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4 Sensitivity, Specificity, and Predictive Value

4 Sensitivity, Specificity, and Predictive Value

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4.5 Random and Systematic Errors in Measurements















False positive results may mislead the clinician and lead to unnecessary

investigation and diagnostic tests as well as increased anxiety of the patient.

A false negative result is more dangerous than a false positive result

because diagnosis of a disease may be missed or delayed, which can

cause serious problems.

For a test, as clinical sensitivity increases, specificity decreases. For

calculating clinical sensitivity, specificity, and predictive value of a test,

the following formulas can be used:



TP 5 True positive (result correctly identifies a disease)



FP 5 False positive (result falsely identifies a disease)



TN 5 True negative (result correctly excludes a disease when the

disease is not present in an individual)



FN 5 False negative (result incorrectly excludes a disease when the

disease is present in an individual).



Therefore, when assay results are positive, results are a combination of TP

and FP, and when assay results are negative, results are combination of TN

and FN (Equations 4.6À4.8).

Sensitivity ðindividuals with disease who show positive test resultsÞ

TP

3 100

5

TP 1 FN



ð4:6Þ



Specificity (individuals without disease who show negative test results)

5

Positive predictive value 5



TN

3 100

TN 1 FP



TP

3 100

TP 1 FP



ð4:7Þ

ð4:8Þ



A positive predictive value is the proportion of individuals with disease who

showed a positive value compared to all individuals tested. Let us consider

an example where a particular analyte was measured in 100 normal individuals

and 100 individuals with disease. The following observations were made:

TP 5 95, FP 5 5, TN 5 95, and FN 5 5. Therefore, sensitivity 5 95/(95 1 5) 3

100 5 95%, and specificity 5 95/(95 1 5) 3 100 5 95%.



4.5 RANDOM AND SYSTEMATIC ERRORS

IN MEASUREMENTS

Random errors and systematic errors are important issues in the laboratory

quality control process. Random errors are unavoidable and occur due to

imprecision of an analytical method. On the other hand, systematic errors

have certain characteristics and are often due to errors in measurement using



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CHAPTER 4:



Laboratory Statistics and Quality Control



a particular assay. Because random errors cannot be eliminated or controlled,

the goal of quality control in a clinical laboratory is to avoid or minimize

systematic errors. Usually recalibration of the assay is the first step taken by a

clinical laboratory technologist to correct systematic error, but more serious

problems such as instrument malfunction may also be responsible for systematic errors.



4.6 LABORATORY QUALITY CONTROL: INTERNAL

AND EXTERNAL

Good quality control is the heart of a good laboratory operation. Because the

value of an analyte in a patient’s specimen is unknown, clinical laboratory

professionals rely on producing accurate results using controls for an assay.

Controls can be purchased from a commercial source or can be made inhouse. A control is defined as a material that contains the analyte of interest

with a known concentration. It is important that the control material has a

similar matrix to serum or plasma. Different types of controls used in clinical

laboratories are listed below:













Assayed Control: The value of the analyte is predetermined. Most

commercially available controls have predetermined values of various

analytes. The target value must be verified before use.

Un-Assayed Control: The target value is not predetermined. This

control must be fully validated (run at least 20 times in a single run

and then run once a day for 20 consecutive days to establish a target

value).

Homemade Control: If the assayed control material is not easily

commercially available (e.g. for an esoteric test), the control material may

be prepared by the laboratory staff by dissolving correctly weighed pure

material in an aqueous-based solvent or in serum or whole blood (for an

analyte not present in humans, e.g. a drug).



Commercially available control materials may be obtained as a ready-to-use

liquid control or as a lyophilized powder. If control material is available in

the form of lyophilized powder, it must be reconstituted prior to use by

strictly following the manufacturer’s recommended protocol. Control materials must be stored in a refrigerator following manufacturer’s recommendations and the expiration date of the control must be clearly visible so that an

expired control is not used by mistake. Usually low, medium, and high controls of an analyte are used to indicate analyte concentrations both in a normal physiological state and a disease state. At least two controls must be

used for each analyte (high and low controls). Control materials must be run

along with patient samples or at least once in each shift (a minimum of

three times in a 24 h period) depending on the assay.



4.6 Laboratory Quality Control: Internal and External



Quality control in the laboratory may be both internal and external. Internal

quality control is essential and results are plotted in a LeveyÀJennings chart

as discussed below. The most common example of external quality control is

analysis of CAP (College of American Pathologists) proficiency samples for

most tests offered by a clinical laboratory. Proficiency samples may not be

available for a few esoteric tests. CLIA 88 (Clinical Laboratory Improvement

Act) requires all clinical laboratories to register with the government and to

disclose all tests these laboratories offer. The test may be “waived tests” or

“non-waived tests:”













“Waived tests” are ones where laboratories can perform such tests as long

as they follow manufacturer protocol. Enrolling in an external

proficiency-testing program such as a CAP survey is not required for

waived tests.

“Non-waived tests” are moderately complex or complex tests.

