Reference limits

If a balanced chemical reaction involves more than one reagent, one of them will be the reference limiting reagent which will define the scale of the entire reaction. The numerator in the stoichiometric factor term takes into account the sum of the masses of all excess reagents used as appropriate. For any balanced chemical reaction in which all byproducts are identified, equation (4.1) maybe used to determine RME under a variety of scenarios. 

The outputs provided by the model can be used to perform a risk assessment if they are compared with reference limit values and literature data in order to determine whether the situation is risky or not. The values obtained by USEtox and used for the characterization of the risk in China are presented in the following tables. Table 4 presents the values for the concentration into the environmental compartments of the concerning additives (Pb and DeBDE). 

It is interesting to mention that USEtox is mainly a tool for LCIA studies where characterization factors are obtained for a wide list of substances. However, the model also provides intermediate output parameters (e.g., intake doses, concentrations in environmental compartments, substance exposure) that can be used for risk assessment studies. This was the case in the present study comparing the values from USEtox with reference limit values. 

A ML can be simply defined as a one-molecule thick 2D film, but the molecular surface density has to be defined for each molecule-substrate system because it depends on the shape, size and relative orientation of the molecules. To clarify this point let us consider the examples of PTCDA and Ceo on the Ag(l 11) surface. The surface density of the substrate is 1.4 x 10 atoms cm , which is usually defined as 1 ML as a reference limit. The surface density of the (102) plane of PTCDA, the cleavage plane, is 8.4 x 10 and 8.3 x 10 cm (molecules cm ) for the monocliiuc a and polymorphs, respectively. Therefore, full coverage corresponds to 0.02 ML according to this definition. On the other hand, the surface density of a full hexagonal layer of closed-packed Ceo molecules corresponding to the (111) plane in the fcc-Ceo crystal is 1.2 x 10 " cm . Thus, Ceo would fully cover the Ag(l 11) surface at a coverage of 0.09 ML. However, other authors define 1 ML as... 

Rushton DH, Dover R, Sainsbury AW, Norris MJ, GiUces JJ, Ramsay ID. Why should women have lower reference limits for haemoglobin and ferritin concentrations than men . BMJ 2001 322 1355-57. 

In the Maillard sequence, the initial reaction between a carbonyl group and a trivalent nitrogen atom is perhaps the most thoroughly investigated and best understood. As early as 1963, Reynolds (14) published a review with 140 references limited largely to the studies of reactions of aldoses with amines, the determination of the structures and properties of the first products of reaction (a glycosylamine), and the rearrangement of the latter to a more stable ketoseamine. 

LLD, lower limit of detection 99th, 99th percentile reference limit ROC, receiver operator characteristic curve optimized cutoff 10% Cy lowest concentration to provide a total imprecision of 10%. 

Table 5-2. Heparin-Plasma 99th Percentile Reference Limits ( ig/L) by Gender and Race for Cardiac Troponin Assays Cleared by the Food and Drug Administration ...

In the absence of availability of a cardiac troponin or CK-MB assay, total CK greater than two times the upper reference limit may be employed. 

It is accepted that the kinetics of myocardial protein appearance in the circulation depends on infarct perfusion. Early reperfusion causes an earlier increase above the upper reference limit and an earlier and greater enzyme peak after reperfusion. However, once the peak has occurred, there is no difference in the time of clearance of enzymes. In addition, enhanced washout identifies whether an artery is patent or closed but cannot distinguish between nor-... 

Apple FS, Quist HE, Doyle PJ, et al. Plasma 99th percentile reference limits for cardiac troponin and creatine kinase MB mass for use with European Society of Cardiology/American College of Cardiology consensus recommendations. Clin Chem 49 1331-1336,2003. 

Combined use of serum cystatin C and creatinine produces the best possible information on GFR in situations where more accurate, but invasive and more expensive, clearance determinations cannot be performed for biomedical or economic reasons. If both serum cystatin C and creatinine are within the relevant reference limits, the risk of missing a decrease in GFR will be minimal. 

T3. Tencer, J., Thysell, H., and Grubb, A., Analysis of proteinuria Reference limits for urine excretion... 

Grubb A. Diagnostic value of analysis of cystatin C and protein HC in biological fluids. Clin Nephrol 1992 38(Suppl 1) S20-S27. Tencer J,Thysell H, Grubb A. Analysis of proteinuria Reference limits for urine excretion of albumin, protein HC, immunoglobin G, k- and 1-chain immunoreactrivity, orosomucoid and al-antitrypsin. Scand J Clin Lab invest 1996 56 691-700. 

