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1 Definitions and Concepts Karen J. Tietze Laboratory testing is us...

1 Definitions and Concepts Karen J. Tietze Laboratory testing is used to detect disease, guide treatment, monitor response to OBJECTIVES treatment, and monitor disease progression. However, it is an imperfect science. Labo- ratory testing may fail to identify abnormalities that are present (false negatives [FNs]) After completing this chapter, the or identify abnormalities that are not present (false positives [FPs]). This chapter reader should be able to defines terms used to describe and differentiate laboratory tests and describes factors Differentiate between accuracy and to consider when assessing and applying laboratory test results. precision Distinguish between quantitative and DEFINITIONS qualitative laboratory tests Many terms are used to describe and differentiate laboratory test characteristics and Define reference range and identify results. The clinician should recognize and understand these terms before assessing factors that affect a reference range and applying test results to individual patients. Differentiate between sensitivity and specificity, and calculate and assess Accuracy and Precision these parameters Accuracy and precision are important laboratory quality-­control measures. Laborato- Identify potential sources of ries are expected to test analytes (the substance measured by the assay) with accuracy laboratory errors and state the and precision and to document the quality-­control procedures. Accuracy of a quan- impact of these errors in the titative assay is usually measured in terms of analytical performance, which includes interpretation of laboratory tests accuracy and precision. Accuracy is defined as the extent to which the mean measure- ment is close to the true value. A sample spiked with a known quantity of an analyte Identify patient-­specific factors that is measured repeatedly; the mean measurement is calculated. A highly accurate assay must be considered when assessing means that the repeated analyses produce a mean value that is the same as or very laboratory data close to the known spiked quantity. Accuracy of a qualitative assay is calculated as the Discuss the pros and cons of point-­ sum of the true positives (TPs) and true negatives (TNs) divided by the number of of-­care and at-­home laboratory samples tested (accuracy = [(TP + TN) ÷ number of samples tested] × 100%). Preci- testing sion refers to assay reproducibility (ie, the agreement of results when the specimen Describe a rational approach to is assayed many times). An assay with high precision means that the methodology is interpreting laboratory results consistently able to produce results in close agreement. Analyte The analyte is the substance measured by the assay. Some substances, such as phenyt- oin and calcium, are bound extensively to proteins such as albumin. Although the unbound fraction elicits the physiologic or pharmacological effect (bound substances are inactive), most routine assays measure the total substance (bound plus unbound). The free fraction may be assayable, but the assays are not routine. Therefore, the reference range for total and free substances may be quite different. For example, the reference range is 10–20 mcg/mL for total phenytoin, 1–2 mcg/mL for free phenyt- oin, 9.2–11 mg/dL for total serum calcium, and 4–4.8 mg/dL for free (also called ionized) calcium. Some analytes exist in several forms and each has a different reference range. Results for the total and each form are reported. For example, bilirubin circulates in conjugated and unconjugated subforms as well as bound irreversibly to albumin Note: This chapter is based, in part, on the second edition chapter titled “Definitions and Concepts,” which was written by Scott L. Traub. DOI 10.37573/9781585286423.001 3 Edwards_CH01.indd 3 17/03/22 12:04 PM  4 BASIC SKILLS IN INTERPRETING LABORATORY DATA (δ ­bilirubin). Direct bilirubin refers to the sum of the conjugated TABLE 1-1. Relationship of Sensitivity, Specificity, plus the δ forms (water soluble forms); indirect bilirubin refers to Disease Prevalence, and Predictive Value of a the unconjugated form (water insoluble form). Lactate dehydro- Positive Test (the predictive value of a positive test genase (LDH) is separated electrophoretically into five different isoenzymes: LDH1, LDH2, LDH3, LDH4, and LDH5. Creatine increases as the disease prevalence and sensitivity kinase (CK) exists in three isoforms: CK1 (CK-BB), CK2 (CK- and specificity of the test increase) MB), and CK3 (CK-MM). PREDICTIVE Biomarker SENSITIVITY VALUE OF A biomarker (biological marker) is a marker (not necessarily AND POSITIVE a quantifiable laboratory parameter) defined by the Food and SPECIFICITY (%) PREVALENCE (%) TEST (%) Drug Administration (FDA) as “A defined characteristic that 95 0.1 1.9 is measured as an indicator of normal biological processes, pathogenic processes, or responses to an exposure or inter- 1 16.1 vention, including therapeutics interventions.”3 Biomark- 2 27.9 ers are used to diagnose and stage disease (ie, determine the extent of disease), assess disease progression, and predict or 5 50 assess response to therapeutic interventions. For example, 50 95 tumor markers are biomarkers used to identify the presence of some cancers, to stage disease, or to assess patient response 99 0.1 9 to drug and nondrug cancer treatments. Many biomarkers are common laboratory parameters. For example, glyco- 1 50 sylated hemoglobin A1c (HbA1c) is used to assess average 2 66.9 blood sugar levels over the past three months in patients with diabetes. 5 83.9 50 99 Noninvasive Versus Invasive Tests A noninvasive test is a procedure that examines fluids or other Predictive value of positive test = [TP ÷ (TP + FP)] × 100%. substances (eg, urine and exhaled air) obtained without using Predictive value of negative test = [TN ÷ (TN + FN)] × 100%. Disease prevalence = (TP + FN) ÷ number of patients tested. a needle, tube, device, or scope to penetrate the skin or enter TP = diseased persons detected by test (true positives). the body. An invasive test is a procedure that examines fluids FP = nondiseased persons positive to test (false positives). or tissues (eg, venous blood and skin biopsy) obtained by using FN = diseased persons not detected by test (false negatives). a needle, tube, device, or scope to penetrate the skin or enter TN = nondiseased persons negative to test (true negatives). the body. Invasive tests pose variable risk depending on the method of specimen collection (eg, pain and bruising associ- ated with venipuncture) and are less convenient than nonin- vasive tests. in error. The predictive value may also be applied to negative results. As applied to a negative test result, the predictive value Predictive Value indicates the percent of negatives that are true negatives (refer The predictive value, derived from a test’s sensitivity, specificity, to Minicase 1). and prevalence of the disease in the population being tested, is used to assess a test’s reliability (Table 1-1). As applied to a Qualitative Tests positive test result, the predictive value indicates the percent of A qualitative test is a test whose results are reported as either positives that are true positives. For a test with equal sensitivity positive or negative without further characterization of the and specificity, the predictive value of a positive result increases degree of positivity or negativity. Exact quantities may be as the prevalence of the disease in the population increases. For measured in the laboratory but are still reported qualitatively example, the glucose tolerance test has a higher predictive value using predetermined ranges. For example, a serum or urine for diabetes in women who are pregnant than in the general pregnancy test is reported as either positive or negative; a bacte- population as a result of the higher prevalence of diabetes rial wound culture is reported as either positive for one or more in pregnancy compared with the general population due to specific microorganisms or reported as no growth; a urine toxi- gestational diabetes. A borderline abnormal serum creatinine cology drug screen is reported as either positive or negative for concentration has a higher predictive value for kidney disease specific drugs; a hepatitis C virus (HCV) ribonucleic acid (RNA) in patients in a nephrology unit than in patients in a general test is reported as positive or negative for hepatitis C viral