Evidence Based Practice: Diagnosis

1. Evidence Based Practice: Diagnosis Large Group Session Catherine Clase 2009 March 17

2. My First Case of … Xi Shan MD, PhD R4 Internal Medicine Program McMaster University

3. Case ID: 46 year-old male RFR: HTN HPI: Felt unwell for a number of months, main complains were headache, intermittent tremor and palpitation, nocturia (up to 6 times/night), always felt hot, weight loss despite a good appetite

4. Case PMH: • HTN, diagnosed 2 years ago, had tried different antihypertensive agents (only on one at a time), BP not well controlled • Recent diagnosed DM (6 month ago), not monitoring glucose • Migraine Med: • Losartan 50 mg bid • Tylenol # 3 prn (up to 10 per day) • Metformin 500 mg bid

5. Case O/E: • VS: BP = 190/100 bilaterally, HR = 120, afebrile • Hand: palmar erythema and warm, sweaty palms • H&N: no exophthalmopathy, thyroid is not enlarged, no thyroidectomy scar • CVS: normal S1/S2, no S3/S4/m • Extremities: no pretibial myxoedema • Rest exam unremarkable

6. Investigation • Electrolytes and renal function were normal • TSH was normal

7. Differential Diagnosis of Secondary Hypertension - RECAPS • Renal (RAS, CRF, PCKD) • Endocrine (hyperthyroidism, hyperparathyroidism, hypothyroidism, phaeochromocytoma, Cushing’s syndrome, Conn’s syndrome, acromegaly,) • Collagen-vascular disease, Clonidine withdrawal • Aortic coarctation, Alcohol • Polycythemia rubra vera, Pregnancy induced HTN, (acute intermittent) Porphyria • Sleep apnoea

8. Does this patient have phaeochromocytoma?

9. You remember:

10. What is phaeochromocytoma? • Catecholamine-producing tumour usually of adrenals • 10% extra-adrenal • 10% malignant • 10% familial or part of a neoplasia syndrome

11. Don’t we test the urinary excretion of catecholamines (or something) to diagnose this?

12. Structured question – 4 parts • In patients evaluated for secondary causes of hypertension • what are the properties of serum and urine testing for catecholamines • in determining whether a patient has or does not have a phaeochromocytoma • compared with the gold standard of…..

13. Where to search? • Clinical evidence • Not a good idea (too specialized) – no hits • ACP journal club • No hits • UpToDate • Several references to primary papers • Cochrane database • No hits • Medline • Phaeochromocytoma (MeSH) • Diagnosis – specific – post 1990 • Combined with AND

18. x

20. Boolean logic Results of Specific Diagnosis Strategy for post 1990 articles Pheochromocytoma

21. Boolean logic Results of Specific Diagnosis Strategy for post 1990 articles Pheochromocytoma (MeSH)

23. More advanced: text word searching in Ovid • Different spellings • Pheochromocytoma, phaeochromocytoma • Truncation • Symptom$ • Symptom, symptoms, symptomatic etc • ‘Or’ together all the terms that are synonyms • ‘And’ together the final result of the groups of synonyms

24. Synonyms in Boolean Logic Pheochromocytoma.mp Pheochromocytoma (MeSH)

25. If there are two many papers: Don’t • Limit to review • Fail to explode • Use subheadings • In general not well coded • Give up • Limit to English • Limit to locally available

26. If there are two many papers: Do • Use MeSH headings and focus • Use an expert search • Limit to Core Clinical Journals (AIM) • Consider whether your search strategy can be made more specific • Try to diagnose what you are getting that is off topic and why • Limit to human • Quickly scan all the titles • Look for recent work if the field seems to be changing rapidly • Look for a large study • Look for a study in patients like yours • Look for a good study

28. Search Results • 85 articles • Most not on urine or serum measurement in diagnosis • Many are review articles • #43 (Sawka et al) and #47 (Lenders et al) look relevant • Limited to Core journals (AIM): • 24 articles • #13 (Sawka et al) and #14 (Lenders et al) are both in this list

29. 2 articles • Sawka et al J Clin Endocrinol Metab 2003 • N=261 • Plasma metanephrines • Urine metanephrines and catecholamines • Lenders et al JAMA 2002 • N=858 • Plasma metanephrines and catecholamines • Urine metanephrines and catecholamines • Urine vanillylmandelic acid

30. Some Methodologic Questions • Is there an independent gold standard? • Is the assessment of the test and the gold standard blinded each to the other? • Was the study setting and patient population appropriate? • Was an appropriate spectrum of disease studied? • Is the test reproducible?

