Limit of detection, definition

NRC. 1984. Nuclear Regulatory Commission. Lower limit of detection definition and elaboration of a purposed position for radiological effluent and environmental measurements. U.S. Report NUREG/CR-4007. 

Currie, L. A., Lower limits of detection Definition and elaboration of a proposed position. Anal. Chem., 40... 

Currie, L. A. "Lower Limit of Detection Definition and Elaboration of a Proposed Position for Radiological Effluent and Environmental Measurements" U. S. Nuclear Regulatory Commission, NUREG/CR-4007, 1984. 

The limit of detection (LOD) (see Figure 2.6) is defined as the smallest quantity of an analyte that can be reliably detected. This is a subjective definition and to introduce some objectivity it is considered to be that amount of analyte which produces a signal that exceeds the noise by a certain factor. The factor used, usually between 2 and 10 [11], depends upon the analysis being carried out. Higher values are used for quantitative measurements in which the analyst is concerned with the ability to determine the analyte accurately and precisely. 

Figure 2.14. The definition of the limits of detection, LOD, respectively quantitation, LOQ (schematic).

Several terms have been used to define LOD and LOQ. Before we proceed to develop a uniform definition, it would be useful to define each of these terms. The most commonly used terms are limit of detection (LOD) and limit of quantification (LOQ). The 1975 International Union of Pure and Applied Chemistry (lUPAC) definition for LQD can be stated as, A number expressed in units of concentration (or amount) that describes the lowest concentration level (or amount) of the element that an analyst can determine to be statistically different from an analytical blank 1 This term, although appearing to be straightforward, is overly simplified. If leaves several questions unanswered, such as, what does the term statistically different mean, and what factors has the analyst considered in defining the blank Leaving these to the analyst s discretion may result in values varying between analysts to such an extent that the numbers would be meaningless for comparison purposes. 

Similar considerations were taken into account throughout the process of designing the study and committing the design to a protocol. In addition to analytical quality specifications, decisions were made regarding definitions of limits of detection and quantitation, levels of apparent residues at which confirmation was required, and how such confirmation would be achieved. All of these decisions were based on fulfilling the objectives of the study while operating within unavoidable time and resource constraints. 

In order to obtain a comparable risk for the error of second kind (a = P 0.05), a definition of the limit of detection has to consider confidence... 

Long GL, Winefordner JD (1983) Limit of detection. A closer look at the IUPAC Definition. Anal Chem 55 712A... 

Limit of detection The method you choose must be able to detect the analyte at a concentration relevant to the problem. If the Co level of interest to the Bulging Drums was between 1 and 10 parts per trillion, would flame atomic absorption spectroscopy be the best method to use As you consider methods and published detection limits (LOD), remember that the LOD definition is the analyte concentration producing a signal that is three times the noise level of the blank, i.e., a S/N of 3. For real-world analysis, you will need to be at a level well above the LOD. Keep in mind that the LOD for the overall analytical method is often very different than the LOD for the instrumental analysis. 

Quantification of the limits of detection (LOD), or minimum detectable levels (MDL statistically defined in Section 13.4), is an important part of any analysis. They are used to describe the smallest concentration of each element which can be determined, and will vary from element to element, from matrix to matrix, and from day to day. Any element in a sample which has a value below, or similar to, the limits of detection should be excluded from subsequent interpretation. A generally accepted definition of detection limit is the concentration equal to a signal of twice (95% confidence level) or three times (99% confidence) the standard deviation of the signal produced by the background noise at the position of the peak. In practice, detection limits in ICP-MS are usually based on ten runs of a matrix matched blank and a standard. In this case ... 

The minimum detectable level, or detection limit, is defined as that concentration of a particular element which produces an analytical signal equal to twice the square root of the background above the background. It is a statistically defined term, and is a measure of the lower limit of detection for any element in the analytical process. (This definition corresponds to the 95% confidence interval, which is adequate for most purposes, but higher levels, such as 99% can be defined by using a multiplier of three rather than two.) It will vary from element to element, from machine to machine, and from day to day. It should be calculated explicitly for every element each time an analysis is performed. 