RNA; medical unit. The lower the prevalence of disease in the popu- and an acid-­fast stain for Mycobacterium is reported as either lation tested, the greater the chance that a positive test result is positive or negative. Edwards_CH01.indd 4 17/03/22 12:04 PM  C HA P T E R 1 De f i n i t ion s a n d C oncept s  5 MINICASE 1 Bladder Urothelial Carcinoma Recurrence Surveillance Frequent active surveillance is recommended for patients following DISCUSSION: Calculate sensitivity, specificity, predictive value of a treatment for nonmuscle-­invasive bladder cancer (NMIBC). The positive test, and predictive value of a negative test. gold standard active surveillance monitoring strategies for NMIBC Sensitivity = (TP ÷ [TP + FN]) × 100% = (30 ÷ [30 + 14]) × include cystoscopy and urine cytology. For patients with a low risk of 100% = 68.2% recurrence, the American Urological Association/Society of Urologic Oncology recommends patients undergo the first surveillance Specificity = (TN ÷ [TN + FP]) × 100% = (272 ÷ [272 + 37]) × cystoscopy within three to four months after initial treatment, 100% = 88% then six to nine months later, and then annually for five years; Predictive value of positive test = (TP ÷ [TP + FP]) × more frequent active surveillance is recommended for patients at 100% = (30 ÷ [30 + 37]) × 100% = 44.8% a greater risk of recurrence.1 Cystoscopy is an invasive test with Predictive value of negative test = (TN ÷ [TN + FN]) × well-­described risks; a noninvasive active surveillance laboratory 100% = (272 ÷ [272 + 14]) × 100% = 95.1% test would reduce healthcare costs and patient risk. In this study, the noninvasive Bladder EpiCheck urine test had a The sensitivity and specificity of a new noninvasive Bladder high overall negative predictive value (NPV), high specificity, and EpiCheck test in 353 subjects with incident or recurrent bladder clinically acceptable sensitivity. The clinical application of this test urothelial carcinoma undergoing active surveillance with cystoscopy is to surveil for cancer recurrence to determine if a more invasive, and cytology were assessed.2 but more sensitive, monitoring strategy is necessary. If patients test QUESTION: After reviewing the following results, what conclusions can negative and are truly negative, additional testing is not necessary. be made about the clinical performance of the Bladder EpiCheck test? A high overall negative predictive value of 95.1% makes this test useful for this application despite a lower predictive value of Bladder EpiCheck Results (n = 353) positive test. True positives (TP): 30 True negatives (TN): 272 False positives (FP): 37 False negatives (FN): 14 Quantitative Tests The reference range for a given analyte is usually established in the clinical laboratory as the mean or average value plus or A quantitative test is a test whose results are reported as an exact minus two SDs. Acceptance of the mean ±2 SD indicates that numeric measurement (usually a specific mass per unit measure- one in 20 normal individuals will have test results outside the ment) and assessed in the context of a reference range of values. reference range (2.5% have values below the lower limit of the For example, serum potassium is commonly reported in milli- reference range and 2.5% have values above the upper limit equivalents per liter, creatinine clearance is commonly reported of the reference range). Accepting a wider range (eg, ±3 SD) in milliliters per minute, fractional exhaled nitric oxide (FeNO) includes a larger percentage (99.7%) of normal individuals but is commonly reported in parts per billion, and LDH is commonly increases the chance of including individuals with values only reported in units per liter. Some test results are reported as titers slightly outside of a narrower range, thus decreasing the sensi- (dilutions). For example, a serum antinuclear antibody titer of tivity of the test. 1:160 is usually associated with active systemic lupus erythema- Qualitative laboratory tests are either negative or positive tosus (SLE) or other autoimmune diseases, though some patients and lack a reference range; any positivity is considered abnor- may have “low titer” disease with titers of 1:40 or 1:80. mal. For example, any amount of serum acetone, porphobilino- Reference Range gen, or alcohol in serum or plasma is considered abnormal. The presence of glucose, ketones, blood, bile, or nitrate in urine is The reference range (also known as the reference interval or abnormal. The results of the Venereal Disease Research Labo- the reference value) is a statistically-­derived numerical range ratory (VDRL) test, tests for red blood cell (RBC) sickling, and obtained by testing a sample of individuals assumed to be the malaria smear are either positive or negative. healthy. The upper and lower limits of the range are not absolute (ie, normal versus abnormal), but rather points beyond which the probability of clinical significance begins to increase. The Factors That Influence the Reference Range term reference range is preferred over the term normal range.4 Many factors influence the reference range. Reference ranges The reference population is assumed to have a Gaussian distri- may differ between laboratories depending on analytical tech- bution with 68% of the values within one standard deviation nique, reagent, and equipment. The initial assumption that the (SD) above and below the mean (±1 SD), 95% within ±2 SD, sample population is normal may be false. For example, the and 99.7% within ±3 SD (Figure 1-1). reference range is inaccurate if too many individuals with covert Edwards_CH01.indd 5 17/03/22 12:04 PM  6 BASIC SKILLS IN INTERPRETING LABORATORY DATA on discovery of a critical value test result. Critical values may not always be clinically relevant, however, because the reference range varies for the reasons discussed previously. Semiquantitative Tests A semiquantitative test is a test whose results are reported as either negative or with varying degrees of positivity but without exact quantification. For example, urine glucose and urine ketones may be reported as negative or trace, 1+, 2+, 3+, or 4+; the higher numbers represent a greater amount of the measured substance in the urine, but not a specific concentration. Sensitivity The sensitivity of a test refers to the ability of the test to identify positive results in patients who actually have the disease (the true positive rate).8,9 Sensitivity assesses the proportion of true positives disclosed by the test (Table 1-2). A test is completely sensitive (100% sensitivity) if it is positive in every patient who actually has the disease. The higher the test sensitivity, the lower the chance of a false negative result; the lower the test sensitiv- FIGURE 1-1. Gaussian (random) value distribution ity, the higher the chance of a false negative result. However, with a visual display of the area included within a highly sensitive test is not necessarily a highly specific test increments of standard deviation (SD) above and below (see below). the mean: ±1 SD = 68% of total values; ±2 SD = 95% Highly sensitive tests are preferred when the consequences of not identifying the disease are serious; less sensitive tests of total values; and ±3 SD = 99.7% of total values. may be acceptable if the consequence of a false negative is less (Source: Reprinted with permission from Basic Skills in significant or if low sensitivity tests are combined with other Interpreting Laboratory Data, 6th edition.) tests. For example, inherited phenylalanine hydroxylase defi- ciency (phenylketonuria or PKU) results in increased phenyl- disease (ie, no signs or symptoms of disease) are included in alanine concentrations. High phenylalanine concentrations the sample population. Failure to control for physiologic vari- damage the central nervous system and are associated with ables (eg, age, gender, ethnicity, body mass, diet, posture, and intellectual developmental disorder. Intellectual disability is time of day) introduces factors that may result in an inaccurate preventable if PKU is diagnosed and dietary interventions reference range. Reference ranges calculated from nonrandomly are initiated before 30 days of age. The phenylalanine blood distributed (non-Gaussian) test results or from a small number screening test, used to screen newborns for PKU, is a highly of samples may not be accurate. sensitive test when testing infants at least 24 hours of age.10 In Reference ranges may change as new information relating contrast, the prostate specific antigen (PSA) test, a test com- to disease and treatments becomes available. For example, the monly used to screen men for prostate cancer, is highly specific generally accepted upper limit of normal for thyroid-stimulating but has low sensitivity, especially at low PSA cut-­off values of hormone (TSH) (4.12 milli-­international units per liter) is based 4–10 ng/mL.11 Thus, PSA cannot be relied on as the sole pros- on data from the National Health and Nutrition Examination tate cancer screening method. Survey (NHANES III).5 But the availability of more sensitive Sensitivity also refers to the range over which a quantitative assays and the recognition that the original reference popula- assay can accurately measure the analyte. In this context, a sen- tion data were skewed has led some clinicians to conclude that sitive test is one that can measure low levels of the substance; an the upper limit of normal for TSH should be lowered.6 In con- insensitive test cannot measure low levels of the substance accu- trast, recent data supports extending the upper limit of normal rately. For example, a digoxin assay with low sensitivity might for TSH for patients 80 years and older.7 measure digoxin concentrations as low as 0.7 ng/mL. Concen- trations below 0.7 ng/mL would not be measurable and would Critical Value be reported as “less than 0.7 ng/mL” whether the digoxin con- The term critical value refers to a result that is far enough outside centration was 0.6 ng/mL or 0.1 ng/mL. Thus, this relatively the reference range that it indicates impending morbidity (eg, insensitive digoxin assay would not differentiate between medi- potassium < 2.8 mEq/L). Because laboratory personnel are not cation nonadherence with an expected digoxin concentration of in a position to consider mitigating circumstances, a desig- zero and low concentrations associated with inadequate dosage nated member of the healthcare team is notified immediately regimens. Edwards_CH01.indd 6 17/03/22 12:04 PM  C HA P T E R 1 De f i n i t ion s a n d C oncept s  7 TABLE 1-2. Calculation of Sensitivity and Specificitya,b SCREENING TEST RESULT DISEASED NONDISEASED TOTAL Positive TP FP TP + FP Negative FN TN FN + TN Total TP + FN FP + TN TP + FP + FN + TN FN = diseased persons not detected by test (false negatives); FP = nondiseased persons positive to test (false positives); TN = nondiseased persons negative to test (true negatives); TP = diseased persons detected by test (true positives). a Sensitivity = [TP ÷ (TP + FN)] × 100%. b Specificity = [TN ÷ (FP + TN)] × 100%. Specificity blood (eg, blood gases, hemoglobin, hematocrit, complete blood count, and erythrocyte sedimentation rate). Specificity refers to the percent of correctly identified negative results in people without the disease (the true negative rate).8,9 Specificity assesses the proportion of true negatives disclosed LABORATORY TEST RESULTS by the test (Table 1-2); the lower the specificity, the higher the chance of a false positive result. A test with a specificity of 95% for the disease in question indicates that the disease Units Used in Reporting Laboratory Results will be detected in 5% of people without the disease. Tests with Laboratory test results are reported with a variety of units. For high specificity are best for confirming a diagnosis because the example, four different units are used to report serum magne- tests are rarely positive in the absence of the disease. Several sium concentration (1.0 mEq/L = 1.22 mg/dL = 0.5 mmol/L = newborn screening tests (eg, PKU, galactosemia, biotinidase 12.2 mg/L). Additionally, the same units may be reported in deficiency, congenital hypothyroidism, and congenital adrenal different ways. For example, mg/dL, mg/100 mL, and mg% are hyperplasia) have specificity levels above 99%.12 In contrast, equivalent units. Enzyme activity is usually reported in terms the erythrocyte sedimentation rate (ESR) is a nonspecific test; of units, but the magnitude varies widely and depends on the infection, inflammation, and plasma cell dyscrasias increase methodology. Rates are usually reported in volume per unit of the ESR. time (eg, creatinine clearance is measured in mL/min or L/hr), Specificity as applied to quantitative laboratory tests refers but the ESR is reported in mm/hr and coagulation test results are to the degree of cross-­reactivity of the analyte with other sub- reported in seconds or minutes. This lack of standardization is stances in the sample. Quinine may cross-­react with or be mea- confusing and may lead to misinterpretation of the test results. sured as quinidine in some assays, falsely elevating reported The International System of Units (Système Internationale quinidine concentrations. Phenazopyridine interferes with urine d’Unités, or SI) was created over 60 years ago to standardize ketone tests using sodium nitroprusside (eg, Ketostix). quantitative units worldwide.13 Seven base units and symbols are designated: length (meter, m), mass (kilogram, kg), time (sec- Specimen ond, s), electric current (ampere, A), thermodynamic tempera- A specimen is a sample (eg, whole blood, plasma, serum, urine, ture (kelvin, K), luminous intensity (candela, cd) and amount of stool, sputum, sweat, gastric secretions, exhaled air, cerebrospi- substance (mole, mol). Twenty-­two derived units are designated. nal fluid, or tissues) used for laboratory analysis. Whole blood However, it is difficult for clinicians to relate to molar concentra- contains all blood constituents (red blood cells, white blood cells, tions (eg, serum cholesterol 4.14 mmol/L versus 160 mg/dL or platelets, and plasma). Plasma is the watery acellular portion HbA1c 10 mmol/L versus 8%). In the United States, most labo- of blood. Plasma contains dissolved proteins (eg, albumin, ratory results are reported in conventional units. globulins, fibrinogen, enzymes, and hormones), electrolytes (eg, sodium, potassium, chloride, calcium, and magnesium), Rationale for Ordering Laboratory Tests lipids, carbohydrates, amino acids, and other organic substances Laboratory tests are performed with the expectation that the (eg, urea, uric acid, creatinine, bilirubin, ammonium ions). results will: Serum is the liquid that remains after the fibrin clot is removed Discover occult disease from plasma. While some laboratory tests are performed only Confirm a suspected diagnosis on plasma (eg, prothrombin time, activated partial throm- Differentiate among possible diagnoses boplastin time, d-­dimer, and fibrinogen concentrations) or Determine the stage, activity, or severity of disease serum (eg, albumin, creatinine, bilirubin, and acetaminophen concentrations), other laboratory tests can be performed on Detect disease recurrence either plasma or serum (eg, glucose, cortisol, electrolytes, and Assess the effectiveness of therapy phenytoin concentrations). Some tests are performed on whole Guide the course of therapy Edwards_CH01.indd 7 17/03/22 12:04 PM  8 BASIC SKILLS IN INTERPRETING LABORATORY DATA TABLE 1-3. Comparative Features of Screening and Diagnostic Laboratory Tests14 FEATURE SCREENING TEST DIAGNOSTIC TEST Simplicity of test Fairly simple More complex Target population Individuals without signs or symptoms of Individuals with signs or symptoms of the disease the disease Characteristic High sensitivity High specificity Disease prevalence Relatively common Common or rare Risks Acceptable to population Acceptable to individual Laboratory tests are categorized as screening or diagnostic Many laboratories group a series of related tests (screening tests. Screening tests, performed in individuals without signs and/or diagnostic) into a set called a profile. For example, the or symptoms of disease, detect disease early when interventions basic metabolic panel (BMP) includes common serum elec- (eg, lifestyle modifications, drug therapy, and surgery) are likely trolytes (sodium, potassium, and chloride), carbon dioxide to be effective. Screening tests are performed on healthy indi- content, blood urea nitrogen (BUN), calcium, creatinine, and viduals and are generally inexpensive, quick and easy to per- glucose. The comprehensive metabolic panel (CMP) includes form, and reliable, but they do not provide a definitive answer. the BMP plus albumin, alanine aminotransferase (ALT), aspar- Screening tests require confirmation with other clinical tests. tate aminotransferase (AST), alkaline phosphatase (ALP), total Diagnostic tests, performed on at-­risk individuals, are typically bilirubin, and total protein. Grouped together for convenience, more