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Abstract importance of understanding the principles been replaced by a “rifle” (or targeted)
According to Dr. Michael Laposata, the medical for selecting and ordering the most rational approach based on an understanding of the
specialty that nearly every practicing physician laboratory test(s) on a specific patient is test’s diagnostic performance and the major
relies on every day, for which training in many heightened in the current age of managed “legitimate” reasons for ordering a laboratory
medical schools is limited to no more than a care, medical necessity, and outcome-oriented test. Such an understanding is critical to good
scattered few lectures throughout the entire medicine. The days of a “shotgun approach” laboratory practice and patient outcomes.
curriculum, is “laboratory medicine.” The to ordering laboratory tests has, of necessity,
After reading this paper, readers should be able to describe the Chemistry 20903 questions and corresponding answer form are located
“laboratory testing cycle” and discuss the potential sources of error after this CE Update article on page 114.
coupled with thoughtful interpretation of the results of these Table 2_Example of Pattern Recognition Approach
tests, can contribute significantly to diagnostic decision making to Diagnosis
and patient management.
• White blood cell (WBC) and red blood cell (RBC) counts.
• Total protein.
• Glucose.
• Gram stain.
• Bacterial, viral, and/or fungal cultures.
• Rapid polymerase chain reaction (PCR) assay for a
meningococcus-specific insertion sequence (IS).
Sweat chloride
Nasal smear for eosinophils
Nasopharyngeal culture for
pertussis infection
Viral cultures
Stool exam for ova and para-
sites (O & P)
Urinalysis
Purified protein derivative
(tuberculin) (PPD)/
trichophyton/cocci
skin tests
Electrolytes
Glucose
Total bilirubin
Aspartate aminotransferase
(AST)
Alanine aminotransferase
(ALT)
Chest X-ray (×3)
From this data, the values for prevalence, sensitivity, speci- Caucasian men aged less than 50 years to 16% in men aged 50
ficity, efficiency, positive predictive value (PPV), and negative to 64 years and to 83% in men over 64 years of age.
predictive value (NPV) can be determined: In some cases, it may be desirable to use a laboratory test
with high sensitivity while sacrificing “some” specificity or vice
Prevalence (p) = No. of individuals with disease/No. of versa. For example, if the risk associated with failure to diagnose
individuals in population to be tested a particular disease is high (eg, acquired immunodeficiency
= 200/10,000 = 0.020 = 2.0% syndrome [AIDS]), false-negatives are unacceptable and only a
laboratory test with high sensitivity is acceptable. On the other
Sensitivity = percentage of individuals with disease who have hand, if a disease is potentially fatal and no therapy, other than
a positive test result = No. of true-positives/(No. of true- supportive care, is available (eg, cystic fibrosis), false-positives
positives + No. of false-negatives) or TP/(TP + FN) would be unacceptable. Thus, in this situation, a laboratory test
= 160/(160 + 40) = 160/200 = 0.800 = 80% with high specificity is desirable. In general, laboratory tests
with both high sensitivity and high specificity are desirable since
Specificity = percentage of individuals without disease who have both false-negatives and false-positives are equally unacceptable
a negative test result = No. of true-negatives/(No. of true- under most clinical circumstances.
negatives + No. of false-positives) or TN/(TN + FP) Diagnostic sensitivity refers to the proportion of individu-
= 2,940/(2,940 + 6,860) = 2,940/9,800 = 0.30 = 30% als with disease who yield a positive test for an analyte (eg, PSA)
associated with a particular disease. Diagnostic specificity refers
to the proportion of individuals without disease who yield a
Efficiency =percentage of individuals correctly classified by negative test for the analyte. A “perfect” test would have both
The AUC (range: 0.5 to 1.0) is a quantitative representa- reference intervals for an analyte are method dependent (ie, the
tion of overall test accuracy, where values from 0.5 to 0.7 repre- reference interval established using one method cannot auto-
sent low accuracy, values from 0.7 to 0.9 represent tests that are matically be substituted for that of a different assay that mea-
useful for some purposes, and values >0.9 represent tests with sures the same analyte).
