Establishment and Use of Reference Values

Medicine is an art and a science in the service of fellow human beings. To improve the health of their patients, physicians (1) collect empirical data, (2) interpret these data using scientific laiowledge and professional experience, (3) make decisions concerning diagnoses, (4) recommend preventive measures, and (5) execute therapeutic actions. There is a fundamental limitation in this activity as absolute health does not exist. Health is necessarily a relative concept.  

The interpretation of medical laboratory data is an example of decision making by comparison. We therefore need reference values for all tests performed in the clinical laboratory, not only from healthy individuals but firom patients with relevant diseases. 

Ideally an observed value in an individual should be related to relevant collections of reference values, such as values from healthy persons, from the undifferentiated hospital population, from persons with typical diseases, and fi om ambulatory individuals, and previous values from the same subject. A patient s laboratory result simply is not medically useful if appropriate data for comparison are lacking. 

---

If comparison with experiment is not appropriate, what should be used for reference values Clearly, the desirable thing would be to eliminate as many sources of error as possible. For instance, if we wish to establish the reliability of an SCF treatment in a given one-particle basis, we could use numerical Hartree-Fock results for diatomic molecules (that is, essentially complete basis results) as benchmarks. Any difference between the finite basis and numerical results would presumably be due to inadequacies in the former, as otherwise the same approximations are made in both treatments. It is crucial to understand that this approach gives much more informa-... 

In the reference-range approach, reference ranges (or intervals),1 are established, and biomonitoring values from individuals or subgroups are compared with them. The validity and utility of biomonitoring values for use as reference ranges depends on study design and data quality, with special attention to the availability and comparability of data on the reference population in relation to the study population. 

Factors may have associated values called levels of variations. Each state of a black box has a definite combination of factor levels. The more different states of the black box that exist, the more complex is the research subject. Formalization of preliminary information includes analysis of reference data, expert opinions and use of direct data, which enables correct selection of response, factors and null point or center of experiment. Factor limitations are also defined at this stage. If the research is linked with several following responses, then response limitations also have to be analyzed. The next phase refers to defining the research problem. When defining this problem one must keep in mind the research-subject model, and in a general case it is Eq. (2.1) that defines the link between the inlet and outlet of the black box. Defining the research problem is possible only now when its aim has been determined, the criteria established, the factors, limitations and null point defined. The problem is a simple one when only one response or optimization criterion is in... 

The EU Commission Decision EC 2002/657 prescribes the use of RMs or CRMs [4]. Eurachem has published a document that provides instructions to analytical chemists on the selection and use of RMs [31]. Different types of RMs exist, namely, pure substances, standard solutions, matrix RMs, physical-chemical RMs, and reference objects or artifacts. The difference between RMs and CRMs lies in that the values or properties of a CRM are certified during a collaborative trial according to a well-defined protocol, whereas the values or properties of an RM are defined, but have not been established through a collaborative trial. The following classes are generally used for RMs primary, secondary, and in-house or working RMs. The uncertainty associated with primary RMs is the smallest, while in-house RMs have the largest uncertainty. 

Establishment of reference values of general use requires general availability of a well-defined calibrator. The availability of such a calibrator also facilitates accreditation of procedures for quantitative determination of the corresponding analyte. Recombinant human cystatin C can easily be produced and isolated and used for establishing reliable calibrators (A2, Dl). A first step toward an international calibrator for cystatin C has been taken by the production of a solution of recombinant human cystatin C of high purity, determining the concentration of this... 

There are a few analytical techniques, e.g. weighing, where it is possible to directly show traceability to an established value. For most cases, e.g. to verify an analytical procedure, one has to resort to the use of reference materials. Analysis of a reference material means that the analyst can check the result against an established and agreed number. 

Optimal dietary intake is difficult to determine. Dietary Reference Intakes (DRIs) in the US are reference values that are quantitative estimates of nutrient intakes to be used for planning and assessing diets for apparently healthy people. DRIs are composed of reference values including Estimated Average Requirements (EARs), Recoimnended Dietary Allowances (RDAs), Adequate Intakes (AIs) and Tolerable Upper Intake Levels (ULs). Most nations have established the eqnivalent ofthe US DRIs. These are consensus and statistical valnes obtained from retrospective public health dietary studies, controlled experiments on metabolic wards, epidemiological surveys, isotopic tracer investigations, and extrapolation from animal models. 

Cooperative international efforts such as those carried out by the NEA/OECD Thermodynamic Database Project allow sharing of the results of basic research, standardization of techniques for experiments, and establishment of reference values for thermodynamic and kinetic calculations. A comparable effort would be useful for sorption data modeling. A number of alternative SCMs are used in the literature. They are all based... 