Laboratories performing such tests are subjected to all CLIA regulations

and must be inspected by CLIA inspectors every two years or by

inspectors from non-government organizations such as CAP or Joint

Commission on Accreditation of Healthcare Organization (JCAHO). In

addition, a laboratory must participate in an external proficiency program

(most commonly CAP proficiency surveys) and must successfully pass

proficiency testing in order to operate legally. A laboratory must produce

correct results for four of five external proficiency specimens for each

analyte, and must have at least an 80% score for three consecutive

challenges.

Since April 2003, clinical laboratories must perform method validation

for each new test, even if such test already has FDA approval.



Currently, most common external proficiency testing samples are offered by

CAP, and there are proficiency specimens for 580 analytes. The major

features of CAP external proficiency testing include:













CAP proficiency samples are mailed to participating laboratories three

times a year and there are at least five samples for each analyte during

this period.

CAP proficiency samples have matrix similar to patient specimens and

such specimens must be analyzed just like a regular patient specimen. For

example, a CAP specimen cannot be analyzed in duplicate or only on the

day shift; such practice to pass CAP proficiency testing is a violation of

established practice guidelines.

CAP proficiency testing results must be reported to CAP and later graded

or ungraded results must arrive at the laboratory for evaluation by

laboratory professionals. A laboratory director or designee must sign

results of a CAP survey and must act if the laboratory fails a survey.



53



54



CHAPTER 4:



Laboratory Statistics and Quality Control



















CAP proficiency test results are graded based on performance of all

participating laboratories. There are various criteria for acceptability of a

result. Results must be within 6 2 SD of the peer group mean

(calculated by taking into account all values reported by participating

laboratories) or a fixed percentage of a target value (i.e. within 10% of

target value) or the result must be within a fixed deviation from the

target value (e.g. within 6 4 mol/L of the target value).

The best way to evaluate CAP proficiency testing results of an individual

clinical laboratory is to use the e-lab solution available from the CAP for

downloading.

If CAP proficiency testing is not available, then the laboratory must

validate the test every six months by comparing values obtained by the

test with values obtained by a reference laboratory or another laboratory

offering the test (using split samples). Alternatively, if proficiency

samples are available from another source, for example, AACC (American

Association for Clinical Chemistry), passing such proficiency testing is

also acceptable.

In addition to the CAP external proficiency-testing program, a laboratory

may participate in other proficiency testing programs. However, for

laboratory accreditation by CAP, it is required that the laboratory must

participate in a CAP proficiency survey, provided that the proficiency

specimen is available from the CAP.



There are a number of publications that indicate that participating in external

proficiency surveys such as offered by CAP is useful in improving the quality

of a clinical laboratory operation [1À3].



4.7 LEVEYÀJENNINGS CHART AND WESTGARD

RULES

In addition to participating in the CAP program, clinical laboratories must

run control specimens every shift, at least three times in a 24 h cycle. Also,

instruments must be calibrated as needed in order to maintain good laboratory practice. Calibration is needed for all assays that a clinical laboratory

offers. Calibration of immunoassays is discussed in Chapter 2. However,

other assays are calibrated using calibrators that are either commercially

available or homemade:





Calibrators are defined as materials that contain known amounts of the

analyte of interest. For a single assay, at least two calibrators are needed

for calibration, a zero calibrator (contains no analyte) and a high

calibrator containing the amount of the analyte that represents the upper

end of the analytical measurement range. However, five to six calibrators



4.7 LeveyÀJennings Chart and Westgard Rules







are commonly used for calibration. One calibrator must be a zero

calibrator and the highest calibrator must contain a concentration of the

analyte at the upper end of the analytical measurement range. Other

calibrators usually have concentrations in between the zero calibrator and

the highest calibrator, and represent normal values of the analyte as well

as values expected in a disease state (for drugs, values below therapeutic

range, between therapeutic ranges, and then toxic range).

Controls are materials that contain a known amount of the analyte. The

matrix of the control must be similar to the matrix of the patient’s

sample; for example, matrix of the control must resemble serum for

assays conducted in serum or plasma.



A LeveyÀJennings chart is commonly used for recording observed values of

controls during daily operation of a clinical laboratory. A LeveyÀJennings

chart is a graphical representation of all control values for an assay during an

extended period of laboratory operation. In this graphical representation,

values are plotted with respect to the calculated mean and standard deviation, and if all controls are within the mean and 6 2 SD, then all control

values are within acceptable limits and all runs during that period will have

acceptable performance (Figure 4.3). In this figure, all glucose low controls

were within acceptable limits for the entire month. The LeveyÀJennings chart

must be constructed for each control (low and high control or low, medium,

and high control) for each assay the laboratory offers. For example, if the laboratory runs two controls (low and high) for each test and offers 100 tests,

then there will be 100 3 2, or 200 LeveyÀJennings charts each month.

Usually a LeveyÀJennings chart is constructed for one control for one month.

The laboratory director or designee must review all LeveyÀJennings charts

each month and sign them for compliance with an accrediting agency.

93.6



+ 3 SD



90.4



+ 2 SD



87.2



+ 1 SD



84



Mean



80.8



– 1 SD



77.6



– 2 SD

– 3 SD



74.4

0



5



FIGURE 4.3

LeveyÀJennings chart with no violation.



10



15

Days



20



25



30



55



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