Диапазоны и интервалы референсных значений в медицине.

Measured values that are relatively normal for a particular medical test

In medicine and health related fields, a reference range or reference interval is the range or the interval of values that is deemed normal for a physiological measurement in healthy persons (for example, the amount of creatinine in the blood, or the partial pressure of oxygen). It is a basis for comparison for a physician or other health professional to interpret a set of test results for a particular patient. Some important reference ranges in medicine are reference ranges for blood tests and reference ranges for urine tests. The standard definition of a reference range (usually referred to if not otherwise specified) originates in what is most prevalent in a reference group taken from the general (i. e. total) population. This is the general reference range. However, there are also optimal health ranges (ranges that appear to have the optimal health impact) and ranges for particular conditions or statuses (such as pregnancy reference ranges for hormone levels). Values within the reference range (WRR) are those within normal limits (WNL). The limits are called the upper reference limit (URL) or upper limit of normal (ULN) and the lower reference limit (LRL) or lower limit of normal (LLN). In health care–related publishing, style sheets sometimes prefer the word reference over the word normal to prevent the nontechnical senses of normal from being conflated with the statistical sense. Values outside a reference range are not necessarily pathologic, and they are not necessarily abnormal in any sense other than statistically. Nonetheless, they are indicators of probable pathosis. Sometimes the underlying cause is obvious; in other cases, challenging differential diagnosis is required to determine what is wrong and thus how to treat it. A cutoff or threshold is a limit used for binary classification, mainly between normal versus pathological (or probably pathological). Establishment methods for cutoffs include using an upper or a lower limit of a reference range.

The standard definition of a reference range for a particular measurement is defined as the interval between which 95% of values of a reference population fall into, in such a way that 2.5% of the time a value will be less than the lower limit of this interval, and 2.5% of the time it will be larger than the upper limit of this interval, whatever the distribution of these values. Reference ranges that are given by this definition are sometimes referred as standard ranges. Since a range is a defined statistical value (Range (statistics)) that describes the interval between the smallest and largest values, many, including the International Federation of Clinical Chemistry prefer to use the expression reference interval rather than reference range. Regarding the target population, if not otherwise specified, a standard reference range generally denotes the one in healthy individuals, or without any known condition that directly affects the ranges being established. These are likewise established using reference groups from the healthy population, and are sometimes termed normal ranges or normal values (and sometimes "usual" ranges/values). However, using the term normal may not be appropriate as not everyone outside the interval is abnormal, and people who have a particular condition may still fall within this interval. However, reference ranges may also be established by taking samples from the whole population, with or without diseases and conditions. In some cases, diseased individuals are taken as the population, establishing reference ranges among those having a disease or condition. Preferably, there should be specific reference ranges for each subgroup of the population that has any factor that affects the measurement, such as, for example, specific ranges for each sex, age group, race or any other general determinant.

Methods for establishing reference ranges can be based on assuming a normal distribution or a log normal distribution, or directly from percentages of interest, as detailed respectively in following sections. When establishing reference ranges from bilateral organs (e. g., vision or hearing), both results from the same individual can be used, although intra subject correlation must be taken into account.

In reality, biological parameters tend to have a log normal distribution, rather than the normal distribution or Gaussian distribution. An explanation for this log normal distribution for biological parameters is: The event where a sample has half the value of the mean or median tends to have almost equal probability to occur as the event where a sample has twice the value of the mean or median. Also, only a log normal distribution can compensate for the inability of almost all biological parameters to be of negative numbers (at least when measured on absolute scales), with the consequence that there is no definite limit to the size of outliers (extreme values) on the high side, but, on the other hand, they can never be less than zero, resulting in a positive skewness. As shown in diagram at right, this phenomenon has relatively small effect if the standard deviation (as compared to the mean) is relatively small, as it makes the log normal distribution appear similar to a normal distribution. Thus, the normal distribution may be more appropriate to use with small standard deviations for convenience, and the log normal distribution with large standard deviations. In a log normal distribution, the geometric standard deviations and geometric mean more accurately estimate the 95% prediction interval than their arithmetic counterparts.

A method to estimate the reference range for a parameter with log normal distribution is to logarithmize all the measurements with an arbitrary base (for example e), derive the mean and standard deviation of these logarithms, determine the logarithms located (for a 95% prediction interval) 1.96 standard deviations below and above that mean, and subsequently exponentiate using those two logarithms as exponents and using the same base as was used in logarithmizing, with the two resultant values being the lower and upper limit of the 95% prediction interval. The following example of this method is based on the same values of fasting plasma glucose as used in the previous section, using e as a base: corresponding to a probability of 0.5% that a result is at least such far from the mean in the absence of disease.

Optimal (health) range or therapeutic target (not to be confused with biological target) is a reference range or limit that is based on concentrations or levels that are associated with optimal health or minimal risk of related complications and diseases, rather than the standard range based on normal distribution in the population. It may be more appropriate to use for e. g. folate, since approximately 90 percent of North Americans may actually suffer more or less from folate deficiency, but only the 2.5 percent that have the lowest levels will fall below the standard reference range. In this case, the actual folate ranges for optimal health are substantially higher than the standard reference ranges. Vitamin D has a similar tendency. In contrast, for e. g. uric acid, having a level not exceeding the standard reference range still does not exclude the risk of getting gout or kidney stones. Furthermore, for most toxins, the standard reference range is generally lower than the level of toxic effect. A problem with optimal health range is a lack of a standard method of estimating the ranges. The limits may be defined as those where the health risks exceed a certain threshold, but with various risk profiles between different measurements (such as folate and vitamin D), and even different risk aspects for one and the same measurement (such as both deficiency and toxicity of vitamin A) it is difficult to standardize. Subsequently, optimal health ranges, when given by various sources, have an additional variability caused by various definitions of the parameter. Also, as with standard reference ranges, there should be specific ranges for different determinants that affects the values, such as sex, age etc. Ideally, there should rather be an estimation of what is the optimal value for every individual, when taking all significant factors of that individual into account a task that may be hard to achieve by studies, but long clinical experience by a physician may make this method preferable to using reference ranges.

In many cases, only one side of the range is usually of interest, such as with markers of pathology including cancer antigen 19 9, where it is generally without any clinical significance to have a value below what is usual in the population. Therefore, such targets are often given with only one limit of the reference range given, and, strictly, such values are rather cut off values or threshold values. They may represent both standard ranges and optimal health ranges. Also, they may represent an appropriate value to distinguish healthy person from a specific disease, although this gives additional variability by different diseases being distinguished. For example, for NT proBNP, a lower cut off value is used in distinguishing healthy babies from those with acyanotic heart disease, compared to the cut off value used in distinguishing healthy babies from those with congenital nonspherocytic anemia.