expensive, and are associated with some degree of risk, but some profiles may be less costly to perform than the sum of they provide a definitive answer. the cost of each individual test. However, profiles may gen- Comparative features of screening tests are listed in erate unnecessary patient data. Attention to cost is especially Table 1-3. Examples of screening tests include the Papanico- important in the current cost-­conscious era. A test should not laou smear, human papillomavirus (HPV) deoxyribonucleic be done if it is unnecessary, redundant, or provides suboptimal acid (DNA) test, lipid profile, PSA, fecal occult blood (FOB), clinical data (eg, non-­steady-­state serum drug concentrations). tuberculin skin test, human immunodeficiency virus (HIV) Before ordering a test, the clinician should consider the follow- antibody/HIV antigen test, sickle cell tests, fasting blood glu- ing questions: cose (FBG), blood coagulation tests, and serum chemistries. Was the test recently performed and in all probability the Screening tests may be performed on healthy outpatients (eg, results have not changed at this time? ordered by the patient’s primary care provider or performed Were other tests performed that provide the same during public health fairs) or on admission to an acute care information? facility (eg, prior to scheduled surgery). Abnormalities iden- Can the needed information be estimated with adequate reli- tified during screening are followed by more specific tests to ability from existing data? For example, creatinine clearance confirm the results. can be estimated using age, height, weight, and serum creati- Screening tests must be cost-­effective and population nine rather than measured from a 24-­hour urine collection. appropriate. The number needed to screen (NNS) is defined Serum osmolality can be calculated from electrolytes and as “the number of people that need to be screened for a given glucose rather than measured directly. duration to prevent one death or one adverse event.”15 For example, 2,726 women between the ages of 20 and 64 years What will I do if results are positive or negative? For example, need to be screened for cervical cancer to identify one woman if the test result will not aid in clinical decisions or change the with cancer.16 diagnosis, prognosis, or treatment course, the benefits from Diagnostic tests are performed in individuals with signs or the test are not worth the cost of the test. symptoms of disease, a history suggestive of a specific disease or disorder, or an abnormal screening test. Diagnostic tests Factors That Influence Laboratory Test Results are used to confirm a suspected diagnosis, differentiate among Laboratory results may be inconsistent with patient signs, possible diagnoses, determine the stage of activity of disease, symptoms, or clinical status. Before accepting reported labo- detect disease recurrence, and assess and guide the therapeutic ratory values, clinicians should consider the numerous labora- course. Diagnostic test features are listed in Table 1-3. Examples tory- and patient-­specific factors that may influence the results of diagnostic tests include serum human chorionic gonadotro- (Table 1-4). For most of the major tests discussed in this book, pin (HCG), B-­type natriuretic peptide (BNP), FeNO, blood cul- a Quickview chart summarizes information helpful in interpret- tures, serum cardiac-­specific troponin I and T, kidney biopsy, ing results. Figure 1-2 depicts the format and content of a typical and the cosyntropin test. Quickview chart. Edwards_CH01.indd 8 17/03/22 12:04 PM  C HA P T E R 1 De f i n i t ion s a n d C oncept s  9 Laboratory-Specific Factors TABLE 1-4. Factors That Influence Assessment of Laboratory errors are uncommon but may occur. Defined as Laboratory Results a test result that is not the true result, laboratory error most appropriately refers to inaccurate results that occur because of Assay used and form of analyte an error made by laboratory personnel or equipment. However, Free form laboratory error is sometimes used to refer to otherwise accurate results rendered inaccurate by specimen-­related issues. Labora- Bound form tory errors should be suspected for one or more of the follow- Clinical situation ing situations: Acuity of disease The result is inconsistent with trends in serial test results. Severity of disease The magnitude of error is great. The result is not in agreement with a confirmatory test result. Demographics The result is inconsistent with clinical signs or symptoms or Age other patient-­specific information. Gender True laboratory errors (inaccurate results) are caused by Ethnicity one or more laboratory processing or equipment errors, such as deteriorated reagents, calibration errors, calculation errors, Height misreading the results, computer entry or other documenta- Weight tion errors, or improper sample preparation. For example, incorrect entry of thromboplastin activity (International Sensi- Body surface area tivity Index [ISI]) when calculating the International Normal- Drugs ized Ratio (INR) results in accurately assayed but incorrectly reported INR results. Drug–drug interactions Accurate results may be rendered inaccurate by one or more Drug–assay interactions specimen-­related problems. Improper specimen handling prior Food to or during transport to the laboratory may alter analyte con- centrations between the time the sample was obtained from the Time of last meal patient and the time the sample was analyzed in the labora- Type of food ingested tory.17 For example, arterial blood withdrawn for blood gas anal- ysis must be transported on ice to prevent continued in vitro Nutritional status changes in pH, carbon dioxide, and oxygen. Failure to remove Well nourished the plasma or serum from the clot within 4 hours of obtaining blood for serum potassium analysis may elevate the reported Poorly nourished serum potassium concentration. Red blood cell hemolysis Posture elevates the serum potassium and phosphate concentrations. Upright ­Failure to refrigerate samples may cause falsely low concentra- tions of serum enzymes (eg, CK). Prolonged tourniquet time Supine may hemoconcentrate analytes, especially those that are highly Pregnancy protein bound (eg, calcium). Specimen analyzed Patient-Specific Factors Serum Laboratory test values cannot be interpreted in isolation of the patient. Numerous age-­related (eg, decreased renal function) Plasma and other patient-­specific factors (eg, time of day, posture) as Whole blood (venous or arterial) well as disease-­specific factors (eg, time course) affect lab results. The astute clinician assesses laboratory data in context of all that Cerebrospinal fluid is known about the patient. Urine Time course. Incorrectly timed laboratory tests produce mis- Stool leading laboratory results. Disease states, normal physiologic Sputum patterns, pharmacodynamics, and pharmacokinetics time courses must be considered when interpreting laboratory val- Other (eg, tissue, sweat, gastric contents, effusions, ues. For example, digoxin has a prolonged distribution phase. breath) Digoxin serum concentrations obtained before tissue distri- Temporal relationships bution is complete do not accurately reflect true tissue drug concentrations. Postmyocardial infarction enzyme patterns Time of day are complex and evolve over a prolonged period of time. For Time of last dose example, CK increases about 6 hours following myocardial Edwards_CH01.indd 9 17/03/22 12:04 PM  10 BASIC SKILLS IN INTERPRETING LABORATORY DATA QUICKVIEW | Contents of a typical Quickview chart PARAMETER DESCRIPTION COMMENTS Common reference ranges Adults Reference range in adults Variability and factors affecting range Pediatrics Reference range in children Variability, factors affecting range, age grouping Critical value Value beyond which immediate action Disease-­d ependent factors; relative to usually needs to be taken reference range; value is a multiple of upper normal limit Inherent activity Does substance have any physiologic Description of activity and factors affecting activity? activity Location Production Is substance produced? If so, where? Factors affecting production Storage Is substance stored? If so, where? Factors affecting storage Secretion/excretion Is substance secreted/excreted? If so, Factors affecting secretion or excretion where/how? Causes of abnormal values High Major causes Modification of circumstances, other related causes or drugs that are commonly Low Major causes monitored with this test Signs