Other CP Flashcards Preview

Pathology > Other CP > Flashcards

Flashcards in Other CP Deck (82):
1

___ testing is performed on all amniotic fluids having elevated AFP concentrations.

AChE testing is performed on all amniotic fluids having elevated AFP concentrations. The odds of having a fetus with a NTD are considerably greater if both the AFP is elevated and the AChE is positive.

2

Antiphospholipid antibody syndrome.

APS is a common cause of acquired thrombophilia defined by venous or arterial thromboembolism and/or obstetric complications and the presence of antiphospholipid antibodies detected in patient plasma. APAs are acquired autoantibodies directed against phospholipid-protein complexes. Currently recognized laboratory criteria for APS include lupus anticoagulant (LA), IgG or IgM anticardiolipin (aCL) antibodies, or IgG or IgM anti-beta-2 glycoprotein I antibodies (anti-B2GPI). Lupus anticoagulants are IDd by clot-based coagulation tests, whereas aCL and anti-B2GPI Abs are IDd by ELISA. Abs should be demonstrable on at least 2 occasions separated by 12 weeks (this is to exclude transient APAs, which are often secondary to intercurrent infection or other acute illness). Despite the prolongation in clotting times in patients with LA Abs, APS is mostly a prothrombotic disorder and bleeding is uncommon. LAs prolong phospholipid-dependent coagulation tests due to antagonism of reagent phospholipids. The prolongation of clotting times is a laboratory phenomenon due to limited phospholipid in the test reagents. Among APAs, LA positivity carries the strongest risk for thromboembolic events or pregnancy morbidity.

3

Androgen receptor.

The androgen receptor is a nuclear receptor that localizes to the nucleus following phosphorylation and dimerization promoted by ligand binding, where it functions as a transcription factor.

4

List some antiplatelet agents and their mechanisms of action.

Antiplatelet agents include aspirin, clopidogrel (Plavix), prasugrel (Effient), ticagrelor (Brilinta), and glycoprotein IIbIIIa inhibitors. Are indicated for many conditions in which platelet aggregation leads to arterial thrombosis, such as MI, angina, stroke, diabetes in those over age 30, and PAD. Aspirin blocks thromboxane A2 synthesis irreversibly. Clopidogrel, prasugrel, and ticagrelor produce inhibition of platelet ADP receptors. The IV drugs abciximab (Reopro), eptifibatide (Integrilin), and tirofiban (Aggrastat) block glycoprotein IIbIIIa receptors.

5

Cancer-associated myositis?

Dermatomyositis is more frequent than polymyositis. Greater risk in males than females, age >60 years old. Patients with myositis and cancer tend to have more severe weakness and rashes, lower levels of serum creatine kinase, and higher ESRs. The MC associated malignancies are adenocarcinomas of the lungs, breast, GI tract, and ovaries, as well as lymphoma.

6

Chlamydia trachomatis serovars.

There are 18 known serovars. Serovars A, B, Ba, and C usually cause trachoma. Serovars D-K are usually sexually transmitted. Serovars L1-L3 are the causative agents of lymphogranuloma venereum.

7

Dermatomyositis?

Has a peak age of onset of 7 years in children and 30-50 years in adults. Relatively more frequent in children than adults. Is characterized by mild to moderate weakness, and more common in children are dystrophic calcifications, cutaneous and GI ulcerations, and lipodystrophy. 5 year survival in adult dermatomyositis is 75-90% and in juvenile dermatomyositis is >95%. Initial immune processes include activation of the complement cascade through C3 and deposition of the complement C5b-9 membrane attack complex on the endomysial vasculature, with resultant capillary destruction, muscle ischemia, and dilatation of the remaining capillaries. These processes lead to infiltration of B lymphocytes, CD4 helper T cells, and plasmacytoid dendritic cells in perimysial areas of muscle fascicles and in small blood vessels. The MHC class I antigen and intracellular adhesion molecules are upregulated on the cell surfaces of damaged fibers and in perivascular areas, respectively.

8

EGFR protein.

EGFR is a transmembrane tyrosine kinase that belongs to the HER/ErbB protein family. Ligand binding results in receptor dimerization, autophosphorylation, activation of downstream signaling, and internalization. The adaptor protein GRB2 binds activated EGFR phosphorylated at Tyr1068; this binding is necessary for the stimulation of EGFR-induced Ras/MAPK signaling.

9

Ethylene glycol (1,2-ethanediol), isopropyl alcohol (isopropanol), methanol (wood alcohol). Anion gap? Osmolal gap? What enzyme metabolizes it into what metabolites?

Ethylene glycol: anion gap acidosis +, osmolal gap +, no increase in ketones. Metabolized by alcohol dehydrogenase initially into glycolic acid, then to oxalate. The glycolic acid is responsible for the CNS manifestations and for the anion gap acidosis. The oxalate binds calcium to produce calcium oxalate, which is deposited in tissues and can be found in renal tubules and urine. Methanol: anion gap acidosis +, osmolal gap +, no increase in ketones. Metabolized by alcohol dehydrogenase to formaldehyde then formic acid. These metabolites result in ocular toxicity and the anion gap acidosis. Isopropyl alcohol: no anion gap acidosis, osmolal gap +, no increase in ketones. Is metabolized to acetone. Ethanol will have -/+ anion gap acidosis, osmolal gap +, and -/+ increase in ketones. Direct laboratory tests for methanol and ethylene glycol are not widespread, so the osmolal gap is a surrogate marker; ingestion is suspected if the osmolal gap exceeds 10, and is strongly suspected if it exceeds 20.

10

Hemoglobin makes up approximately (#)% of the cytoplasmic protein in a RBC. Hemoglobin is composed of (#) alpha-globins and (#) non-alpha-globins that are conjugated to (#) heme molecules that each contain (#) iron atom. Each hemoglobin molecule is capable of reversibly binding and transporting (#) oxygen molecues.

Hemoglobin makes up approximately 98% of the cytoplasmic protein in a RBC. Hemoglobin is composed of 2 alpha-globins and 2 non-alpha-globins (usually beta-globin in adults) that are conjugated to 4 heme molecules that each contain 1 iron atom. Each hemoglobin molecule is capable of reversibly binding and transporting 4 oxygen molecues.

11

HER2 gene.

