Population-based reference values

We may further distinguish between subject-based and population-based reference values, SuhjecCbased reference values are previous values from the same individual, obtained when he or she was in a known state of health. Population-based reference values are those obtained from a group of well-defined reference individuals and are usually the type of values referred to when the term reference values is used without any qualifying words. This chapter deals primarily with population-based values. 

The topic of the previous sections of this chapter has been univariate population-based reference values and quantities derived from them. Such values do not, however, fit the common clinical situation in which observed values of several different laboratory tests are available for interpretation and decision making. For example, the average number of individual clinical chemistry tests requested on one specimen received in the author s laboratory is 9.7. There are two models for interpretation by comparison in this situation. We can compare each observed value with the corresponding reference values or inteiwal (i.e., we perform multiple, univariate comparisons) or we can consider the set of observed values as a single multivariate observation and interpret it as such by a multivariate comparison. In this section, the relative merits of these two approaches are discussed, and methods for the latter type of comparison are presented. 

Subject-Based Reference Values Figure 16-7 depicts the inherent problem associated with population-based reference values. It shows two hypothetical reference distributions. The one represents the common reference distribution based on single specimens obtained from a group of different reference individuals. It has a true (hypothetical) mean l and a standard deviation other distribution is based on several specimens collected over time in a single individual, the ith individual. Its hypothetical mean is p,- and the standard deviation a . 

Hospital databases may, however, be used for the establishment of reference values that are fuUy concordant with the IFCC recommendations." The requirement is that laboratory data be combined with information stored in clinical databases (i.e., to apply a direct sampling strategy instead of the distribution-based indirect method). Laboratory results are to be used as reference values only if stated clinical criteria are fulfilled. One may define criteria for selecting individuals who have a specified state of health or the disease for which reference data are necessary. Usually certain constraints are also imposed on the use of their laboratory results, such as allowing only one result of each analyte under study from each selected individual. Such reference values have one advantage over those based on direct sampling from other types of populations hospital-based reference values are ideal for the interpretation of results from hospitalized patients because they are produced under similar conditions. 

The other possibility is to use the subject s previous values, obtained when the subject was in a well-defined state of health, as the reference for any future value. The application of subject-based reference values becomes more feasible as health screening by laboratory tests and as computer storage of results become available to large segments of the general population. 

The term evolutionary algorithm (EA) refers to a class of population based metaheuristic (probabilistic) optimization algorithms which imitate the Darwinian evolution ( survival ofthe fittest ). However, the biological terms are used as metaphors rather than in their exact meaning. The population of individuals denotes a set of solution candidates or points of the solution space. Each individual represents a point in the search space which is coded in the individual s representation (genome). The fitness of an individual is usually defined on the basis of the value of the objective function and determines its chances to stay in the population and to be used to generate new solution points. 

Of the European studies reviewed, many measured heavy metals, cotinine, PCBs, pesticides, PAHs, dioxins, phthalates, and VOCs. Germany has taken a substantial lead in this respect through its comprehensive population-based surveys (German Environment Surveys) and concerted efforts to develop health-protective reference values for the general population. In addition European countries have been actively involved in occupational biomonitoring efforts. In fact, some countries have biomonitoring surveillance programs that have been required by law. 

HBM values are derived from toxicologic and human studies and are health based (Jakubowski and Trzcinka-Ochocka 2005). Two types of HBM values exist HBM I, the concentration of an environmental toxin in human biological material below which there is no risk of adverse health effects and HBM II, the concentration above which there is an increased risk of adverse health effects in susceptible individuals in the general population (Jakubowski and Trzcinka-Ochocka 2005). An HBM I value serves as an alert level, and an HBM II value is an action level at which immediate efforts should be made to reduce exposure and further clinical examination should follow (Ewers et al. 1999). HBM values and reference values have been derived for a number of chemicals, including lead, cadmium, mercury, pentachlorophenol (PCP), and arsenic. 

The exposure of the target population to PBLx has been assessed by a group of internationally recognized experts. The estimate of the exposure is 0.34 pg/kg body weight per day (see Appendix l). Normally, this value is communicated with an estimate of toxicity or together with toxicology-based target values, such as, for example, reference dose (RfD) or acceptable daily intake (ADI). 

Breast M ilk. Recent reference values for mercury levels in breast milk in non-exposed individuals in the general U.S. population are very limited. The mean concentration of mercury in breast milk, based on a review of existing data from other countries, is 8 g/L (ppb) (WHO 1990, 1991). Mean concentrations of mercury in breast milk samples from the United States and other countries are summarized in Table 5-17. Pitkin et al. (1976) reported a mean total mercury concentration of 0.93 0.23 ppb in a midwestem community in the United States. This mean value is only about one-third the mean value reported for Inuit... 

The body of this chapter discusses population-based univariate reference values and quantities derived from them. If, for example, we produce, treat, and use separate reference values for cholesterol and triglycerides in serum, we have two sets of univariate reference values. The term multivariate... 

The variation of sensitivity between different sensors was also checked. Calibration curves with five different sensors were performed. A Relative Standard Deviation of 13, 13 and 42% of calibration slopes (sensitivity) were obtained for Cu, Pb and Cd respectively. These variations should have limited consequence on bias and precision when the standard addition method is used. However, for Cd, variations in the limit of quantification between two electrodes could be expected. Finally, the accuracy of the method was evaluated by the measurement of a SWIFT reference material used during the 2nd SWIFT-WFD Proficiency Testing exercise (Table 4.2.2). The reference value was chosen as the consensus value of the selected data population obtained after excluding the outliers. The performances of the device were estimated according to the Z-score (Z) calculation. Based on this score, results obtained with the SPEs/PalmSens method were consistent with those obtained by all methods for Pb and Cu ( Z < 2) while the result was less satisfactory for Cd (2 < Z < 3). 

The majority of genetic variation between humans is due to SNPs. Some of these change coding or regulatory sequences, and thereby alter proteins in structure or concentration. Although there is no strict consent, a single base pair change in a population is referred to as a mutation , if the allele frequency is below 1%, above that value as a SNP [32]. 

Dust may be regarded as the ideal material for detection and identification of indoor biocides and any of their residues still existing. Commercial vacuum cleaners ean be used for taking samples. Analysis using the < 63-pm fraction of dust lead to results that are more reproducible than those for any other fraction. Reliable results are only obtained under equilibrium conditions in rooms therefore there should be no cleaning for at least one week before dust samples are taken. Since the Umweltsurveys and two case control studies published recently are based on representative samples for household du.st of the German population (especially PCP, lindane and pyrethroids), the assessment of results is possible by comparison with reference values. 

A good, well-chosen biomarker of exposure should have several qualities. One is it should be specific for the exposure of interest some metabolites are common to multiple chemical substances and may not be a suitably specific biomarker. Even a small quantity of the biomarker should be easily detectable therefore, high sensitivity is important. Also, the biomarker should be associated with exposure. Ideally, biomarkers should provide good predictive value to a specific health status and have reference values in the population if possible. Low overall analysis expense is another desirable characteristic of biomarker analysis for use in biomonitoring. The availability of suitable economical reference standards, as well as low-cost sample preparation, is an important consideration for extensive studies. This also implies that the analytical measurement procedure for the biomarker should have high throughput capability. Finally, measurements by non-invasive techniques are desirable. Urine-based biomarkers, either parent compounds or metabolites, are widely used in biomarker research today. Blood drawing is... 

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