high accuracy. The ROC curve (AUC = 0.66; 95% confidence Since reference intervals for all analytes are based typi-
interval: 0.60–0.72) in Figure 2.3A demonstrates that PSA has cally on the limits for the analyte that include 95% of all values
only modest ability in discriminating BPH from organ-confined obtained on healthy individuals with the assumption that the
prostate cancer. distribution of these values is Gaussian (or “bell-shaped”), it is
However, other data using ROC curves to assess the abil- important to recognize that 5% (or 1 out of 20; ie, the 2.5% of
ity of the tumor markers, prostatic acid phosphatase (PAP) and healthy individuals with analyte values in the left tail of the data
prostate specific antigen (PSA), to differentiate prostate cancer distribution and the 2.5% of healthy individuals with analyte
from BPH and prostatitis at various cutoff values is illustrated values in the right tail of the distribution when the reference
in Figure 2.3B. Qualitatively, the ROC curve corresponding to interval is defined as the limits of the 2.5th and 97.5th percen-
PSA is displaced further toward the upper left-hand corner of tiles of the distribution of all analyte values obtained on healthy
the box than the curve for PAP. Quantitatively, the AUC val- individuals) of healthy individuals will have values outside these
ues for PSA and PAP are 0.86 and 0.67, respectively. Thus, both limits, either low or high (Figure 2.4).
qualitative and quantitative ROC analysis demonstrates that Thus, reference intervals are intended to serve as a guide-
PSA provides better discrimination than PAP in distinguishing line for evaluating individual values and, for many analytes,
men with prostate cancer from those with BPH or prostatitis. information on the limits of an analyte for a population of
Moreover, the diagnostic accuracy (ie, sensitivity and specific-
individuals with the disease or diseases the test was designed The degree of imprecision (ie, lack of reproducibility) in
to detect is even more informative. Also, it is important to rec- the quantitative measurement of any analyte is given by the
ognize that values for some analytes in a population of healthy magnitude of the coefficient of variation (CV), expressed usu-
individuals may not be Gaussian distributed. ally as a percent, obtained from multiple measurements of the
Figure 2.5 provides an illustration of this point applicable analyte using the formula: %CV = (SD/mean) × 100; where
to the analyte, gamma-glutamyl transferase (GGT), in which mean and SD are the mean and standard deviation of the values
the data is positively skewed. The reference interval for this data obtained from the multiple measurements of an analyte. There
must be determined using a non-parametric statistical approach is a direct relationship between the magnitude of the CV and
that does not make the assumption that the data is Gaussian the degree of imprecision (ie, the lower the CV, the lower the
distributed. imprecision [or the higher the degree of precision]). The mag-
Lastly, to accurately interpret test results, it may be neces- nitude of analytical variation is given by CVa, while biological
sary to know gender-specific and/or age-stratified reference variability is defined by CVb. Approaches to determining assay-
intervals since the values for many analytes vary with devel- specific values for CVa, CVb, and CD are beyond the scope of
opmental stage or age. For example, alkaline phosphatase, an this CE Update.
enzyme produced by osteoblasts (bone-forming cells), would be Fortunately, most assays for a wide variety of analytes have
expected to be higher in a healthy 10- to 12-year-old during pu- excellent precision (ie, <5% to 10% CVa), such that the princi-
berty and the growth spurt (ie, increased bone formation dur- pal component among these 2 sources of variation (ie, analytical
ing lengthening of the long bones) that normally accompanies or biological) is biological variation (CVb). In addition, a change
puberty in adolescent males and females than those observed in in values for an analyte that exceeds the change (ie, reference
a prepubertal or elderly individual. change value [RCV]) expected due to the combined effects of
data is never a substitute for a good physical exam and patient 6. Obuchowski NA, Lieber ML, Wians FH Jr. ROC curves in clinical chemistry:
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8. Veltri RW, Chaudhari M, Miller MC, et al. Comparison of logistic regression
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