Cell membrane surface-bound receptor TK, encoded by HER2/neu, a proto-oncogene. The gene is on 17q21-q22. HER2, neu, and ErbB-2 are all the same gene.

12

Human cases caused by the following domestic arboviruses are nationally reportable to the CDC:

West Nile, St. Louis encephalitis, Powassan, eastern equine encephalitis, western equine encephalitis, and California serogroup viruses (i.e., La Crosse, Jamestown Canyon, California encephalitis, Keystone, snowshoe hare, and trivittatus).

13

Idiopathic inflammatory myopathies or myositis syndromes?

The most common forms are polymyositis, dermatomyositis, and inclusion body myositis.

14

In prenatal screening tests, what is included in the first trimester panel and second trimester panel?

The first trimester panel includes total or free beta-hCG, PAPP-A (Pregnancy Associated Placental Protein-A), and NT (Nuchal Translucency). The second trimester panel can be a quadruple panel or a triple panel. The quadruple panel includes MSAFP (Maternal Serum Alpha-FetoProtein), uE3 (unconjugated estriol), beta-hCG, and DIA (Dimeric Inhibin-A). The triple panel is the quadruple panel minus the DIA.

15

In testing for lupus anticoagulant, what aspects of blood collection and processing must be paid attention to?

Anticoagulant meds such as heparin, direct thrombin inhibitors, and vitamin K antagonists such as warfarin can interfere with LA testing due to their effects on coagulation assays. Heparin and DTIs are of particular concern b/c they prolong phospholipid-dependent coagulation tests and behave as inhibitors in mixing studies, potentially mimicking an LA. A thrombin time, or other means of IDing heparin, should be routinely performed on test plasma to ID the presence of heparin or DTIs. The commercial dilute Russell viper venom time reagents used for LA testing contain heparin neutralizers; however, if the content of heparin in the test plasma exceeds the reagent neutralization capacity (typically greater than 0.8-1.0 U/mL), it can give rise to a false-positive LA result. Activated partial thromboplastin time reagents generally do not neutralize heparin. LMW heparin has less effect on LA testing than unfractionated heparin. In general, blood for LA testing should be collected before starting anticoagulant drugs or after their discontinuation. For vitamin K antagonists, wait 1-2 weeks after discontinuation or until the INR is <1.5. For processing, double centrifugation is recommended to ensure that the plasma is platelet-poor, b/c contaminating platelets can neutralize the Abs, resulting in a false-negative result. Plasma filtration introduces variables such as loss of VW factor and is not recommended. To prevent the loss of coagulation factors, the plasma should be tested or frozen as quickly as possible following collection. The sample should be thawed at 37 C for 5 minutes to avoid formation of cryoprecipitate and mixed thoroughly before testing.

16

Inclusion body myositis?

Is seen mainly in older white males. Is characterized by slowly progressive weakness primarily involving the quadriceps and finger flexors, rapid development of muscle atrophy, and dysphagia. 5 year survival is 100%, but there is much functional disability. Immune processes include a predominant cytotoxic T lymphocyte mediated process involving perforin, with CD8 T cells accompanied by smaller numbers of macrophages surrounding and invading otherwise normal-appearing myocytes in endomysial areas. The MHC class I antigen is upregulated on the surface of the majority of muscle fibers, even those not affected by inflammation. These immune processes are the same as in polymyositis.

17

Indirect and direct measurements of serum sodium.

Most modern high-throughput analyzers use indirect ion-selective electrodes to estimate electrolyte concentrations in serum samples. This analysis is preceded by a dilution step of the sample. If the water concentration is altered by the presence of increased lipid or protein, the dilution step and subsequent calculation of concentration by the analyzer results in a falsely low sodium value. Other indirectly measured analytes, such as potassium, calcium, and chloride, are subject to the same effects as sodium. Although the relative effect on all aqueous solutes is the same, the absolute change in sodium is far greater in view of its higher concentration in serum. With the use of indirect sodium measurement of routine analysis, measurements using a direct-reading ISE (direct potentiometry) should be undertaken under the following circumstances: 1) If the specimen is overtly lipemic or hyperviscous. However, correlation between visual turbidity and the concentration of triglycerides is poor. 2) If there is a significant discrepancy between measured osmolality and calculated osmolality. 3) Any low sodium in a patient with DM and hyperglycemia (pseudohyponatremia secondary to associated hyperlipidemia, in these patients, should be differentiated from true hyponatremia secondary to the positive osmotic effects of hyperglycemia). If a direct-reading instrument is not available, the serum water fraction can be calculated by the equation: serum water fraction = {99.1 - (0.001 x lipid concentration in mg/dL) - (0.7 x protein concentration in g/dL)} / 100 and then used in the equation: corrected sodium value = (indirect sodium value x 0.93) / calculated serum water fraction.

18

Lineweaver-Burke plots, competitive inhibition, noncompetitive inhibition, uncompetitive inhibition.

Lineweaver-Burke plots are a means to express a non-linear asymptotic concept (how the rate of the reaction varies with the substrate concentration) in a linear fashion by using the reciprocals of substrate concentration (1/[S]) and reaction rate (1/v). The x intercept is -1/Km, the y intercept is 1/Vmax, and the slope is Km. In competitive inhibition, the enzyme's substrate and the inhibitor compete for the same binding site. This type of inhibition can be overcome by increasing substrate concentration. On the Lineweaver-Burke plot, the y intercept is unchanged and the slope is increased. In noncompetitive inhibition, the inhibitor binds the enzyme at a different site from the substrate binding site, effectively decreasing the amount of useful enzyme without affecting the binding of substrate to enzyme. On the Lineweaver-Burke plot, the Km (a function of binding) is unaffected, but the reaction rate decreases. In uncompetitive inhibition, the inhibitor binds and stabilizes the enzyme-substrate complex. On the Lineweaver-Burke plot, the Km is decreased (can't bind enzyme if it's in a stable complex), and the Vmax is decreased (product can't be formed if the substrate and enzyme are stuck together).

19

Microscopic examination of stool for WBCs?