The use of Reference Materials (RMs) is part of good QA practices that insure analytical data of documented quality. An RM is a material or substance one or more properties of which are sufficiently well established to be used for the calibration of an apparatus, the assessment of a measurement method or for the assignment of values to materials. A CRM is an RM one or more of whose values are certified by a technically valid procedure accompanied by or traceable to a certificate or other documentation which is issued by a certifying body such as NRC, NIST or others. An SRM is a CRM produced and certified by NIST. 

The exclusion criteria may be relaxed. As already discussed, the set of relevant sources of biological variation differs among different analytes. One may define a minimum set of exclusion criteria for a given laboratory test. In the Kristianstad study, the complete group of individuals could probably be used for establishment of reference values (e.g., serum sodium), and most of the individuals would be acceptable for the determination of reference values for several other analytes. ... 

Preanaiyticai procedures used before routine analysis of patient specimens and when establishing reference values should be as similar as possible. In general it is much easier to standardize the routines for studies of reference values than those used in the daily clinical setting, especially when collecting specimens in emergency or other unplanned situations. Thus two approaches have been suggested ... 

ADDITIONAL TOPICS Transferability of Reference Values The determination of refiable reference values for each test in the laboratory s repertoire is a major task and is often far beyond the capabilities of the individual laboratory. It would therefore be convenient if reference values generated in another laboratory could be used. This is especially important when ethical considerations limit the number of available individuals (e.g., when producing pediatric reference values). Then, cooperative establishment of reference values may be necessary. 

An alternative to adding additional reference materials is to use a so-called external reference. Here the spectrum of a separate reference substance is acquired before and/or after the sample of interest and the spectrum reference value carried over. Identical field settings should be used for both which, on some older instruments, requires the same lock solvent, or an additional correction to the spectrum reference frequency must be used to compensate any differences. This restriction does not arise on instruments that use shifting of the lock transmitter frequency to establish the lock condition. 

Terrestrial wildlife movements are such that site-specific tools are more efficiently used to refine exposure estimate. In this case, site-specific exposure estimates are used and compared with safe thresholds for toxicity, termed toxicity reference values (TRVs). Toxicity reference values for wildlife have been developed for energetic compounds. This chapter presents a brief overview of the processes used to establish these tools for ERA for explosives and related soil contaminants that are frequently of potential ecological concern at the affected military sites. This chapter also provides recommendations for use of these values in the ERA process. Investigations addressing the importance and extent of habitat disturbance as a component of the ERA process on explosives-contaminated ranges are reviewed in Chapter 11. General bioaccumulation principles and applications of the bioaccumulation factor and bioconcentration factor (BAF and BCF, respectively) concepts that are often employed in the ERA process to determine bioaccumulation potential of MC for terrestrial receptors are reviewed in Chapter 10. 

A series of hydrocarbons has been studied in cyclohexylamine, using cesium cyclohexylamide as base. For many of the compounds studied, spectroscopic measurements were used to determine the relative extent of deprotonation of two hydrocarbons and thus establish relative acidity. For other hydrocarbons, the acidity was derived by kinetic measurements. It was shown that the rate of tritium exchange for a series of related hydrocarbons is linearly related to the equilibrium acidities of these hydrocarbons in the solvent system. This method was used to extend the scale to hydrocarbons such as toluene for which the exchange rate, but not equilibrium data, can be obtained. Representative values of some hydrocarbons with pK values ranging from 16 to above 40 are given in Table 6.2. The pK values of a wide variety of organic compounds have been determined in DMSO, and some of these values are listed in Table 6.2 as well. It is not expected that these values will be numerically identical with those in other solvents, but for most compounds the same relative order of acidity is observed. For synthetic purposes, carbanions are usually generated in ether solvents, often THF or DMF. There are relatively few quantitative data available on hydrocarbon acidity in such solvents. Table 6.2 contains a few entries for Cs salts. The numerical values are scaled with reference to the pK of 9-phenylfluorene. ° The acidity trends are similar to those in cyclohexylamine and DMSO. 

Kley, S., P Tshudi, A. Busato, and F. Gaschen. 2004. Establishing canine clinical chemistry references values for the Hitachi 912 using the International Federation of Clinical Chemistry (IFCC) recommendations. Comparative Clinical Pathology 12 106-112. 

The majority of chemical reference materials (CRMs) are widely analyzed materials having one or more chemical or physical properties sufficiently well established to be used as reference values for calibration or performance assessment. Items as diverse as gas chromatography-mass spectrometry system performance standards, human or bovine serum, fly-ash, soils, estuarine sediments, rice flour, and stainless steels are included in the vast range of CRMs available. 

---