Limit of Quantification For the limit of quantification, or limit of determination, definitions and formulas are very similar to those of LOD, except that for LOQ, is taken to be 5, 6, or even 10 [2, 4,15, 56,72, 96]. A value of 10 for means that the %RSD at the limit of quantification is 10%. The LOQ thus corresponds to that concentration or amount of analyte quantifiable with a variation coefficient not higher than 10% [98]. The LOQ is always higher than the LOD and is often taken as a fixed multiple (typically 2) of the detection limit [4]. Also, the determination limit is referred to as the signal 10 times above the noise or background signal, corresponding to a signal-to-noise ratio of 10 1 [72, 85]. 

Long, G L and Winefordner, J D (1983), Limit of detection—A closer look at the IUPAC definition. Analytical Chemistry, 55, 712A-24A. 

These terms have been defined in different ways, thus giving rise to a great deal of confusion (29-42). The limit of detection has been described as the lowest concentration or quantity of an analyte that an analytical method can detect with reasonable certainty (31) or can reliably detect (29). Such descriptions based on definition of the terms reasonable certainty and reliable detect allow considerable freedom to define the limit of detection. 

Performance is defined by the sensitivity threshold, or the minimum concentration of element in solution that will yield an analytical signal with amplitude equal to twice that of the average background signal. This classical definition leads to optimistic values that can vary from element to element. The limit of detection represents the concentration of an element that can be detected with a 95% confidence limit (cf. chapter 21). In general, measurements are made in a concentration domain that corresponds to 50 times the limit of detection. 

Analytical methods validation—As mentioned earlier, a good CVMP should allow the analytical method to develop concurrently with the product formulation, thus in the early stages of development, an analytical method may not be fully validated but may still be used for cleaning tests as the best available method. At the time of the PAI, however, and definitely by the time the formal cleaning validation occurs, a fully validated analytical method should be developed. This methods validation package should include all the standard parameters, with special attention to the sensitivity of the analytical method as expressed by the limit of detection (LOD) and... 

Various approaches have been used to define detection limit for the multivariate situation [24], The first definition was developed by Lorber [19]. This multivariate definition is of limited use because it requires concentration knowledge of all analytes and interferences present in calibration samples or spectra of all pure components in the calibration samples. However, the work does introduce the important concept of net analyte signal (NAS) vector for multivariate systems. The NAS representation has been extended to the more usual multivariate situations described in this chapter [25-27], where the NAS is related to the regression vector b in Equation 5.11. Mathematically, b = NAS/ NAS and NAS = 1/ b. Thus, the norm of the NAS vector is the same as the effective sensitivity discussed in Section 5.4.9.1 A simple form of the concentration multivariate limit of detection (LOD) can be expressed as LOD = 3 MINI, where e denotes the vector of instrumental noise values for the m wavelengths. The many proposed practical approaches to multivariate detection limits are succinctly described in the literature [24],... 

Here RA is the response of the analyte at unit concentration, c E is a matrix of expected, or estimated, errors and F is the Froebus norm, or root sum of the squared elements, of a matrix. It should be noted that while the NAS is a matrix quantity, selectivity (SEL), sensitivity (SEN), and signal-to-noise (S/N) are all vector quantities. The limit of detection and the limit of quantitation can also be determined via any accepted univariate definition by substituting NAS P for the analyte signal and E P for the error value. 

One of the most important performance characteristics in residue analysis is certainly the detection capability of a method. Unfortunately, many different definitions with regard to the detection and quantifying capability of an analytical method are found in the literature. Attempts have been made to harmonize the definitions with regard to the limit of detection (LoD) and the limit of quantification (LoQ). For the sake of consistency, here reference is made only to the harmonized definitions of IUPAC and ISO for the detection decision (Lc, critical value), LoD (minimum detectable value) and LoQ (minimum quantifiable value) (45 -47). ISO terminology is given between brackets. 

The definition of the limit of quantitation (LOQ) is handled quite differently. For example, an easy, often used approach is the definition of using the double of the mean blank value as LOQ. This definition sounds simple and a scientific theoretical justification seems not to be available. However, the thus defined LOQ is then a reasonable value when standard deviation (SD) of the blank values is low (< 10 %, according to own experience). More sophisticated is the following definition The mean blank value plus 3 times the standard deviation is required for a limit of detection (LOD) and the mean blank value plus 10 times the standard deviation is required for LOQ (see for instance Krull (1998)). Outliers can be identified for instance by the Grubbs test (for instance explained in www.graphpad.com). 

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