Microscopic examination of a nonconcentrated wet or stained preparation is the traditional means for identifying and quantifying WBCs in fresh or fixed stool. The test can produce false-negative results if the WBCs have degenerated. Prolonged transportation time, collection of stool a on swab, and storage at room temperature can all negatively affect morphology. WBCs can also be lysed by toxin-producing organisms such as C. difficile. Fecal lactoferrin can be used in place of, or in addition to, a traditional slide exam. Fecal lactoferrin is an iron-binding glycoprotein found in the secondary granules of neutrophils and is therefore an alternative marker of fecal PMNs. This compound remains stable in feces despite leukocyte deterioration. Commercially available fecal lactoferrin antigen detection methods are rapid, accurate, and easy to perform. However, the tests are not quantitative, so microscopic examination is still needed to quantify fecal leukocytes. Lactoferrin is present in mother's milk and the test can be positive in nursing infants who do not have intestinal inflammation.

20

Monitoring patients on LMW heparin.

Because LMW heparin is more predictable in its effect, typically no monitoring is done. Notable exceptions are for obesity and low body mass, impaired renal function, pregnancy, and for patients on long-term therapy. In these cases, monitoring is done with the anti-factor Xa assay, using a target of 0.5-1 U/mL. Another important indication for monitoring is a pregnant patient previously on warfarin. Since warfarin causes birth defects, these women are switched to LMW heparin. However, as the fetus grows, it metabolizes LMW heparin faster than the mother, so the dose must often be increased as the pregnancy progresses.

21

Oncotype DX (Genomic Health Inc.), MammaPrint (Agendia), Mammostrat (Clarient). How do they work?

Oncotype DX is a real-time RT-PCR assay measuring RNA expression in 16 cancer-related genes and five reference genes, using paraffin-embedded tissue. Results are given as a recurrence score between 0 and 100, which are translated as low risk (a score of 18 or lower), medium risk (19 to 30), or high risk (31 or above). MammaPrint microarray measures expression of 70 genes in fresh or FFPE tissue; it categorizes patients as either high risk, (a so-called poor signature), or low risk (a so-called good signature) for recurrence. Mammostrat is an IHC test measuring five markers: p53, HTF9C, CEACAM5, NDRG1, and SLC7A5. The results are combined into a quantitative risk index: low, moderate, and high. Oncotype DX and MammaPrint are send-out tests, with TATs of 10-14 days, while results from the IHC-based Mammostrat, also a send-out test, are available to local pathologists within 48-72 hours. As of 3/2014, only MammaPrint has FDA clearance.

22

Plasmapheresis vs. plasma exchange?

In plasmapheresis, plasma is removed and replaced with a mixture of normal saline and 5% albumin. In plasma exchange, plasma is removed and replaced with allogeneic plasma.

23

Polymyositis?

Is seen mainly in adults, with peak onset at age 30-50 years. Is characterized by moderate to severe weakness, interstitial lung disease, and cardiac disease (including heart failure, arrhythmias, ventricular dysfunction). 5 year survival in adults is 75-94%. Immune processes include a predominant cytotoxic T lymphocyte mediated process involving perforin, with CD8 T cells accompanied by smaller numbers of macrophages surrounding and invading otherwise normal-appearing myocytes in endomysial areas. The MHC class I antigen is upregulated on the surface of the majority of muscle fibers, even those not affected by inflammation. These immune processes are the same as in inclusion body myositis.

24

Possible causes of a prolonged PTT?

A deficiency of Factor VIII, IX, XI, XII, prekallikrein, or high-molecular-weight kininogen. A lupus anticoagulant. Heparin. A direct thrombin inhibitor (such as argatroban, hirudin, or bivalirudin). A specific factor inhibitor (ie an antibody against Factor VIII, IX, XI, or XII).

25

Pseudohyponatremia, pseudonormonatremia, and pseudohypernatremia.

Hyponatremia occurs on a backdrop of hyperosmotic, isoosmotic, and hypoosmotic plasma; hence measurement of plasma osmolarity is important in the assessment of hyponatremia. For example, in the presence of hyperlipidemia or hyperproteinemia, measured serum sodium can also be depressed without concomitant depression of serum osmolarity. This artifact of measurement is termed pseudohyponatremia in the context of physiologically normal sodium levels and pseudonormonatremia when the result masks physiologically increased sodium. The phenomenon of pseudohypernatremia can occur as a result of severe hypoproteinemia.

26

Solid organ transplant-associated acute graft-versus-host disease.

The occurrence of an immunologically mediated and injurious set of reactions by cells genetically disparate to their host is known as GVHD. Acute GVHD is most commonly associated with hematopoietic stem cell transplantation (35-50%). With solid organs, the highest occurrence is with small intestine transplantation (5.6%), followed by liver transplantation (1-2%). Cases have also been reported after kidney, pancreas, heart, lung, and multivisceral transplants. The clinical presentation of solid organ transplant-associated GVHD includes skin rash (red to violet maculopapular rashes which may coalesce) and diarrhea (green, mucoid, watery, sometimes bloody), and most cases quickly advance to become a multisystem disease affecting bone marrow and other nontransplanted solid organs. The patient often dies of bleeding and infection from bone marrow failure. The mortality rate of solid organ transplant-associated GVHD ranges from 30 to >75%. In the rare reported cases after lung or pancreas transplant, the mortality rate reaches 100%. The diagnosis is based on clinical symptoms, characteristic histopathologic findings on biopsied tissues, and evidence of microchimerism of donor T cells. Solid organ transplant-associated GVHD often occurs between 2-6 weeks after liver transplantation, although this is variable with late-onset cases seen in other transplant settings.

27

Tube for collecting joint fluids for analysis?

Synovial fluid from inflamed joints can clot when collected and therefore should be collected into an anticoagulant for accurate cell counts, differential counts, and crystal analysis. It can be transported and stored at room temperature but should be examined as soon as possible, and definitely within 24 hours, because cellular degeneration will occur. Sodium heparin or EDTA tubes can be used for crystal analysis. Lithium heparin can form rhomboid crystals that can mimic calcium pyrophosphate dihydrate crystals, and oxalate will cause the formation of calcium oxalate crystals, so these 2 should not be used. If there is sufficient volume, chemistry studies such as glucose, protein, CH50, C3, and C4 can be performed on tubes without anticoagulant, or in the case of C3 and C4, with EDTA. A fluoride tube can also be used for glucose. Synovial fluid for culture should be collected into SPS (Sodium Polyanethol Sulfate) tubes without anticoagulant, or at least with an anticoagulant that does not have a suppressive effect on bacterial growth.

