CAPSTONE: How to Order and Interpret Clinical Laboratory Tests

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Learning Objectives (1). Define the following as they apply to a lab test:Specificity, SensitivityCutoff, Reference rangePositive predictive valueNegative predictive value. Learning objectives (2) . Describe how lowering or raising a cutoff effects test specificity and sensitivity.Describe the

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CAPSTONE: How to Order and Interpret Clinical Laboratory Tests

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1. CAPSTONE: How to Order and Interpret Clinical Laboratory Tests Michael L. Astion, MD, PhD, HTBE University of Washington Dept of Laboratory Medicine

2. Learning Objectives (1) Define the following as they apply to a lab test: Specificity, Sensitivity Cutoff, Reference range Positive predictive value Negative predictive value

3. Learning objectives (2) Describe how lowering or raising a cutoff effects test specificity and sensitivity. Describe the effects of pretest probability, test sensitivity and test specificity on the predictive value of a lab test. Discuss 3 reasons for an abnormal lab test result. Examples will use tests usually classified as “clinical chemistry” or “clinical immunology”, but the principles apply to all lab testing (and all Dx tests).

4. Sensitivity, Specificity Sensitivity: The probability that a person with the disease being tested for will test positive Sens = TP / (TP + FN) Specificity: The probability that a person who does not have the disease being tested for, will test negative. Spec = TN / (TN + FP)

5. Medical Rules: After a drug is released to market, its side effects will increase over time. After a new lab test is released to market, its specificity will decrease over time.

6. Case: The laboratory that you use is putting a new test for B-Natriuretic Peptide (BNP) online. How will they evaluate the test’s sensitivity and specificity?

7. To calculate Sensitivity, perform the test on patients with the disease / syndrome being tested for: Suppose the BNP test shows the following results from 100 patients with Congestive Heart Failure 95 test positive and 5 test negative. Sensitivity = 95 / (95 + 5) = 95%

8. To calculate Specificity, perform the test on patients without the disease / syndrome: Suppose the BNP test shows the following results from 100 patients without CHF: 10 test positive and 90 test negative. Specificity = 90 / (90+10) = 90%

9.

10. BNP in the diagnosis and monitoring of CHF Diagnosis Determines if dyspnea is due to CHF Helps reduce echocardiography since if low BNP, then echo is unlikely to detect LV dysfunction. Monitoring Inpatients: decreases need for invasive monitoring Outpatients: tailor therapy based on BNP result

11. Decision thresholds for laboratory tests Cutoffs Reference Ranges These concepts are closely related since a reference range can be viewed as 2 cutoffs, one a low cutoff and one a high cutoff.

12. Cutoffs The cutoff is the threshold above which a test is considered positive. Examples of cutoffs: Total cholesterol of 200mg/dL separates borderline from desirable total cholesterol. PSA: 4ng/mL cutoff = decision limit in men > age 50 being screened for prostate cancer The specificity and sensitivity of a test are strongly influenced by the value of the cutoff!

13. As a test’s cutoff value increases, test sensitivity decreases and specificity increases

14. The reference range for a test is the distribution of lab values that covers the majority (usually 95%) of the results for a healthy population.

15. Reference ranges often vary by age and gender.

16. Two labs might have different reference ranges for the same test because of different test methods or different methods for calculating a range.

17. Positive Predictive Value (PPV), Negative Predictive Value (NPV) PPV = the probability that a person with a positive test result has the disease being tested for PPV = TP / (TP + FP) NPV = the probability that a person with a negative test result does not have the disease being tested for. NPV = TN / (TN + FN)

18. PPV, NPV are strongly influenced by the… …prevalence of the disease in the population …pretest probability of the disease in the individual

19. 3 Cases: Should you order an ANA test? A 40 y.o. male presents with a burning feeling on urination. He says that his new girlfriend was recently diagnosed with “Lupus”. He read about lab tests for “Lupus” online and wants an ANA test. A 40 y.o. woman presents with 1 month of fatigue, hair loss and a describes a “brief rash near her nose” although none is now present. A 40 y.o. woman presents with overwhelming fatigue, hair loss, a malar rash, oral ulceration on the inside of her lip, and joint pain bilaterally in her hands, wrists, and knees.