and symptoms High level Major signs and symptoms with a high or Modification of circumstances/other positive result related signs and symptoms Low level Major signs and symptoms with a low Modification of circumstances/other result related causes After event, time to… Initial elevation Minutes, hours, days, weeks Assumes acute insult Peak values Minutes, hours, days, weeks Assumes insult not yet removed Normalization Minutes, hours, days, weeks Assumes insult removed and nonpermanent damage Causes of spurious results List of common causes Modification of circumstances/assay specific Additional information Any other pertinent information regarding the laboratory value of assay FIGURE 1-2. Contents of a typical Quickview chart. (Source: Reprinted with permission from Basic Skills in Interpreting Laboratory Data, 6th edition.) Edwards_CH01.indd 10 17/03/22 12:04 PM  C HA P T E R 1 De f i n i t ion s a n d C oncept s  11 infarction (MI) and returns to baseline about 48–72 hours after Geriatric reference ranges are more difficult to establish the MI. Lactate dehydrogenase increases about 12–24 hours because of physiologic variability with increasing age and the following MI and returns to baseline about 10 days after the presence of symptomatic and asymptomatic disease states that MI. Troponin increases a few hours following MI and returns influence reference values. Dental problems and digestive issues to baseline in about 5–7 days. Serial samples are used to assess may lead to inadequate nutrition influencing some laboratory myocardial damage. tests. Some physiologic functions (eg, cardiac, pulmonary, Lab samples obtained too early or too late may miss crit- renal, and metabolic functions) progressively decline with age, ical changes and lead to incorrect assessments. For exam- but each organ declines at a different rate.18 Other physiologic ple, cosyntropin (synthetic adrenocorticotropic hormone changes associated with aging include decreased body weight, [ACTH]) tests adrenal gland responsiveness. The baseline 8 decreased height, decreased total body water, increased extracel- a.m. plasma cortisol is compared with the stimulated plasma lular water, increased fat percentage, and decreased lean tissue cortisol obtained 30 and 60 minutes following injection of the percentage; and loss of cell membranes integrity.18 Published drug. Incorrect timing leads to incorrect results. The sputum studies sometimes lead to contradictory conclusions due to dif- acid-­fast bacilli (AFB) smear may become AFB-­negative with ferences in study methodology (eg, single point versus longitu- just a few doses of antituberculosis drugs, but the sputum cul- dinal evaluations) and populations assessed (eg, nursing home ture may remain positive for several weeks. Expectations of residents versus general population). Little data is available for a negative sputum culture too early in the time course may the very elderly (≥ 90 years of age).19,20 Most laboratory reference lead to the inappropriate addition of unnecessary antituber- texts provide age-­specific reference values. culosis drugs. Despite the paucity of data and difficulties imposed by differ- Non-­steady-­state drug concentrations are difficult to inter- ent study designs and study populations, there is general con- pret; inappropriate dosage adjustments (usually inappropriate sensus that some laboratory reference ranges are unchanged, dosage increases) may occur if the clinician fails to recog- some are different but of uncertain clinical significance, and nize that a drug has not reached steady-­state concentrations. some are significantly different in the elderly (Table 1-5). For Although non-­steady-­state drug concentrations may be useful example, decreased lean muscle mass with increased age results when assessing possible drug toxicity (eg, overdose situations in decreased creatinine production. Decreased renal function and new onset adverse drug events), all results need to be inter- is associated with decreased creatinine elimination. Taken preted in the context of the drug’s pharmacokinetics. Absorp- together, the serum creatinine reference range in the elderly tion, distribution, metabolism, and elimination may change is not different from younger populations though creatinine with changing physiology. For example, increased/decreased clearance declines with age. Significant age-­related changes are hepatic or renal perfusion may affect the clearance of a drug. reported for the 2-­hour postprandial glucose test, serum lipids, Some drugs (eg, phenytoin) have very long half-­lives; constantly and arterial oxygen pressure (Table 1-5). The 2-­hour postpran- changing hemodynamics during an acute care hospitalization dial glucose increases by about 5–10 mg/dL per decade. Pro- may prevent the drug from achieving steady-­state while the gressive ventilation-­perfusion mismatching from loss of elastic patient is acutely ill. recoil with increasing age causes progressively decreased arte- Age. Age influences many physiologic systems. Age-­ related rial oxygen pressure with increasing age. Total cholesterol and changes are well-­described for neonates and young children, but LDL-­cholesterol (LDL-C) increase with age then decline in the less data is available for the elderly and the very elderly (usually very old. described as ≥ 90 years of age). Age influences some but not all Genetics, ethnicity, and gender. Inherited ethnic and/or gen- laboratory values; not all changes are clinically significant. der differences are identified for some laboratory tests. For Pediatric reference ranges often reflect physiologic imma- example, the hereditary anemias (eg, thalassemias and sick- turity, with laboratory values approaching those of healthy ling disorders such as sickle cell anemia) are more common adults with increasing age. For example, the complete blood in individuals with sub-Saharan African, Asian, and Medi- count (CBC) (hemoglobin, hematocrit, RBC count, and RBC terranean ancestry.28 Glucose-6-­ phosphate dehydrogenase indices) ranges are greatly dependent on age with different (G6PD) deficiency is an example of an inherited sex-­linked values reported for premature neonates, term neonates, and (X-­chromosome) enzyme deficiency found primarily in men young children. The fasting blood glucose reference range in of African, Asian, Middle Eastern, and Mediterranean ances- premature neonates is approximately 20–65 mg/dL compared try.29 The ­A-G6PD variant occurs mostly in Africans and with 60–105 mg/dL for children 2 years of age and older and affects about 13% of African-American males and 3% of Afri- 70–110 mg/dL for adults. The serum creatinine reference range can-American females in the United States. The Mediterra- for children 1–5 years of age differs from the reference range nean G6PD variant, associated with a less common but more for children 5–10 years of age (0.3–0.5 mg/dL versus 0.5– severe enzyme deficiency state, occurs mostly in individuals 0.8 mg/dL). Reference ranges for children are well-­described of Greek, Sardinian, Kurdish, Asian, and Sephardic Jewish because it is relatively easy to identify age-­differentiated popu- ancestry. lations of healthy children. Most laboratory reference texts pro- Other enzyme polymorphisms influence drug metabolism. vide age-­specific reference values. The genetically linked absence of an enzyme may lead to drug Edwards_CH01.indd 11 17/03/22 12:04 PM  12 BASIC SKILLS IN INTERPRETING LABORATORY DATA TABLE 1-5. Laboratory Testing: Tests Affected toxicity secondary to drug accumulation or lack of drug effect if by Aging18;20-27 the parent compound is an inactive prodrug (eg, codeine). The cytochrome P450 (CYP450) superfamily consists of greater than No Change 100 isoenzymes with selective but overlapping substrate speci- ficity. Some individuals are poor metabolizers while some are Amylase ultra-­rapid metabolizers. Several of the cytochrome P450 pheno- Lipase types vary by race. For example, the CYP2D6 poor metabolism phenotype occurs in 5%–10% of Caucasians and the CYP2C19 Hemoglobin poor metabolism phenotype occurs in 10%–30% of Asians.30,31 Hematocrit Additional enzyme polymorphisms include pseudocholines- terase deficiency, phenytoin hydroxylation deficiency, inefficient Red blood cell count N-­acetyltransferase activity, inefficient or rapid debrisoquine hydroxylase activity, diminished thiopurine methyltransfer- Red blood cell indices ase activity, partial dihydropyrimidine dehydrogenase inactiv- Platelet count ity, and defective uridine