28

What diseases are antiphospholipid antibodies seen in conjunction with?

SLE, RA, Behcet syndrome, hematolymphoid malignancies, MGUS, Waldenstrom macroglobulinemia, and liver disease. Certain infections such as hepatitis C, HIV syndrome, HTLV-1 associated spastic paraparesis, Q fever, and malaria may also be associated with APAs.

29

What is Non-HDL-C?

Non-HDL-Cholesterol, which includes all atherogenic particles: LDL, very-low-density-lipoprotein, intermediate-density lipoprotein, and chylomicrons.

30

What is the LAP score?

Alkaline phosphatase activity is found in the cytoplasm of neutrophils, osteoblasts, vascular endothelial cells, and some lymphocytes. The alk phos level of peripheral blood neutrophils is quantitated by the leukocyte alkaline phosphatase (LAP) score and is a useful screening test to differentiate chronic myelogenous leukemia from leukemoid reactions and other myeloproliferative disorders. The LAP score is usually performed using the Kaplow procedure. The LAP score is determined by evaluation of the staining intensity (ranging from 0 to 4+) of 100 counted neutrophils or bands. Normal LAP scores range from 15 to 130, but there may be variation in these ranges between laboratories. Entities with a low LAP score (130): Infections, growth factor therapy, myeloproliferative disorders other than CML, inflammatory disorders, pregnancy, oral contraceptives, stress, drugs (lithium, corticosteroids, estrogen). There is rapid loss of alk phos activity in samples drawn in EDTA anticoagulant. The test is optimally performed on fresh capillary blood fingerstick smears or on blood anticoagulated with heparin and should be performed within 48 hours after collection of the sample. The blood smears may be held in the freezer for 2-3 weeks with little loss of activity.

31

What patient information do prenatal screen requisitions require?

The patient's EDC (Estimated Date of Confinement), date of LMP, or EGA by US dating. Maternal birth date (to calculate the patient-specific risk for Down syndrome). Patient race (Black women have ~10% higher MSAFP levels than White women, ~57% higher PAPP-A, and ~8% lower DIA). Maternal weight (The average concentration of all analytes used for screening decreases with increasing maternal weight, since maternal blood volume increases with weight). History of patient receiving medication for DM (since pregnant women who have diabetes prior to conception have 12% lower MSAFP levels than nondiabetics of the same gestational age, but a higher birth prevalence of NTDs). Clinical evidence of multiple gestations. If this sample is an initial screen or a repeat test (since the interpretation of a repeat maternal serum sample may be different from the interpretation of an initial serum specimen).

32

What are phase 0, phase I, and phase II deficiencies in a CAP laboratory inspection checklist?

Each checklist requirement bears a designation of Phase 0, Phase I or Phase II. Phase 0 deficiencies do not require a formal response though should be corrected by the laboratory. Deficiencies to Phase I requirements do not seriously affect the quality of patient care or significantly endanger the welfare of a laboratory worker. If a laboratory is cited with a Phase I deficiency, correction and a written response to the CAP are required, but supportivedocumentation of deficiency correction is not required. A Phase I requirement may also be a new checklist requirement, which in subsequent checklist editions may be changed to Phase II. Deficiencies to Phase II requirements may seriously affect the quality of patient care or thehealth and safety of hospital or laboratory personnel. All Phase II deficiencies must be corrected before accreditation is granted by the Accreditation Committee. Correction requires both a plan of action and supporting documentation that the plan has been implemented.

33

If a test has high sensitivity, a negative result means ___.
If a test has high specificity, a positive result means ___.

If a test has high sensitivity, a negative result is used to rule out the disease/there is a low probability of disease.
If a test has high specificity, a positive result is used to rule in the disease/there is a high probability of disease.
SPIN and SNOUT are commonly used mnemonics which says: A highly SPecific test, when Positive, rules IN disease (SP-P-IN), and a highly 'SeNsitive' test, when Negative rules OUT disease (SN-N-OUT).

34

A small positive predictive value indicates that many of the positive results from this testing procedure are ___. Thus it will be necessary to follow up any positive result with a more reliable test to obtain a more accurate assessment. Nevertheless, such a test may be useful if it is inexpensive and convenient.

A small positive predictive value indicates that many of the positive results from this testing procedure are false positives. Thus it will be necessary to follow up any positive result with a more reliable test to obtain a more accurate assessment. Nevertheless, such a test may be useful if it is inexpensive and convenient.

35

Out of HAV, HBV, HCV, alcoholic hepatitis, and toxic hepatitis, which 2 are the most common causes of jaundice?

HAV and alcoholic hepatitis are the most common causes of jaundice (~70%).

36

Are physician office laboratories (POLs) regulated under the Clinical Laboratory Improvement Amendments of 1988?

Yes. CLIA '88 defines a laboratory as "any site where clinical laboratory testing occurs." Most POLs perform waived testing predominantly, if not exclusively. To perform waived tests, a lab must enroll in the CLIA program, pay applicable certificate fees, follow manufacturers' instructions for tests that are FDA approved for waived testing, and be inspected if complaints or issues arise. Waived laboratory testing performed by a POL must be performed according to the manufacturer's instructions for quality control and test performance. This typically includes running controls on each new lot or shipment of test materials, and on each day of patient testing. If the manufacturer's instructions are not followed, the lab is not in compliance with regulations. If the POL develops its own procedures for performing the test or QC that deviate from the manufacturer's instructions, the test is then considered high complex under CLIA '88 rules, and all the requirements for a high-complexity lab come into play.

37

POC PT/INR devices are approved for __. POC PT/INR devices have not been approved for __.

POC PT/INR devices are approved for warfarin monitoring in the stabilized patient. Once the patient's dose requirements and anticoagulation effects have been stabilized for 1-2 weeks, using a central laboratory, testing can be moved to a POC device. POC PT/INR devices have not been approved for coagulation screening, testing for DIC, or use in the trauma/ED setting.

38

What are the equations for calculating sensitivity and specificity?

Sensitivity is the probability that a person having a disease will be correctly identified (positive in disease). Sensitivity = TP/(TP+FN). Specificity is the probability that a person who does not have a disease will be correctly identified. Specificity = TN/(TN+FP).