20. PPV increases with increasing disease prevalence (sensitivity = 95%; specificity = 85%).

21. PPV increases with increasing specificity (sensitivity constant at 95%)

22. NPV increases with decreasing pretest probability (sensitivity = 95%, specificity = 75%)

23. Screening vs confirmatory tests. Screening tests: Usually in setting of low pretest probability Test selection and cutoffs err on the side of high sensitivity to give high NPV Confirmatory tests: Usually higher pretest probability relative to the setting of the screening test. Test selection and cutoffs err on the side of high specificity to give high PPV

24. ANA test: Summary Sensitive (>95%), non-specific screening test for SLE. False positives seen in: Infection Malignancy Aging Many other rheumatic and non-rheumatic conditions

25. Lab workup of systemic rheumatic diseases Clinical presentation guides choice of lab tests Specific Dx not dependent on lab tests! Dx is guided by criteria provided by Am Coll Rheum. Past: 2 main tests = ANA test, Rheumatoid factor Now, A 3rd test, anti-CCP,has become important test in Dx of Rheumatoid Arthritis

26. Overutilization issues Why are too many screening tests ordered in ambulatory settings? Patient pressure via googlification. Rare diseases often have common symptoms.

27. Patient pressure Google search for “joint pain” on March 8, 2009. This is the # 1 listing. What tests might an insured “worried well” patient want? “I’m waiting for my lab results.”

28. Don’t put your head in the sand: False positive screening or monitoring tests can be dangerous! Harm can be caused by: Worry Unnecessary diagnostic procedures Unnecessary treatment Medical care is dangerous relative to other risks.

29. Evidence-based recommendations for screening tests in asymptomatic adults with no family history

30. Should we use PSA to screen for prostate cancer ?

32. Tumor marker uses: a realistic summary. Most tumor markers are used for monitoring, not Dx.

33. Potential tumor markers for ovarian cancer (NACB, 2005, www.nacb.org/lmpg/tumor/chp3e_ovarian.pdf)

34. Practical Tips: Ordering Lab Tests Before ordering a test, decide what you’ll do if it is + or - . If answers are the same, don’t order. Do not order lab tests out of curiosity. If a test requires “pathologist approval”, there is a > 50% chance you do not need it.

35. Practical Tips: Ordering Lab Tests Beware of using 3rd party (e.g. medical assistant) to order tests. “I told the medical assistant to order a free T4, but the laboratory performed a free testosterone.”

36. Practical Tips: Ordering Lab Tests Get some help from a colleague if it is the first time you are ordering a particular test.

37. Practical Tips: Ordering Lab Tests Do not participate in laboratory quackery.

38. Quackery / nonstandard tests usually involve false ++ results for tests that are …………….. Bogus, or not ready for use, or real but should not be ordered in asymptomatic or vaguely symptomatic patients

39. Some Examples Dysbiosis / Comprehensive stool analysis Parasitology profile Irritable Bowel antibodies Nonstandard organisms Stealth virus testing Quack Lyme testing Candida causes everything Hair analysis of all sorts Trace minerals metals Trace nutrient deficiency Anti-malignin antibodies Salivary hormones Adrenal stress panel Genetic risk panels. Detoxification capacity 500 allergen IgG food allergy testing Urine neurotransmitters Chemical antibodies profile (e.g. anti-benzene) Live Blood Cells And many more….

40. 8 warning signs that a lab test is quackery Claims to rule in a syndrome that is not well accepted dysbiosis; stealth viruses; emotional problems) Claims to rule in syndrome for which no specific lab tests exist chronic fatigue, fibromyalgia, autism, irritable bowel syndrome, multiple chemical sensitivity Involves a huge panel of testing costing >$400. Many or all tests come back positive

41. 8 warning signs that a lab test is quackery (continued) Huge inter and intra laboratory variability Tests do not appear in a search of PubMed, UpToDate, or the National Guidelines Clearinghouse. Tests offered as “special” by chiropractors, naturopaths… Offered by one of the labs on the “nonstandard” list

42. CLIA-certified labs doing high volumes of nonstandard lab testing Genova Diagnostics Prometheus Diagnostics The Great Plains Laboratory IGeneX Doctor’s Data Medical Diagnostics Laboratories MetaMetrix Many others (Sage Medical, ALCAT) Special note regarding Lipids: (Atherotech, Liposcience, Berkeley Heart Lab)

43. The typical nonstandard lab sequence…. Ask a broad question Make a broad claim Sell a diagnostic test or test battery Use results to sell advice/products Repeat testing, sell more products

44. Ask a broad question “Are you chronically tired” “Are you angry?” “Are you anxious?” “Are you overweight?” “Is your hair thinning?” “Having trouble sleeping?”