International Federation of Clinical Chemistry. Approved recommendation (1987) on the theory of reference values. Part 5. Statistical treatment of collected reference values. Determination of reference limits. J Clin Chem Clin Biochem 1987 25 645-56. 

The International Federation of Clinical Chemistry and Laboratory Medicine (IFCC) recommends the term reference values and related terms, such as reference individual, reference limit, reference interval, and observed values. The definitions given below and the presentation in the following sections of this chapter are in accordance with the IFCC recommendations. ... 

The IFCC also defines other terms related to the concept of reference values reference population, reference sample group, reference distribution, reference limit, and reference interval. Some of these terms are introduced in later sections of this chapter. 

These practical problems have led to the search for simpler and less expensive approaches. The indirect method has become rather popular.It is based on the observation that most analysis results produced in the clinical laboratory seem to be normal, Figure 16-1 shows one example from the author s laboratory. As can be seen, the values of the serum sodium concentration have a distribution with a preponderant central peak and a shape not too far from that of the Gaussian distribution. The underlying assumption of the indirect method is that this peak is composed mainly of normal values. The advocates of the method therefore claim that it is possible to estimate the normal interval If we extract the distribution of normal values from this part of the distribution. Normal limits determined by the indirect method on the basis of the distribution shown in Figure 16-1 would, however, obviously be biased compared with the shown health-associated reference limits. (Note that the term normal is here used intentionally to distinguish between the concepts of normal values and reference values.)... 

Figure 6-1 Distribution of sodium concentrations in serum obtained in a routine laboratory.The histogram shows the distribution of 53,128 serum sodium concentrations measured in consecutive clinical specimens during a 6-month period in 1982 at Rikshospitaiet, Oslo, Norway. The shaded area is within health-associated reference limits as determined by a direct method (193 healthy adults of both sexes).

This section deals with two main topics the partitioning of reference values into more homogeneous classes and the determination of reference limits and intervals. The subject matter is presented in the order in which data often are treated. Figure 16-2 gives an outline and refers to the corresponding sections in the text. Before the presentation of the... 

As mentioned previously, reference values provide a basis for interpretation of laboratory data. In clinical practice, one usually compares a patient s result with the corresponding reference interval, which is bounded by a pair of reference limits. This interval, which may be defined in different ways, is a useful condensation of the information carried by the total set of reference values. 

The precision of a percentile as an estimate of a population value depends on the size of the subset it is less precise when there are few observations. If the assumption of random sampling is fulfilled, we may determine the confidence interval of the percentile (i.e., the limits within which the true percentile is located with a specified degree of confidence) (Figure 16-4). The 0.90 confidence interval of the 97.5 percentile (upper reference limit) for serum triglycerides may, for example, be 2.22 to 2.62mmol/L. We would expect to find the true percentile in this interval with a confidence of 0.90 if we measured aU serum triglyceride concentrations in the total reference population. 

The parametric method for the determination of percentiles and their confidence intervals assumes a certain type of distribution, and it is based on estimates of population parameters, such as the mean and the standard deviation. We are, for example, using a parametric method if we believe that the true distribution is Gaussian and determine the reference limits (percentiles) as the values located 2 standard... 

Originally a simple nonparametric method for determination of percentiles was recommended by the IFCC. However, the newer bootstrap method is currently the best method available for determination of reference limits. The more complex parametric method is seldom necessary, but it will also be presented here owing to its popularity and frequent misapplication. When we compare the results obtained by these methods, we usually find that the estimates of the percentiles are very similar. Detailed descriptions of these methods are given later in this chapter. 

Commonly used statistical computer program packages may aid in the estimation of reference limits, but these packages lack some of the techniques described here. The RefVal program, however, implements these methods completely. 

The differences of location or variation, however, may be statistically significant and still too small to justify replacing a single total reference interval with several class-specific intervals. Alternately, statistically nonsignificant differences can lead to situations in which the proportions of each subclass above the upper or below the lower reference limits (witlrout partitioning) are much different from the desired 2.5% on each side. Harris and Boyd therefore suggested criteria based on the ratio between the subclass standard deviations, a normal deviate test of means, and calculation of critical decision values dependent on the sample size. 

Lahti and co-workers focused on distances between reference limits instead of distances between means, and suggested new distance and proportion criteria for partitioning. Their model also makes it possible to account for unequal subclass prevalences and is applicable to distributions of various types. 

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