39

What are the definitions of sensitivity and specificity in statistics?

Sensitivity is the probability that a person having a disease will be correctly identified (positive in disease). Sensitivity = TP/(TP+FN). Specificity is the probability that a person who does not have a disease will be correctly identified. Specificity = TN/(TN+FP).

40

How are positive predictive value and negative predictive value calculated?

Positive predictive value is the probability that an individual who tests positive has the disease. PPV = TP/(TP+FP). Negative predictive value is the probability that an individual who tests negative does not have the disease. NPV = TN/(TN+FN).

41

What are the definitions of positive predictive value and negative predictive value?

Positive predictive value is the probability that an individual who tests positive has the disease. PPV = TP/(TP+FP). Negative predictive value is the probability that an individual who tests negative does not have the disease. NPV = TN/(TN+FN).

42

How are incidence and prevalence calculated?

Incidence is the number of new cases of disease in the population over a given time. Incidence is generally calculated by: number of new cases/susceptible population. Prevalence is the total number of cases in a population at a given time. Prevalence is calculated by: TP+FN/(TP+FP+TN+FN) but generally calculated by: incidence x duration of disease.

43

What is the relationship among the statistical variables: sensitivity, false-negative ratio, and negative predictive value?

Sn and FNR are inversely related: Sn=1-FNR. Therefore, increasing the sensitivity of a test decreases the FNR (the number of false negatives) and increases the NPV.

44

What is the relationship among the statistical variables: specificity, false-positive ratio, and positive predictive value?

Sp and FPR are inversely related: Sp=1-FPR. Therefore, increasing the specificity of a test decreases the FPR (the number of false positives) and increases the PPV.

45

Why is a screening test more useful in a population where the disease is highly prevalent?

As prevalence increases, PPV increases, and clinical usefulness if reflected in PPV.

46

High-sensitivity tests are better suited for ___, while high-specificity tests are better suited for ___.

High-sensitivity tests are better suited for screening purposes, while high-specificity tests are better suited for confirmatory testing.

47

What is the purpose of serial measurements of elevated troponins in suspected AMI?

Increased sensitivity. The specificity of a single elevated troponin is very high; serial measurements don't change that. However, a mildly elevated troponin may not be sensitive enough to detect AMI. Serial measurements of troponin increase the sensitivity, but don't change the ability of the test to change its negative predictive value.

48

Screening tests require high (sensitivity/specificity) so that no case is missed. Confirmatory tests require high (sensitivity/specificity) to be certain of the diagnosis. Receiver operator characteristic (ROC) curves plot the ___ rate versus the ___ rate and graphically present the range of sensitivities and specificities at all test cutoffs. If two tests are compared, the more accurate test is closer to the upper left-hand corner of the ROC curve.

Screening tests require high sensitivity so that no case is missed. Confirmatory tests require high specificity to be certain of the diagnosis.
Receiver operator characteristic (ROC) curves plot the true-positive rate versus the false-positive rate and graphically present the range of sensitivities and specificities at all test cutoffs. If two tests are compared, the more accurate test is closer to the upper left-hand corner of the ROC curve.

49

What is Bayes' theorem?

Bayes' theorem uses information about test characteristics (sensitivity and specificity) and disease prevalence (pretest probability) to obtain the posttest probability of disease, given a positive test. Similarly, it can be used to determine the posttest probability of no disease, given a negative test.

50

Evidence-based medicine is a process by which ___.

Evidence-based medicine is a process by which medical decisions can be made by using as many objective tools as possible; it integrates the most current and the best medical evidence with clinical expertise and patient preferences.

51

What is a critical value?

A critical value (also known as a panic or alert value) is a laboratory result that may represent a life-threatening situation that may not otherwise be readily detectable and therefore requires rapid communication with a health care provider who can provide necessary medical interventions. The speedy communication of such results is required by federal law and regulatory agencies, and The Joint Commission has made it one of its National Patient Safety Goals.

52

Describe sensitivity and specificity.

Sensitivity is the ability of a test to detect disease and is expressed as the proportion of persons with disease in whom the test is positive. It may also be thought of as the probability of a positive test given a true disease state as defined by the gold standard. A test that is 90% sensitive will give positive results in 90% of diseased patients (TP) and negative results in 10% of diseased patients (FN). Specificity is the ability to detect the absence of disease and is expressed as the proportion of persons without disease in whom the test is negative. It may be thought of as the probability of a negative test, given no disease as defined by the gold standard. Thus a test that is 90% specific will give negative results in 90% of patients without disease (TN) and positive results in 10% of patients without disease (FP). A test with a higher sensitivity identifies a greater proportion of persons with disease, and a test with a higher specificity excludes a greater proportion of persons without disease.

53

How are sensitivity and specificity related to lab test value cutoffs?

Sensitivity and specificity are measures of the diagnostic accuracy of a test; they are indicators of a test's ability to distinguish between disease and absence of disease at a chosen cutoff. Sensitivity and specificity therefore are not fixed characteristics of a test and must be calculated from a different 2 × 2 table for each cutoff chosen. When a test cutoff is altered, an inverse relationship between sensitivity and specificity is noted, and a trade-off between the numbers of FP and FN results can be seen. Altering a cutoff changes a test's sensitivity and specificity because it relates to overlapping normal and abnormal patient distributions along the test value continuum. For tests where high values indicate disease, lowering the cutoff (i.e., moving the cutoff line to the left) will lead to more diseased patients being classified as abnormal. Thus, changing the cutoff increases sensitivity. If the cutoff is moved to the point where the diseased curve croses the x axis, then all diseased persons will have a positive test, and the sensitivity will be 100%. However, increased sensitivity is associated with decreased specificity, and the number of nondiseased persons with a positive test (FPs) increases as the cutoff is moved downwards. If the cutoff is raised (i.e., the cutoff line is moved to the right), more nondiseased patients are classified correctly, and specificity increases. If the cutoff is moved to the point where the non-diseased curve crosses the x axis, then all nondiseased persons will have a negative test, and the specificity will be 100%. However, this will be accompanied by concomitant decreased sensitivity and additional FN results.

54

How does prevalence affect PPV and NPV?