31. Lenders et al • Consider the following • Independent gold standard • Blinded assessment • Study setting and patient population appropriate • Appropriate spectrum • Reproducible test • Look at the methods section

32. The study population was selected from a total of 1003 patients tested for pheochromocytoma using plasma free metanephrines. Patients were tested between 1994 and 2001 at 4 referral centers (National Institutes of Health, Bethesda, Md; St Radboud University Medical Center, Nijmegen, the Netherlands; Sahlgren's University Hospital, Göteborg, Sweden; and University of Florence, Florence, Italy). Patients were either tested as part of routine screening for hereditary pheochromocytoma or after referral to 1 of the 4 centers because of a suspicion of pheochromocytoma based on a previous history of the tumor, the finding of an adrenal mass, or more often because of suggestive signs (eg, therapy-resistant or paroxysmal hypertension) and symptoms (eg, sweating, headache, palpitations). Procedures were approved by the intramural research board or hospital ethics committee of the centers in which patients were studied and all patients provided informed consent.

33. For the purposes of patient selection into the study, the results of biochemical tests could not be used to exclude or confirm pheochromocytoma, since by definition this would bias the analyses of test performance. Therefore, selection of patients for inclusion in the final analyses was based on whether pheochromocytoma could be excluded or confirmed by standard criteria that were necessarily independent of the diagnostic biochemical tests being evaluated. Confirmation of pheochromocytoma required pathological examination of surgically resected or biopsied tumor tissue or a diagnosis of inoperable malignant pheochromocytoma based on findings of metastatic disease by imaging studies. Exclusion of pheochromocytoma required lack of radiological evidence of a tumor by computed tomography or magnetic resonance imaging, pathological examination of a surgically resected or biopsied adrenal mass, or lack of pheochromocytoma on patient follow-up 2 or more years after initial testing. Using the above criteria, pheochromocytoma was confirmed in 214 patients and excluded in 644 patients, all of whom were included in the final analyses (Table 1)

34. Among the 145 patients who did not fulfill the criteria for exclusion or confirmation of pheochromocytoma, and who were not included in the final analyses, 25 patients had a high likelihood of pheochromocytoma but had not been operated on at the time of analysis. All 25 patients had evidence of a small adrenal mass by imaging studies. All had some biochemical evidence of pheochromocytoma and most had a hereditary predisposition to the tumor but were asymptomatic and normotensive. Pheochromocytomas in the remaining group of 120 patients were unlikely based on findings that did not fulfill the criteria of the study for selection of patients into the final analyses (eg, patients in whom pheochromocytoma was excluded solely on the basis of negative biochemical test results).

35. Lenders et al • Independent gold standard for disease and nondisease - yes • Blinded assessment – not stated, perhaps doesn’t matter too much given the nature of both new and definitive test • Study setting and patient population appropriate – yes, but not consecutive patients. • Appropriate spectrum – yes. Excluding unclassified or difficult to determine patients is a problem; however, not a large number were excluded on this basis and it is the price for the independent gold standard. • Reproducible test – yes (data not shown)

36. How to interpret the information Our patient Urine catecholamines • Epinephrine = 168 (N < 110 nmol/d) • Norepinephrine = 25452 (N < 660 nmol/d) Look at the Results section ‘A … positive result was defined as a value for either or both measurements equal to or higher than the appropriate upper reference limit’ Therefore – test result is positive

