Reference individual

Fig. 3.2 Schematic of the CATS descriptor calculation, (a) The hydrogen-depleted two-dimensional molecular graph provides the input, (b) The graph is simplified for the distance matrix computation different bond orders are not considered (unweighted graph) and all element types are disregarded. The algorithm starts at an arbitrary chosen atom and visits all nodes of the graph in a breadth-first manner, thereby building up the distance matrix. The numbers at the vertices are used to reference individual atoms in the distance matrix.

Refer individuals/families to appropriate health care resources and services. 

Array constants can contain number or text values, but they cannot contain references. Individual text values in an array constant must be enclosed in quotes. 

The simplest method of accounting for variability consists in identifying the parameters, experimental data, and model output with an average or reference individual [45], One shortcoming of this approach is that although general model behavior is representative, much of the actual population may not be well described. Methods attempting to explicitly account for variability and uncertainty include Monte Carlo simulations [18,46,48], Bayesian population methods [49-51,53,56], the use of fuzzy sets [44,52], and other probability based methods [43], Monte Carlo simulations, which model the parameter variability in terms of probability distributions, are the most common methods. Each individual is characterized by a set of parameters whose values are drawn from a... 

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 definition of reference values is based on that of the reference individuals ... 

If, for example, we measure the concentration of triglycerides in sera collected from a group of reference individuals selected for comparison according to a sufficiently exact set of criteria, the triglyceride results are our 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. 

AH groups of reference individuals should be clearly defined. 

The patient examined should sufficiently resemble the reference individuals (in all groups selected for comparison) in all respects other than those under investigation. 

A set of selection criteria determmes which individual should be included in the group of reference individuals. Such selection criteria include statements describing the source population, specifications of criteria for health, or the disease of interest. 

Often, separate reference values for each sex, different age groups, and other criteria are necessary. Our group of reference individuals may therefore have to be divided into more homogeneous subgroups. For this purpose, we need to specify rules for the division, called stratification or partitioning criteria. 

Several methods have been suggested for the selection of reference individuals. Table 16-1 shows three pairs of concepts that may be used to describe a sampling scheme. The concepts of each pair are mutually exclusive. For example, the sampling is either direct or indirect. One may, however, combine one concept from several pairs to obtain a more exact description. For example, the selection may be direct, a posteriori, and nonrandom. 

Direct selection of reference individuals (see Table 16-1) is the only method that agrees with the concept of reference... 

The first step in the process of producing reference values for a laboratory test should always be the collection of quantitative information about the sources of biological variation for the analyte studied. A search through relevant literature may give the required information (see Chapter 17). If the relevant information cannot be found in the fiterature, pilot studies may be necessary before the selection of reference individuals is planned in detail. 

It is important to distinguish between controllable and noncontrollable sources of biological variation. Some factors may be controlled by the standardization of the procedure for preparation of reference individuals and specimen collection (see a later section of this chapter). Other factors, such as age and gender, may be relevant partitioning criteria, The remaining sources of variation should be considered when defining the criteria for the selection of reference individuals. 

The a priori strategy is best suited for smaller studies. Possible reference individuals from the parent population are interviewed and examined clinically and by selected laboratory methods to decide whether they fulfill the defined inclusion criteria. If the decision is positive, specimens for analysis are collected by a standardized procedure (including the necessary preparation of the individuals before the collection). 

A study performed in Kristianstad, Sweden, highlights a practical problem often met when selecting reference individuals the number of subjects fulfilling the inclusion criteria may be too small. In that study, only 17% of the participants were accepted by the criteria used, leaving an insufficient reference sample group. The frequency of... 

Ideally, the group of reference individuals should be a random sample of all the individuals fulfilling the defined inclusion criteria in the parent population. Statistical estimation of distribution parameters (and their confidence intervals) and statistical hypothesis testing require this assumption. 

For several reasons, most collections of reference values are, in fact, obtained by a nonrandom process. That means that aU possible reference individuals in the entire population under study do not have an equal chance of being chosen for inclusion in the usually much smaller sample of individuals studied. A strictly random sampling scheme is in most cases impossible for practical reasons. It would imply the examination of and application of inclusion criteria to the entire population (thousands or millions of persons) and then the random selection (e.g., conduct a raffle) of a subset of individuals from among those accepted. 

It is important to realize that we do not obtain a random sample, in the strict sense, if we start by selecting individuals randomly from the entire population and then apply inclusion criteria to sort out the subset of individuals fulfilling these criteria, even though this may be the best approximation we can hope to obtain. Usually the situation is less satisfactory. A sample of reference individuals obtained by selecting among blood donors, persons working in a factory,... 

The selection of reference individuals consists essentially of applying defined criteria to a group of examined candidate persons,The required characteristics of the reference values determine which criteria should be used in the selection process. Box 16-1 lists some important criteria to consider when the production of health-associated reference values is the aim. 

It may also be necessary to define partitioning criteria for the subclassification of the set of selected reference individuals into more homogeneous groups (Box 16-2). We shall return in later sections to the question of determining when stratification of the reference sample group is necessary and justified. The number of partitioning criteria should usually be kept as small as possible to obtain sufficient sample sizes to derive valid estimates. 

The first step in the establishment of reference values is the selection of a group of reference individuals. It is usually not feasible to obtain observations on aU possible reference individuals of a certain category of the general population. We therefore hope that the smaller group examined, the subset (sometimes called the reference sample group), can give us the desired information about the characteristics of the complete set of individuals (the reference population). 

Deviating values identified as possible outliers cannot always be discarded automatically. Values should be included or excluded on a rational basis. Check the records of the dubious values and correct errors. In some cases, deviating values should be rejected because noncorrectable causes have been found, such as previously unrecognized conditions, quahfying individuals for exclusion from the group of reference individuals. 

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 . 

Berg B, Nilsson JE, Solberg HE, et al. Practical experience in the selection and preparation of reference individuals Empirical testing of the provisional Scandinavian recommendations. In Grasbeck R, Alstrom T, eds. Reference values in laboratory medicine. Chichester, England John Wiley, 1981 55-64. 

The 500 mgs iron store Reference Individual is assumed to absorb 23% of ingested heme iron (estimated at 40% of meat, fish or poultry iron) and 3-8% of ingested nonheme iron (plant iron plus remaining meat, fish, poultry iron). The quantity of enhancing factors consumed at a specific meal, i.e. mgs ascorbic acid plus gms cooked meat/fish/poultry, determines % absorption of nonheme iron ... 

Recognition is made of the importance of the extent of an individual s iron stores as it will influence the amount of nonheme iron and heme iron that would be absorbed. The conservative model suggests utilization of an individual with 500 mgs of iron stores as the reference individual for whom bioavailable iron may be calculated. As the purpose of such a model is to compare one diet with another, it is immaterial what level of iron stores an individual has in that the comparison between diets will not be affected. The calculated values will, of course, be lower for the amount of total available iron with an individual with moderate iron stores of 500 mgs than they would be for an individual with zero iron stores. 

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