The higher the prevalence, or pre-test probability, the higher the posttest probability, or predictive value of a positive test. For a disease with low prevalence, even a test with high sensitivity and specificity will yield a low predictive value because most positive test results will be FPs. On the other hand, the predictive value of a negative test decreases as the prevalence of disease increases. However, the effect is small, especially when sensitivity and specificity are high. Prevalence influences the predictive value of a negative test to a noticeable extent only when the starting prevalence is high.

55

Sensitivity and specificity influence the predictive value. Further, the predictive value of a positive test increases with increasing ___ and improved ___. (Sensitivity/Specificity) has the biggest impact on the predictive value of a positive test, whereas (sensitivity/specificity) determines the predictive value of a negative test.

Sensitivity and specificity influence the predictive value. Further, the predictive value of a positive test increases with increasing prevalence and improved accuracy (i.e., sensitivity and specificity). Specificity has the biggest impact on the predictive value of a positive test, whereas sensitivity determines the predictive value of a negative test.

56

What is Bayes' theorem? Why is it used?

Clinical assessment and diagnostic tests are inherently flawed, and these uncertainties must be considered when medical decisions are made. Sensitivity and specificity represent a summary of the diagnostic accuracy of a test, but they do not indicate the probability that an individual patient has a disease after the test result is obtained. It would be useful to know how the test result changes the probability of disease (i.e., posttest probability), given certain assay characteristics and disease prevalence (i.e., pretest probability). Alternatively, it is useful to know that a condition can be ruled out given a negative test if the probability of disease after a negative test is very low. To determine this information, one must consider predictive value theory, also known as Bayes' theorem. Bayes' theorem describes the relationship between posttest and pretest probability of disease or no disease based on the sensitivity and specificity of the test. The theorem applies population data and test characteristics directly to an individual subject, and calculates the probability of the presence of a disease for a particular patient after a positive test result is obtained and, alternatively, the probability of the absence of disease given a negative test. Although sensitivity and specificity describe a test at a particular cutoff value (e.g., what percent of diseased patients have abnormal results?), the predictive value describes the state of the patient (e.g., how likely is it that a given patient's positive result indicates disease?).

57

What are likelihood ratios?

The LR is a convenient measure that combines sensitivity and specificity into a single number. Similar to these other measures of test accuracy (sensitivity and specificity), the LR is an assessment of test performance, and not of disease status, in the patient being tested. Two likelihood ratios are known: the likelihood ratio of a positive test (LR+) and the likelihood ratio of a negative test (LR−). LR+ is the ratio of two probabilities: the probability of a positive test result when disease is present (TP) divided by the probability of the same test result when disease is absent (FP). In other words, the calculation gives the likelihood that a test result will occur in a diseased patient as opposed to a healthy one. Alternatively, the LR− is the probability that an individual with the disease will have a negative test divided by the probability that an individual without the disease will have a negative test. Additional advantages of the LR are that it is not influenced by disease prevalence, and the LR can be calculated for multiple test cutoffs. Thus, a result's degree of abnormality can be taken into account and medical decisions can be made at a point where fewer FN and FP results are seen.

58

What are the formulas for likelihood ratios?

LR = (probability of test result in persons with no disease) / (probability of same result in persons with no disease). LR+ = (sensitivity) / (1-specificity). LR- = (1-sensitivity) / (specificity).

59

What is a Fagan nomogram?

Calculating out posttest probability can be cumbersome. The Fagan nomogram is a convenient graphic tool that uses a logarithmic scale to determine posttest probability, given the LR at a specified cutoff and the pretest probability. The pretest probability (e.g., clinical suspicion, prevalence) is plotted on the y-axis on the left-hand side, the posttest probability on the right-hand side, and the LR between them. When the Fagan nomogram is used, the pretest probability is located on the left axis, and a line is drawn from that point to the LR+ value. Then this line is further extended until it intersects the right axis at the posttest probability.

60

What is a ROC curve?

Because diagnostic tests are not perfect, there is always a tradeoff between sensitivity and specificity, making it difficult to determine an optimal cutoff. The receiver operator characteristic (ROC) curve is a useful tool for identifying the optimal cutoff for a diagnostic test by calculating the sensitivity and specificity combinations across the entire range of cutoff values. In addition, the ROC curves of two or more tests can be compared to identify the one with the greatest discriminating ability.

61

How are ROC curves constructed?

The receiver operator characteristic (ROC) curve is a useful tool for identifying the optimal cutoff for a diagnostic test by calculating the sensitivity and specificity combinations across the entire range of cutoff values. An ROC curve is constructed by calculating sensitivity and specificity across the entire range of cutoffs for the diagnostic test being evaluated. Sensitivity is plotted on the y-axis and 1− specificity (or the FP rate) on the x-axis; construction of the curve shows the tradeoff between sensitivity and specificity at each cutoff. The ROC curve for a test with no ability to predict disease (i.e., random chance) is a 45-degree line drawn through the origin. As the discriminatory ability of a test increases, the curve progresses outward toward the upper left-hand corner. The area under the ROC curve (AUC) is a single measure of the overall discriminating ability of a test; the minimum AUC is 0.5, which is the area under the 45-degree line, and the maximum AUC is 1.0 for a perfect diagnostic test.

62

What is AUC?

The ROC curve for a test with no ability to predict disease (i.e., random chance) is a 45-degree line drawn through the origin. As the discriminatory ability of a test increases, the curve progresses outward toward the upper left-hand corner. The area under the ROC curve (AUC) is a single measure of the overall discriminating ability of a test; the minimum AUC is 0.5, which is the area under the 45-degree line, and the maximum AUC is 1.0 for a perfect diagnostic test. Because diagnostic tests are not absolutely perfect, the AUC will range from 0.5 to 1.0; the higher the AUC, the greater is the overall discriminating ability of the test. In general, an AUC that is greater than 0.8 suggests that the diagnostic test has good discriminatory power.

63

How can you compare two ROC curves (ie two diagnostic tests) with their AUC?

The receiver operator characteristic (ROC) curve is a useful tool for identifying the optimal cutoff for a diagnostic test by calculating the sensitivity and specificity combinations across the entire range of cutoff values. The optimal cutoff is identified by the coordinate that maximizes discriminatory power, the location on the ROC curve with the largest distance perpendicular from the 45-degree line. The second useful application for the ROC curve is to compare two or more diagnostic methods by calculating the area under the curve. If the area under the curve is similar, then no difference is observed between the two tests. However, if one ROC curve has a greater AUC than a comparison test, it has better sensitivity and specificity at all cutoffs. However, curves may cross, indicating that performance depends on the desired use of the test (i.e., whether a higher sensitivity or specificity is required for clinical use). If test A has a lower FP rate than test B at high sensitivity, test A is a better screening test while test B would be the better confirmatory test because it has greater sensitivity at high specificities.