diphosphate glucuronosyl transferase activity.32 Other examples of genetic polymorphisms include White blood cell count and differential variations in the β-2 adrenoceptor gene that influence response Serum electrolytes (sodium, potassium, chloride, to sympathomimetic amines and variations in drug transporters bicarbonate, magnesium) such as P-­glycoprotein (P-­gp), multidrug resistance gene associ- ated proteins (MRP1, MRP2, MRP3), and organic anion trans- Coagulation porting peptide (OATP).32 Total iron binding capacity Biologic rhythms. Biologic rhythms are oscillatory (cyclical) temporal patterns of varying lengths. The master clock, located Thyroid function tests (thyroxine, T3RU) in the suprachiasmatic nucleus of the hypothalamus, coordi- Liver function tests (AST, ALT, LDH) nates timing signals and multiple peripheral clocks.33 A cir- cadian rhythm is an approximately 24-­ hour endogenously Some change (unclear clinical significance) generated cycle.34 Ultradian rhythms are shorter than 24-­hour; infradian rhythms are longer than 24-hour.35,36 Alkaline phosphatase Well-­described, human circadian rhythms include body Erythrocyte sedimentation rate temperature, cortisol production, melatonin production, and hormonal production. Platelet function, cardiac function, and Serum albumin cognition also follow a circadian rhythm.37 Other biologic Serum calcium rhythms include the 8-­hour rhythm for circulating endothe- lin, the approximately weekly (circaseptan) rhythm for urinary Serum uric acid 17-­ketosteroid excretion, and the seasonal rhythms for choles- Thyroid function tests (TSH, T3) terol and 25-­hydroxycholecalciferol.38,39 Statistically significant circadian rhythms have been reported Clinically significant change for CK, ALT, γ glutamyl transferase (GGT), LDH, and some serum lipids.40,41 Glomerular filtration has a circadian rhythm.42 Arterial oxygen pressure Circadian variations in aminoglycoside pharmacokinetics, 2-­hr postprandial glucose including netilmicin, amikacin, and gentamicin, have been reported.43 Though the clinical significance of diurnally vari- Serum lipids (total cholesterol, low-­d ensity lipoprotein, able laboratory results is not well understood, diurnal variability triglycerides) should be considered when assessing laboratory values. Obtain- Serum testosterone (in men) ing laboratory results at the same time of day (eg, ­routine 7 a.m. blood draws) minimizes variability due to circadian rhythms. Serum estradiol (in women) Different results obtained at different times of the day may be due to circadian variability rather than acute physiologic No change but clinically significant decrease in renal changes. function Drugs. The four generally accepted categories of drug–­ Serum creatinine laboratory interactions include methodological interference; drug-­induced end-­organ damage; direct pharmacologic effect; ALT = alanine aminotransferase; AST = aspartate aminotransferase; LDH = lactate dehydrogenase; TSH = thyroid-­s timulating hormone; and a miscellaneous category. Many drugs interfere with T3RU = triiodothyronine resin uptake; T3 = triiodothyronine. ­analytical ­methodology. Drugs that discolor the urine inter- fere with fluorometric, colorimetric, and photometric tests and Edwards_CH01.indd 12 17/03/22 12:04 PM  C HA P T E R 1 De f i n i t ion s a n d C oncept s  13 mask abnormal urine colors. For example, amitriptyline and relative hyponatremia (eg, serum sodium decreased by about propofol turn the urine a blue–green color, phenazopyridine 5 mEq/L) and modest decreases in hematocrit. The meta- and rifampin turn the urine an orange–red color, and doxoru- bolic adaptations to pregnancy include increased RBC mass bicin turns the urine red. Other drugs directly interfere with and altered carbohydrate (eg, 10%–20% decrease in fasting the laboratory assay. For example, high doses of ascorbic acid blood glucose) and lipid (eg, 300% increase in triglycerides (greater than 500 mg/day) cause false negative stool occult (TG) and a 50% increase in total cholesterol) metabolism. blood tests. Some drugs interfere with urinary fluorescence Pregnancy changes the production and elimination of thy- tests for urine catecholamines by producing urinary fluores- roid hormones, resulting in different reference values over cence themselves (eg, ampicillin, chloral hydrate, and eryth- the course of pregnancy.47 For example, thyroxine-­binding romycin). Monoclonal antibodies interfere with a variety of globulin increases during the first trimester, but pregnancy-­ laboratory tests.44 For example, daratumumab (Darzalex) FDA-­ associated accelerated thyroid hormone metabolism occurs approved in 2015 for treatment of multiple myeloma, interferes later in the pregnancy. Other physiologic changes during with indirect antiglobulin tests (indirect Coombs test), serum pregnancy include an increased cardiac output (increases by protein electrophoresis (SPE), and immunofixation electro- 30%–50%), decreased systemic vascular resistance, increased phoresis (IFE) assays.45 Omalizumab (Xolair) complexes with glomerular filtration rate (increases by 40%–50%), shortened immunoglobulin E (IgE) elevating serum total IgE for up to a prothrombin and partial thromboplastin times, and hyper- year following administration.46 ventilation resulting in compensated ­respiratory alkalosis and Direct drug-­induced, end-­organ damage (eg, kidney, liver, increased arterial oxygenation.48 and bone marrow) change the expected laboratory results. For example, amphotericin B causes renal damage evidenced Other Factors by increased serum creatinine. Bone marrow suppressants, Organ function, diet, fluid status, patient posture, and altitude such as doxorubicin and bleomycin, cause thrombocytopenia. affect some laboratory tests. Some drugs alter laboratory results as a consequence of a direct pharmacologic effect. For example, thiazide and loop diuretics Organ Function increase serum uric acid by decreasing uric acid renal clear- Renal dysfunction may lead to hyperkalemia, decreased creati- ance or tubular secretion. Narcotics, such as codeine and mor- nine clearance, and hyperphosphatemia. Hepatic dysfunction phine sulfate, increase serum lipase by inducing spasms of the may lead to reduced clotting factor production with prolonged sphincter of Oddi. Urinary specific gravity is increased in the partial thromboplastin times and prothrombin times. Bone presence of dextran. Other examples of drug–laboratory inter- marrow dysfunction may lead to pancytopenia. actions include drugs that cause a positive direct Coombs test (eg, isoniazid, sulfonamides, and quinidine), drugs that cause a Diet positive antinuclear antibody test (eg, penicillins, sulfonamides, Serum glucose and lipid profiles are best assessed in the fasting and tetracyclines), drugs that interfere with the C-­urea breath state. Unprocessed grapefruit juice down-­regulates intestinal test (eg, proton pump inhibitors), and drugs that inhibit bacte- CYP3A4 and increases the bioavailability of some orally admin- rial growth in blood or urine cultures (eg, antibiotics). istered drugs. Thyroid function tests are a good example of the complex- Fluid Status ity of potential drug-­induced laboratory test changes. Thyrox- ine (T4) and triiodothyronine (T3) are displaced from binding Hypovolemia is associated with a decreased amount of fluid proteins by salicylates, heparin, and high-­doses of furosemide. in the bloodstream; all blood constituents (eg, sodium, potas- Free T4 levels initially increase, but chronic drug administration sium, creatinine, glucose, and BUN) become more concen- results in decreased T4 levels with normal TSH levels. Phenytoin, trated. This effect is called hemoconcentration. Although the phenobarbital, rifampin, and carbamazepine stimulate hepatic absolute amount of the substance in the body has not changed, metabolism of thyroid hormone, resulting in decreased serum the loss of fluid results in an abnormally high concentration of hormone concentration. Amiodarone, high-­dose β-­adrenergic the measured analyte. The converse is true with hemodilution. blocking drugs, glucocorticosteroids, and some iodine contrast Relativity must be applied or false impressions may arise (refer dyes interfere with the conversion of T4 to T3. Ferrous sulfate, to Minicase 2). aluminum hydroxide, sucralfate, colestipol, and cholestyramine Posture decrease T4 absorption. Somatostatin, octreotide, and glucocor- Plasma renin release is stimulated by upright posture, diuret- ticosteroids suppress TSH