45. Make a broad claim that is plausible but unlikely to be true. YOU MAY HAVE A… Parasites /gut flora imbalance “Stealth” infection A nutritional deficiency metal imbalance or toxicity been poisoned! hormone imbalances genetic risks for disease an early cancer a food allergy

46. Sell a test, then advice or products based on test results Nutritional supplements Detoxification treatments, especially colon cleanings, chelation therapy “Natural” medicines Creams

47. Practical tips: Interpreting abnormal results 3 causes of an abnormal lab result: Some healthy patients have abnormal results. Abnormal results are sometimes erroneous. The disease for which you are testing can cause an abnormal result.

48. Some “healthy” patients have abnormal lab results 5% of “healthy” people are outside the reference range. For tests using cutoffs: False positive % = 100% - specificity.

49. Practical tips: abnormal results 3 causes of an abnormal lab result: Some healthy patients have abnormal results. Abnormal results are sometimes erroneous. ~ 1% of test results are erroneous. The disease for which you are testing can cause an abnormal result.

50. Lab error and the 3 phases of lab testing Preanalytic phase: all events from test ordering and specimen collection through arrival at the instrument Analytic: analysis by manual or automated methods Postanalytic: includes result validation and reporting of results by a variety of methods Most lab errors are in the preanalytic phase.

51. Examples of pre-analytic lab errors Improper filling out of the requisition Improper entering of data into the Lab information system poor phlebotomy technique (tourniquet too tight, blood draw too slow) Errors in drawing from a line improper labeling of the specimen improper centrifuging of the specimen improper tube selection improper shaking or storage of the tube delays in specimen transport improper freeze / thawing of a specimen

52. Practical tips: If a test result is abnormal, what do you do? If the result is inconsistent with clinical findings, repeat the result. Use rigorous pre-analytic methods. Many errors will NOT repeat, -for example, mislabeling or dropping the specimen. Some errors will repeat, e.g., some phlebotomists make mistakes consistently.

53. Lab tests for diagnosis of diabetes: Current guidelines on ADA website www.diabetes.org 1) Preferred Method: Fasting serum glucose >126 mg/dL. Fasting = no caloric intake for >8 hours. 2) Symptoms of diabetes plus random serum glucose >200 mg/dL 3) oral glucose tolerance test (OGTT; for pregnant woman) Dx is confirmed by repeat testing on another day with same or different method. To reduce error, avoid OGTT when possible.

54. If the result repeats on a new specimen: How far outside the reference range / cutoff? Highly abnormal lab values are more likely to be clinically significant. Highly abnormal values require an explanation.

55. If the result repeats, and the value is a little outside the reference range: This is your biggest quandary. Here you must apply the predictive value theory that you recently mastered. You need to do a mental estimate of the pre-test probability that the patient has a disease associated with the abnormal value.

56. Case: A 52 y.o. patient has a total calcium that is consistently about 10.4 g/dL (Reference range 8.9 – 10.2 mg/dL). You have checked your pre-analytic technique and it is rigorous. What is your approach to such a patient?

57. Mild Hypercalcemia (continued) If the patient has no other evidence for a hypercalcemia-related condition unlikely that the Ca+2 result is meaningful Follow patient and repeat Ca+2 later If the patient has other evidence for a hypercalcemia-related condition increased Ca+2 is probably disease-related continue your work-up.

58. Summary and Conclusions Ordering and interpreting lab tests require a qualitative understanding of predictive values. Predictive value of a lab test is influenced by: test sensitivity and specificity patient’s pretest probability of having the disease Testing in a setting of low pretest probability can often reassure the patient, but it can also lead to false positives and adverse outcomes.

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