64

What is the positivity criterion?

The likelihood ratio may be used to select the optimal cutoff for an assay that best separates disease from nondisease. The LR, like sensitivity and specificity, varies with the cutoff. To select the optimal discriminatory cutoff, one might simply pick the cutoff resulting in the greatest LR for a positive test. However, this approach does not take into account the clinical impact of the test result. The clinical consequences of a FP test (e.g., unnecessary surgery) or a FN test (e.g., a missed chance to treat) need to be weighed when the optimal cutoff is determined. The positivity criterion is a method that allows one to assess the optimal cutoff with numeric estimates for clinical impact, or consequences, of test results. In determining which cutoff will serve as the positivity criterion, a finite list of possible cutoffs is generated, and an LR for a positive test is calculated for each cutoff value. Next, the consequences of each of the four possible testing outcomes (TP, TN, FP, and FN) are assigned numeric estimates with respect to some outcome (e.g., morbidity, mortality, cost). Values for the estimated consequences, as well as prevalence estimates of the disease, are then used in the LRthreshold equation, which gives the optimal assay cutoff. From the list of possible analyte concentrations, one can now select the cutoff that most closely approximates the LRthreshold. In this way, one may select a test cutoff that not only optimizes the discriminatory power of the assay, but also fits the clinical need that the test is meant to address.

65

What is evidence-based medicine?

In contrast to traditional approaches, EBM is a process by which medical decisions can be made by using as many objective tools as possible. This, in turn, can help reduce the uncertainty of medical decision making. EBM is a systematic practice that integrates the most current and best evidence with clinical expertise and patient preferences when making medical decisions. It places emphasis on critically analyzing information from the literature and developing knowledge for medical practice. Also, it encourages the cultivation of continuous learning and sharing of medical knowledge at all levels of training from medical student to attending physician.

66

The things that we measure, count, or otherwise delineate are termed variables because the values they can assume vary. Variables are usually considered to fall into what 3 scales?

Nominal scale is where a variable can take on only a limited number of values, usually called categories (or characters). Examples of nominal variables are gender (male or female) and risk factors (e.g., smoker or nonsmoker). Ordinal scale is where the variable takes on specific values that have some inherent order such as magnitude but without equivalent distances between categories (e.g., trace amount, 1+, 2+, etc. of protein in urine). Interval scale is where a variable takes on values in a quantitative range with defined differences between points. It is conventional to treat most numeric laboratory measurements as continuous variables, even though they may be reported as discrete values (e.g., glucose values of 123 or 124 mg/dL, but not 123.857… mg/dL).

67

What are: standard deviation, coefficient of variation, and confidence interval?

Standard deviation (SD) is the square root of the sum of the squared differences of each data point from the mean divided by n−1 for samples (divided by n for populations). The SD is a predictable measure of dispersion from the mean in a Gaussian normal distribution. Coefficient of variation (CV) is the standard deviation of a set of data points divided by the mean result expressed as a percentage or as a decimal fraction. Confidence interval (CI) is the interval that is computed to include a parameter such as the mean with a stated probability (e.g., commonly 90%, 95%, 99%) that the true value falls into that interval.

68

What is Gaussian (normal) distribution?

Gaussian (normal) distribution is a spread of data in which elements are distributed symmetrically around the mean with most values close to the center. It is explicitly described by a mathematical equation and so is a parametric distribution. Random scatter or random selection of a population often results in a Gaussian normal distribution. This type of distribution is often a criterion for completely valid application of many parametric tests.

69

What are parametric and nonparametric statistics?

Parametric statistics are statistical measures that are calculated based on the assumption that the data points follow a Gaussian distribution and include parameters such as mean, variance, and standard deviation. Nonparametric statistics are based on rank or order of data and include parameters such as median.

70

What are significance level and statistical power?

Significance level (p or α) is the probability that a difference between groups occurred by chance alone, by convention set at less than .05. Statistical power (1−β) is the probability that a difference between groups will be detected by the study, generally set at least to 80%.

71

In statistics, what are independent and dependent variables?

Statistical questions are often posed in terms of input versus output, cause and effect, or correlation between two or more variables. The input or cause is considered an independent variable because it is already determined and so is not influenced by other factors. Examples of independent variables are age, gender, temperature, and time. In contrast, dependent variables are those things that might change in response to the independent variable. Examples of dependent variables are blood glucose concentration, enzyme activities, and the presence or absence of malignancy. Of course we can change our thinking and switch which is the independent and which is the dependent variable if the experimental question changes.

72

In a Gaussian (normal) distribution, __% of data points will fall within +/- 1 SD, __% will fall within 2 +/- SD, and __% will fall within 3 +/- SD.

In a Gaussian (normal) distribution, 68.2% of data points will fall within +/- 1 SD, 95.5% will fall within 2 +/- SD, and 99.7% will fall within 3 +/- SD.

73

What is analytic sensitivity and how is it determined?

The lowest value that an assay can reliably detect is termed the analytic sensitivity. A common approach to making this judgment is to measure a zero standard multiple times (e.g., 10 times) and calculate the SD of the signal detected, which is noise. Then set the lowest reliable detection threshold at three or four times the value of the SD. This approach is often individualized within laboratories. This characteristic is also termed the detection limit. Another use of the term analytic sensitivity refers to the change in response of an assay for a given change in the amount or concentration of the analyte. In this respect, a highly sensitive assay has the characteristic of readily detecting small changes in analyte at concentrations in the mid-range of measurement.

74

Define analytical sensitivity, analytical specificity, diagnostic sensitivity, and diagnostic specificity.