production. ics, and low-­sodium diets; plasma renin testing usually occurs Pregnancy. Pregnancy is a normal physiologic condition that after 2–4 weeks of normal sodium diets under fasting supine alters the reference range for many laboratory tests. Nor- conditions. mal pregnancy increases serum hormone concentrations (eg, e­strogen, testosterone, progesterone, human chorionic Altitude gonadotropin, prolactin, corticotropin-­ releasing hormone At high altitude, hemoglobin initially increases secondary to (CRH), ACTH, cortisol, and atrial natriuretic hormone). dehydration. However, hypoxia stimulates erythropoietin The plasma volume increases by 30%–50%, resulting in a production, which in turn stimulates hemoglobin production, Edwards_CH01.indd 13 17/03/22 12:04 PM  14 BASIC SKILLS IN INTERPRETING LABORATORY DATA MINICASE 2 Interpretation of Laboratory Parameters in Dehydration Christopher, a 67-­year-­old male with a long history of asthma, clearance is less than 50 mL/min. The manufacturer provides dosing presented to the emergency department (ED) with a one-­day recommendations based on estimated creatinine clearance using history of sudden onset fever, chills, dry cough, nasal congestion, the Cockcroft Gault equation. Is it appropriate to use Christopher’s muscle aches, fatigue, nausea, and diarrhea. On admission to the admission creatinine to estimate his creatinine clearance? ED, his temperature was 100.4°F (oral) and he was hypotensive and DISCUSSION: No. Christopher is severely dehydrated; all tachycardic with decreased skin turgor and dry mucus membranes. laboratory parameters are hemoconcentrated. His admission A BMP and CBC were ordered. The BMP was notable for elevated serum creatinine is high and underestimates his renal function. serum electrolytes, BUN, and serum creatinine. The BUN to The regimen for patients with estimated creatinine clearance at creatinine ratio was greater than 20 to 1. The CBC was notable least 50 mL/min is a one-­time 600 mg dose. Given that Christopher for an elevated white blood cell (WBC) count with an increased has two risk factors for influenza complications (age ≥ 65 y and percentage of lymphocytes and elevated platelets, hematocrit, and chronic pulmonary disease), the peramivir (Rapivab) dose needs to hemoglobin. A rapid influenza diagnostic test was positive. Fluid be optimal. The best approach is to recheck the serum creatinine resuscitation and peramivir (Rapivab) were ordered. after the couple of hours of rehydration, and then estimate the QUESTION: Peramivir (Rapivab) is dosed according to renal creatinine clearance. function. Dose reduction is required if the estimated creatinine resulting in increased hemoglobin concentration and increased The major advantages of POC testing include reduced turn- blood viscosity. Physiologic changes depend on altitude and around time (TAT) and test portability.53 Reduced TAT is espe- duration of exposure. Serum hemoglobin reference ranges are cially advantageous in settings where rapidly available laboratory adjusted progressively upward for individuals living 1000 m or test results may improve patient care (eg, emergency depart- more above sea level.49 ments, operating rooms, critical care units, accident scenes, and patient transport). Reduced TAT also enhances patient care in more traditional ambulatory settings by reducing patient and NONCENTRALIZED provider time and minimizing delays in initiating therapeutic LABORATORY TESTS interventions. Patient care sites without local access to central- ized laboratories (eg, nursing homes, rural physician practices, and military field operations) also benefit from POC testing. Point-­of-Care Testing Other POC advantages include blood conservation (POC tests Point-­of-­care (POC) testing (POCT), also known as near patient usually require drops of blood as opposed to the several millili- testing, bedside testing, or extra-laboratory testing, is clinician-­ ters required for traditional testing); less chance of preanalyti- directed diagnostic testing performed at or near the site of cal error from inappropriate transport, storage, or labeling of patient care rather than in a centralized laboratory.50 Typically, samples; and overall cost savings. Although the per test cost is nonlaboratory healthcare personnel (eg, pharmacists, physi- usually higher with POC testing, cost analyses must consider the cians, physician assistants, nurses, nursing assistants, respira- per unit cost of the test as well as other costs such as personnel tory therapists, and paramedics) perform POC testing. POC test time, length of stay, and quality of life. equipment ranges from small, hand-­held devices to table-­top The major disadvantages of POC testing include misuse or analyzers. In vitro, in vivo, and ex vivo POC testing refer to tests misinterpretation of results, loss of centrally-­generated epide- performed near the patient (eg, fingerstick blood glucose), in miologic data, documentation errors, inappropriate test mate- the patient (eg, specialized intra-­arterial catheter that measures rial disposal, and quality assurance issues.53 All laboratory lactate), and just outside the patient (eg, intra-­arterial catheter testing must meet the minimum standards established by the attached to an external analyzer), respectively. Although POC Clinical Laboratory Improvement Amendments of 1988 (CLIA- testing is not a new concept, recent technological advances 88).54 Under CLIA-88, tests are categorized into one of three (eg, microcomputerization, miniaturization, biosensor devel- groups based on potential public health risk: waived tests, tests opment, and electrochemical advances) and apps enabled by of moderate complexity, and tests of high complexity. Waived smart phones, smart watches (wearable testing), and tablets tests (eg, fecal occult blood test) pose no risk of harm to the have rapidly expanded the variety of available POC tests beyond patient if used incorrectly or use such simple and accurate the traditional urinalysis dipsticks or fingerstick blood glucose methodologies that inaccurate results are unlikely. Many POC monitors.51 The availability of multiplexed point-­of-­care testing tests meet the criteria for waived status but increasingly sophis- (xPOCT), defined as the simultaneous detection of more than ticated POC tests may be subject to more stringent control. one analyte from a single specimen, will expand as technology State-­specific regulations may be more stringent than ­federal advances.52 regulations. Edwards_CH01.indd 14 17/03/22 12:04 PM  C HA P T E R 1 De f i n i t ion s a n d C oncept s  15 Home Testing Baseline Results Home testing refers to patient-­directed diagnostic and monitor- Baseline studies establish relativity and are especially useful ing testing usually performed by the patient or family member when reference ranges are wide or when reference values vary at home. Numerous FDA-­approved, home-­use, nonprescription significantly among patients. For example, lovastatin and other laboratory test kits are marketed; home glucose and pregnancy hydroxymethyl glutaryl coenzyme A (HMG CoA) reductase testing are among the most popular. The FDA’s Office of In Vitro inhibitors cause myopathy and liver dysfunction in a small Diagnostics and Radiological Health (OIR) maintains a search- percentage of patients. The myopathy is symptomatic (muscle able list of approved home-­testing kits. Many non-FDA-­approved pain or weakness) and elevates CK concentrations. The drug-­ home testing kits are marketed via the Internet. induced liver dysfunction is asymptomatic and causes elevated Nonprescription home testing kits are available for the AST and ALT. FDA labeling for statins recommends obtain- screening, detection, and monitoring of a wide range of medi- ing liver function tests before starting therapy then as clinically cal conditions. Home testing laboratory test kits are marketed indicated.55 Baseline laboratory values are also used to estab- for pregnancy (HCG), menopause (follicle stimulating hormone lish relative therapeutic goals. For example, the activated partial [FSH]), ovulation (luteinizing hormone [LH]), drugs of abuse, FOB, breath alcohol, blood glucose, HbA1c, ketones, prothrom- thromboplastin time (aPTT) is used to assess patient response bin time (PT), carcinoembryonic antigen (CEA), PSA, allergies, to heparin anticoagulation. Therapeutic targets are expressed in thyroid hormones, estrogen, testosterone, urinary tract infec- terms of how much higher the patient’s aPTT is compared with