39. Sensitivity = a/(a+c) = 97/107 = 0.91 (or 91%) • Specificity = d/(b+d) = 159/211 = 0.75 (or 75%) • Likelihood ratio for + test result =LR+=sens/(1-spec) = 0.91/(1 - 0.75) = 3.64 • Likelihood ratio for - test result =LR -=(1-sens)/spec = (1 – 0.91)/0.75) = 0.12 • Positive Predictive Value = a/(a+b) = 97/(97 + 52) = 0.65 or 65% • Negative Predictive Value = d/(c+d) = 159/(10 + 159) = 0.94 or 94% • Pre-test probability (prevalence) = (a+c)/(a+b+c+d) 107/318 = 0.34 or 34% • Pre-test odds = prevalence/(1-prevalence) = 0.34/(1 – 0.34) = 0.5 • Post-test odds = pre-test odds  LR • Post-test probability = post-test odds/(post-test odds +1)

40. Post Test Probabilities Positive predictive value = the probability that someone with a positive test result has the disease for someone with a positive test result, = the post test probability = 65% in the example

41. Post-Test Probabilities Negative predictive value = the probability that someone with a negative test result does not have the disease For someone with a negative test result, = the probability that they do not have the disease 94% in the example

42. How to Apply to a Different Population What differs for different populations is the prevalence of the condition Prevalence is also known as • Pre-test probability • Prior probability • Priors

43. Applying to a Different Population If you know the sensitivity, and the specificity and can estimate the prevalence of the condition you can calculate the PPV and the NPV For example, in primary care, 5% of hypertension is thought to be due to secondary causes, and the rest is essential hypertension Assume 1% of hypertension in primary care is due to phaeochromocytoma Examine performance of test as a screening test for people with hypertension in primary care….

44. 4 6 8 5 7 9 3 2 1

45. Likelihood ratios These are ways of summarizing test properties in 2 numbers (LR +ve and LR –ve) that allow you to do these calculations in your head, starting with any rough estimate of the pretest odds of disease An excellent and detailed explanation is found in: Clinical Epidemiology – A Basic Science for Clinical Medicine Sackett DL, Haynes RB, Guyatt GH and Tugwell P

46. Sensitivity = a/(a+c) = 97/107 = 0.91 (or 91%) • Specificity = d/(b+d) = 159/211 = 0.75 (or 75%) • Likelihood ratio for + test result =LR+=sens/(1-spec) = 0.91/(1 - 0.75) = 3.64 • Likelihood ratio for - test result =LR -=(1-sens)/spec = (1 – 0.91)/0.75) = 0.12 • Positive Predictive Value = a/(a+b) = 97/(97 + 52) = 0.65 or 65% • Negative Predictive Value = d/(c+d) = 159/(10 + 159) = 0.94 or 94% • Pre-test probability (prevalence) = (a+c)/(a+b+c+d) 107/318 = 0.34 or 34% • Pre-test odds = prevalence/(1-prevalence) = 0.34/(1 – 0.34) = 0.5 • Post-test odds = pre-test odds  LR • Post-test probability = post-test odds/(post-test odds +1)

47. : : 2 1 1 0.5 Diagnosis caseOdds = probability/(1 - probability) = 0.34/(1 – 0.34) = 0.5 34% 66% Always express odds as x:1

48. : 1 0.5 Take a different patient, in whom the pre-test probability is higher at 34%Odds = probability/(1 - probability) = 0.34/(1 – 0.34) ~= 0.5Post-test odds = pre-test odds  LReg, 0.52 * 3.64 = 1.87 34% 66%

49. : : 1 1 1.87 2 Odds = probability/(1 - probability) = 0.34/(1 – 0.34) = 0.5Post-test odds = pre-test odds  LReg, 0.51 * 3.64 = 1.87Post-test probability = post-test odds/(post-test odds +1)= 1.87/(1.87 + 1) = 0.66 (66%) 66% 34% The positive test result takes the patient from 0.5:1 odds to 2:1 odds of having the disorder; or from 34% probability to 66% probability

50. : : : 99 1 99 1 0.01 1 Screening casePrevalence is 1%Odds = probability/(1 - probability) = 0.01/(1 – 0.01) = 0.01Post-test odds = pre-test odds  LReg, 0.01 * 3.64 = 0.0364 1% 99% Always express odds as x:1