"Analytical sensitivity" represents the smallest amount of substance in a sample that can accurately be measured by an assay. "Analytical specificity" refers to the ability of an assay to measure on particular organism or substance, rather than others, in a sample. An assay's analytical sensitivity and analytical specificity are distinct from that assay's clinical diagnostic sensitivity and diagnostic specificity. "Diagnostic sensitivity" is the percentage of persons who have a given disorder who are identified by the assay as positive for the disorder. High analytical sensitivity does not guarantee acceptable diagnostic sensitivity. "Diagnostic specificity" is the percentage of persons who do not have a given condition who are identified by the assay as negative for the condition.

75

What is quality control in the clinical laboratory?

Quality control (QC, also called statistical process control) is a process to periodically examine a measurement procedure to verify that it is performing according to preestablished specifications. QC of an analytic measurement procedure uses QC sample materials intended to simulate clinical samples from patients. Such QC sample materials are called surrogate samples. The QC samples are measured periodically in the same manner as clinical samples and their results examined to ensure that the measurement procedure meets performance requirements appropriate for patient care.

76

What is calibration in the clinical laboratory?

Calibration of the analytic measurement procedure is a key component in achieving quality results. Calibration of a method establishes the relationship between the signal measured and the quantitative value of analyte in the calibrator materials. This relationship is used to convert the measurement signal from a patient sample into a reportable concentration for the analyte. Specific techniques for calibration are unique to individual methods. Calibration of methods is most often performed by the laboratory using calibrator materials provided by the method or instrument manufacturer. In some cases (such as POC devices), methods are calibrated during the manufacturing process, and the laboratory performs a verification of that calibration. In either situation, traceability of result accuracy to the highest-order reference system is provided by the method manufacturer. The method manufacturer's calibrator material(s) and assigned target value(s) are designed to produce accurate results with clinical patient samples assayed using that particular manufacturer's routine method.

77

When should calibrations be performed in the clinical laboratory?

In principle, a measurement procedure should be calibrated only when evidence indicates that the current calibration is no longer valid. A recalibration event may introduce a small change in the relationship between analytic system response and sample concentration that contributes to overall long-term variability in method performance. Evidence that a recalibration is needed could come from QC sample results that demonstrate a shift or trend in bias over a time period. However, QC results are expected to have random variability that may make identification of a trend in bias difficult to detect. Consequently, it is common practice to recalibrate methods on a time schedule that is established based on experience with the sources of drift that are important for a given technology. CLIA regulations require calibration or calibration verification at least every 6 months, or more frequently if recommended by the method manufacturer. When no change in method performance parameters has occurred, it is acceptable to verify that the current calibration has not changed (calibration verification), rather than perform a recalibration.

78

What are the Ranson criteria?

Clinical prediction rules for predicting the severity of (non-gallstone) acute pancreatitis. AT ADMISSION: Age in years >55. WBC count >16,000 cells/uL. Blood glucose >200 mg/dL. Serum AST >250 IU/L. Serum LDH >350 IU/L. WITHIN 48 HOURS: Hematocrit fall of 10% or more. BUN increase by 5 mg/dL or more in spite of fluids. Serum calcium level 6 L. pO2 4 mEq/L. INTERPRETATION: If score is 3 or more, severe pancreatitis is likely, and if score is less than 3, severe pancreatitis is unlikely. Alternatively, score of 0-2 = 2% mortality, 3-4 = 15% mortality, 5-6 = 40% mortality, and 7-8 = 100% mortality.

79

List some anticoagulants and their mechanisms of action.

Anticoagulants include the oral agents warfarin (Coumadin), dabigatran (Pradaxa), rivaroxaban (Xarelto), and the IV/SQ agents unfractionated heparin, the LMW heparins enoxaparin (Lovenox) and dalteparin (Fragmin), fondaparinux (Arixtra), lepirudin (Refludan), and argatroban (no brand; generic only). Are indicated for venous thrombosis and to prevent stroke in patients with atrial fibrillation. Warfarin reduces the synthesis of the coagulation factors II, VII, IX, and X. The heparins bind to antithrombin, changing its configuration and allowing antithrombin to bind activated coagulation factors and inactivate them. Unfractionated heparin inactivates many factors. LMW heparin inactivates factors Xa and IIa (thrombin); fondaparinux inactivates only factor Xa. Lepirudin and argatroban are direct thrombin inhibitors.

80

The CAP makes recommendations for the minimum requirements for the retention of laboratory records and materials. They meet or exceed the regulatory requirements specified in the Clinical Laboratory Improvement Amendments of 1988 (CLIA 88). For the general laboratory, how long must the following be kept: accession logs, maintenance/instrument maintenance records, quality control records?

Accession logs - 2 yrs. Maintenance/instrument maintenance records - 2 yrs. Quality control records - 2 yrs.

81

The CAP makes recommendations for the minimum requirements for the retention of laboratory records and materials. They meet or exceed the regulatory requirements specified in the Clinical Laboratory Improvement Amendments of 1988 (CLIA 88). For clinical pathology, how long must the following be kept: patient test records, serum/heparinized or EDTA plasma/CSF/body fluids (except urine), urine, peripheral blood smears/body fluid smears, permanently stained slides for microbiology (Gram, trichrome, etc)?

Patient test records - 2yrs. Serum/heparinized or EDTA plasma/CSF/body fluids (except urine) - 48 yrs. Urine - 24 hrs (but exceptions may be made at the discretion of the lab director). Peripheral blood smears/body fluid smears - 7 days. Permanently stained slides for microbiology (Gram, trichrome, etc) - 7 days.

82

The CAP makes recommendations for the minimum requirements for the retention of laboratory records and materials. They meet or exceed the regulatory requirements specified in the Clinical Laboratory Improvement Amendments of 1988 (CLIA 88). For blood bank, how long must the following be kept: donor and recipient records; patient records; records of employee signatures, initials, and identification codes; quality control records; records of indefinitely deferred donors, permanently deferred donors, or donors placed under surveillance for the recipient's protection (e.g., those donors that are hepatitis B core positive once, donors implicated in a hepatitis positive recipient); specimens from blood donors units and recipients?

Donor and recipient records - 10 yrs. Patient records - 10 yrs. Records of employee signatures, initials, and identification codes - 10 yrs. Quality control records - 5 yrs. Records of indefinitely deferred donors, permanently deferred donors, or donors placed under surveillance for the recipient's protection (e.g., those donors that are hepatitis B core positive once, donors implicated in a hepatitis positive recipient) - indefinitely. Specimens from blood donors units and recipients - 7 days post-transfusion.