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4.11: Reference Intervals

  • Page ID
    122352
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    A 49 year old black male is brought to an emergency room following several hours of chest pain and shortness of breath while working. He is a large, muscular, 230-pound, 6’1” man who works as a construction worker. Following admission to the CCU, a series of “cardiac” enzyme values are obtained to rule out the possibility of a myocardial infarction.

    Time (hours) CK (U/L) LD (U/L)
    Admission (0) 105 98
    6 91 105
    12 112 92
    24 104 101
    48 99 90

    The laboratory’s reference intervals for CK and LD are 10-80 and 0-100 U/L, respectively. The physician in charge of the patient is concerned that since the total CK values are significantly greater than the reference interval, the patient might have had a myocardial infarction.

    QUESTION

    Can we be certain that the reference intervals in use by the laboratory are valid in this case for helping the physician determine whether his patient had an M.I.? Why?

    Questions to Consider

    1. What biological parameters should be considered when a reference interval is defined?
    2. How can the laboratory determine if a reference interval for a test should differentiate test values by the parameters listed in 1.
    3. Why do you think this laboratory established the reference intervals using its own personnel?
    Answer

    This laboratory’s reference interval was based on values obtained from young Caucasian (in this case) females and might be inappropriate for this patient. This is true for CK since most serum CK is derived from muscle, and this very muscular male might be expected to have a higher serum CK concentration, especially when compared to young females. The physician should be told that the values for his patient are probably very normal.

    Answers to Questions to Consider

    1. The most important factors are age, sex, and race (page 366). Other factors may also be very important depending on the specific analyte in question. Preanalytical variables must be properly controlled (se Chapter 3) when obtaining samples for a reference range study. For example posture during phlebotomy, is important for properly defining the reference interval for serum catecholamines, and many reference intervals must be determined in healthy individuals not taking certain foods or medications that might interfere with the analysis.
    2. When establishing a reference interval, or validating a company's reference interval for a test, the laboratory should first review the appropriate journals (i.e., Clinical Chemistry) or textbooks (such as Clinical Chemistry, by Kaplan and Pesce) to see if age, sex or race differences have been reported for the method to be used. If they have, the laboratory should immediately begin to determine if such a difference exists for their method. If there is no such report, the laboratory may decide to evaluate these differences themselves.

      Laboratory data should be divided on the basis of sex and race (usually Caucasian and Black). With 30-40 values in each group, one can test for significant differences between the means of each population, i.e. male vs. female or Caucasian vs. Black (see Chapter 19). One can usually do this by the t-test (pp. 350-353). (One should also prepare histograms or distribution plots of the data [p. 343-346] to determine whether the data is normally distributed.) If there is no difference between the groups, the data should then be pooled into a single population. If there is a difference, one has then to determine if this difference is clinically significant (p. 370-371). If it is, two separate reference intervals must be reported for the analyte. For these analytes, differences in the reference interval based on sex and race have been reported (See Method Creatine Kinase in CD-ROM).
    3. The supervisor and clinical chemist of the laboratory go back to the data used to establish the reference interval for CK and find that the laboratory personnel were used. Many laboratories typically use their personnel as healthy subjects for reference interval studies because of the ready accessibility and professional cooperation of the medical technologists. However, the majority of medical technologists are young females. Thus, if age or gender would normally affect the data, the reference intervals might be inappropriate for older people or males. In addition, if the race of most of the workers differs from that of the typical hospital patient, an additional bias might be introduced.

    This page titled 4.11: Reference Intervals is shared under a CC BY-NC-SA 4.0 license and was authored, remixed, and/or curated by Lawrence Kaplan & Amadeo Pesce.

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