tions, sexually transmitted infections, group A Streptococcus the baseline control. infection, HIV, hepatitis C, Lyme disease, and paternity and genetic testing. Specimens tested include urine, blood, hair, Laboratory Value Compared with breath, feces, semen, saliva, and oropharyngeal secretions. Reference Range Advantages of home testing include convenience, cost-­­savings Not all laboratory values above the upper limit of normal (ULN) (as compared with physician office visit), quickly available results, require intervention. Some elevations may be transient and and privacy. Home monitoring of chronic drug therapy, such as resolve with continued drug administration. Risk-­to-­benefit blood glucose control with insulin therapy, may give the patient considerations may require that some evidence of drug-­induced a better sense of control over the disease and improve patient organ damage is acceptable given the ultimate benefit of the outcomes. Disadvantages of home testing include misinterpreta- drug. For example, a 6-­month course of combination drug tion of test results, delays in seeking medical advice, and lack of therapy, including isoniazid, a known hepatotoxin, is recom- pre- and posttest counseling and psychological support. In addi- mended for treatment of latent tuberculosis.56 The potential tion, home test kits typically do not provide the consumer with benefit of at least 6 months of therapy (ie, lifetime protection information regarding sensitivity, specificity, precision, or accu- racy. Home-­use test kits are marketed either as complete test kits from tuberculosis in the absence of reinfection) means that clini- (the individual obtains his or her own sample, tests the sample cians are willing to accept some evidence of liver toxicity with and reads the results) or as collection kits (the individual obtains continued drug therapy (eg, isoniazid is continued until AST is the sample, mails the sample to the laboratory, and receives the greater than five times the ULN in asymptomatic individuals or results by mail, Internet, or telephone). Consumers should read greater than three times the ULN in symptomatic patients).57 and follow the test instructions to minimize testing error. Rate of Change The rate of change of a laboratory value provides the clinician GUIDELINES FOR INTERPRETING with a sense of risks associated with the particular signs and LABORATORY RESULTS symptoms. For example, a patient whose RBC count falls from 5 million/mm3 to 3.5 million/mm3 over several hours is more Laboratory results must be interpreted in context of the patient likely to need immediate therapeutic intervention than if the and the limitations of the laboratory test. However, a laboratory decline took place over several months. result is only one piece of information; diagnostic and therapeu- tic decisions cannot be made on the basis of one piece of infor- Isolated Results Versus Trends mation. Clinicians typically give more weight to the presence or absence of signs and symptoms associated with the medical An isolated abnormal test result is difficult to interpret. However, problem rather than to an isolated laboratory report. For example, one of several values in a series of results or similar results from an asymptomatic patient with a serum potassium concentration the same test performed at two different times suggests a pattern of 3.1 mEq/L (reference range: 3.5–5.0 mEq/L) does not cause as or trend. For example, a random serum glucose concentration of much concern as a patient who has a potassium concentration 300 mg/dL (reference range ≤ 200 mg/dL in adults) might cause of 3.3 mEq/L and is symptomatic. Tests for occult disease, such concern unless it was known that the patient was admitted to as colon cancer, cervical cancer, and hyperlipidemia, are excep- the hospital the previous night for treatment of diabetic ketoaci- tions to this logic because, by definition, the patients being tested dosis with an admission random serum glucose of 960 mg/dL. are asymptomatic. Baseline results, rate of change, and patterns A series of laboratory values adds perspective to an interpreta- should be considered when interpreting laboratory results. tion but may increase overall costs. Edwards_CH01.indd 15 17/03/22 12:04 PM  16 BASIC SKILLS IN INTERPRETING LABORATORY DATA Spurious Results do not have access to patient laboratory data. Though lack of A spurious laboratory value is a false laboratory value. The only access to laboratory data is currently a barrier, the increasing way to differentiate between an actual and a spurious laboratory use of electronic health records will improve pharmacist access value is to interpret the value in context of what else is known to patient laboratory data. about the patient. For example, a serum potassium concen- tration of 5.5 mEq/L (reference range: 3.5–5.0 mEq/L) in the SUMMARY absence of significant electrocardiographic changes (ie, wide, flat P waves, wide QRS complexes, and peaked T waves) and Clinical laboratory tests are convenient methods to investigate risk factors for hyperkalemia (ie, renal insufficiency) is most disease- and drug-­related patient issues, especially since knowl- likely a spurious value. Possible causes of falsely elevated potas- edge of pathophysiology and therapeutics alone is insufficient sium, such as hemolysis, acidosis, and laboratory error, have to provide high-­quality clinical considerations. This chapter to be ruled out before accepting that the elevated potassium should help clinicians appreciate general causes and mecha- accurately reflects the patient’s actual serum potassium. Repeat nisms of abnormal test results. However, results within the refer- testing of suspected spurious laboratory values increases the ence range are not always associated with a lack of signs and cost of patient care but may be necessary to rule out an actual symptoms. Many factors influence the reference range. Knowing abnormality. the sensitivity, specificity, and predictive value is important in selecting an assay and interpreting its results. Additionally, FUTURE TRENDS an understanding of the definitions, concepts, and strategies discussed should also facilitate mastering information in the Point-­of-­care testing will progress and become more widely following chapters. available as technological advances produce smaller and more portable analytical devices. Real-­time, in vivo mobile and wearable POC testing may become standard in many patient LEARNING POINTS care areas. Laboratory test specificity and sensitivity will improve with more sophisticated testing. Genetic testing (laboratory 1. What factors should be considered when assessing a lab- analysis of human DNA, RNA, chromosomes, and proteins) will oratory parameter that is outside the reference range? undergo rapid growth and development in the next few decades; ANSWER: The upper and lower limits of the reference range genetic testing will be increasingly used to predict an individual’s are not absolute; by definition, some normal results fall outside risk for disease, identify carriers of disease, establish diagnoses, the reference range. Other factors to consider include the sen- and provide prognostic data. Genetic links for a diverse group of sitivity and specificity of the test, the critical value for the test, diseases including cystic fibrosis, Down syndrome, Huntington the acuity of the change, drug-­drug and drug-­test interactions, disease, breast cancer, Alzheimer disease, schizophrenia, PKU, patient signs and symptoms, laboratory error, specimen han- and familial hypercholesterolemia are established; genetic links dling, patient age, and the timing of the test. for many additional diseases will be established. Variations in DNA sequences will be well-­described and linked to individu- 2. What factors should be considered when assessing labo- alized disease management strategies.58 Nanobiosensor-­based ratory parameters in a pregnant patient? POC technology is being developed for the detection, diagnosis, ANSWER: Physiologic changes during pregnancy, including and monitoring of medical conditions such as cancer, diabetes, increased plasma volume, increased RBC mass, altered carbohy- and HIV.59 Advances in array-­based technologies (ie, simultane- drate and lipid metabolism, serum hormone changes, increased ous evaluation of multiple analytes from one sample) will reduce cardiac output, increased glomerular filtration rates, and acid-­ sample volume and cost. base alterations, result in different laboratory reference ranges.