measure."
The concept embodied in the author's definition is synonymous with "quantitation limit" or "limit of quantitation (LOQ)"—terms already defined by at least two authoritative bodies (3)(4):
Quantitation limit/limit of quantitation, n: the lowest amount of analyte in a sample that can be quantitatively determined with stated, acceptable precision and stated, acceptable accuracy, under stated experimental conditions.
That definition applies broadly to all quantitative measurements without, I believe, limiting its usefulness in understanding the concept for immunoassay.
I would further suggest that "minimal detectable concentration" corresponds more closely to the term "detection limit," or "limit of detection (LOD)," defined by the same two authoritative bodies as "the lowest amount of analyte in a sample which can be detected but not quantified as an exact value"—clearly, a different concept.
Finally, the report, strictly speaking, does not define, but rather describes how one might quantify the concept already defined. As the American Society for Testing and Materials (2), echoed by the National Committee for Clinical Laboratory Standards (3), clearly states: "The definition of a quantity shall express its qualitative meaning or significance in words [whereas] a formula ... indicate[s] application of the definition."
My points should not in the slightest take away from the efforts embodied in the report. However, I believe that minimization of the use of new terms and acronyms, when perfectly good ones exist, would be appreciated by all who are drowning in the alphabet soup of daily life.
To the Editor:
We appreciate the suggestions from Dr. Moran to clarify the NCCLS use of the words "terms," "definition," and "concepts" (1). We used the framework developed by Currie because to our knowledge, he was the first to present the concepts, terms, and statistical algorithms for defining the critical limit, detection limit, and determination limit or limit of quantitation (LOQ) (2). Had we been aware of the NCCLS definitions, we would ceretainly have used them in presenting the ideas in our report. The term "minimal detectable concentration," which we used to represent the concept of "the smallest analyte concentration an immunoassay can reliably measure," is synonymous with the concept of LOQ as defined by the NCCLS. This concept of LOQ, as well as our mathematical representation of it, can be applied to systems of quantitative measurements other than immunoassays. However, we have yet to study its use in another system.
The term LOQ is often taken to mean the determination limit (1)(3)(4)(5). However, the determination limit, defined usually in terms of the assay CV, fails to make a precise quantitative statement about the probability that a given measurement is not zero. Contrary to what Moran suggests, the term "minimal detectable concentration" as used by Rodbard is not the detection limit but the critical limit (6)—a term not defined in the NCCLS document referenced. The critical limit is, as we discussed, the most frequently computed yet least-reliable measure of the smallest quantity an analytical procedure can measure. Our mathematical representation of the smallest quantity an analytical procedure can measure, and our approach to computing it, unify the concepts embodied in the terms critical limit, detection limit, and LOQ. If our concept is termed the LOQ, and is computed by using our Bayesian paradigm, then we believe that assay laboratories, rather than drowning in an alphabet soup of definitions, will be able to make reliable quantitative statements about the behavior of their immunoassays when measuring small quantities of analyte.
References
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