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Clinical Epidemiology – the basics

Clinical Epidemiology – the basics. What do the terms relative risk and absolute risk mean? What are the advantages and disadvantages of each?

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Clinical Epidemiology – the basics

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  1. Clinical Epidemiology – the basics

  2. What do the terms relative risk and absolute risk mean? What are the advantages and disadvantages of each? • A new screening test is described as having a sensitivity of 78%, a specificity of 89%,a positive likelihood ratio of 13 and a negative likelihood ratio of 0.05. Explain these terms.

  3. A 2 minute exercise • What do you know about this topic? Could you explain what you know to others? • What bits would you like clarifying? (Hint – do you understand RR, OR, CIs etc)

  4. EVIDENCE BASED MEDICINE EBM is an approach to practicing medicine in which the clinician is aware of the evidence in support of his / her clinical practice, and the strength of that evidence.

  5. EVIDENCE BASED HEALTHCARE Evidence based health care promotes the collection, interpretation, and integration of valid, important and applicable patient-reported, clinician-observed and research derived evidence. The best available evidence, moderated by patient circumstances and preferences, is applied to improve the quality of clinical judgements and facilitate effective healthcare.

  6. EFFECTIVE SAFE PATIENT FACTORS COST

  7. QUALITY OF CARE 100% SYSTEMATIC APPLICATION OF THERAPY 0%

  8. LEVELS OF EVIDENCE • LARGE WELL DESIGNED RCT • META ANALYSIS OF SMALLER RCTs • CASE CONTROL AND COHORT STUDIES • (CASE REPORTS AND CASE SERIES) • CONSENSUS FROM EXPERT PANELS • I THINK

  9. Why don’t we always use an RCT then? • Ethics • Cost • Feasibility • Practicality

  10. Why read journals? • Need to make the best possible decisions for patients • Need to make the best possible decisions for healthcare • Need to feel confident about being “on top of the job” • Need to feel knowledgeable themselves and credible with peers

  11. WHY THE MOVE TO EBM? • RANDOMISED CONTROLLED TRIALS PRE-1960 WERE ODDITIES • REVIEWS AND META-ANALYSES AVAILABLE AS ACCESSIBLE DIGESTS OF EVIDENCE • ACCESS TO EVIDENCE VIA I.T. • METHODOLOGICAL ADVANCEMENTS E.G. NUMBERS NEEDED TO TREAT

  12. EBM IS ABOUT ... • CLINICAL EXPERIENCE, DIAGNOSTIC SKILLS AND CLINICAL INSTINCT ARE A NECESSARY PART OF A COMPENTENT PHYSICIAN. • HOWEVER, CLINICAL PRACTICE BASED SOLELY UPON CLINICAL EXPERIENCE “BECOMES TOMORROW’S BAD JOKE”. • “RATIONAL” TREATMENT BASED SOLELY UPON BASIC PATHOLOGICAL PRINCIPLES MAY IN FACT BE INCORRECT, LEADING TO INACCURATE TREATMENT. • UNDERSTANDING CERTAIN RULES OF EVIDENCE IS NECESSARY TO CORRECTLY INTERPRET LITERATURE ON CAUSATION, PROGNOSIS, DIAGNOSTIC TESTS AND TREATMENT STRATEGY.

  13. 20,000 biomedical journals in print. So why isn’t all practice based on scientific evidence? • Not RELEVANT • Upstream to clinical decisions being made, e.g. animal or in vitro studies • Study populations and / or settings do not reflect question type, practice population and settings. • Not RELIABLE • Poor study design • Bias and confounding • Measurement validity • Insufficient power

  14. BIAS • Selection bias • Observer bias • Participant bias • Withdrawal or drop out bias • Recall bias • Measurement bias • Publication bias

  15. CONFOUNDING

  16. Power The ability of the study to detect an effect if in truth there is an effect. An RCT may be underpowered if:- • The duration is too short (too few events) • It includes too few people (too few events) • The wrong outcome was used (too few events) • Expecting a higher level of statistical proof than is realistic for the condition and the intervention being tested

  17. EBM SKILLS - STATISTICS • CHANCE - p = 1 in 20 (0.05). • > 1 in 20 (0.051) = not significant • < 1 in 20 (0.049) = statistically significant • CONFIDENCE INTERVALS • what is the range of values between which we could be 95% certain that this result would lie if this intervention was applied to the general population

  18. TYPES OF STUDY - HYPOTHESIS FORMING • CASE REPORTS / CASE SERIES • CROSS SECTIONAL / PREVALENCE STUDIES measure personal factors & disease states – a snapshot • CORRELATIONAL / ECOLOGICAL / GEOGRAPHIC STUDIES. prevalence &/or incidence measurement in one population c/w another pop.

  19. TYPES OF STUDY - HYPOTHESIS TESTING CASE CONTROL STUDIES

  20. CASE CONTROL EXAMPLE -SMOKING & LUNG CANCER DISEASE Cases Controls EXPOSURE Yes a b EXPOSURE No c d Odds Ratio = ad/bc (1 = no association, > 1 = possible association, < 1 = protective effect) DISEASE Cases Controls (lung cancer) EXPOSURE Yes 56 230 (smoking) No 7 246 The odds ratio would therefore be 56 x 246 = 13776 = 8.6. 7 x 230 1610

  21. TYPES OF STUDY - HYPOTHESIS TESTING COHORT STUDIES

  22. COHORT STUDIES OUTCOME Yes No Exposed a b Not exposed c d Relative risk "How many times are exposed persons more likely to develop the disease, relative to non-exposed persons?" i.e. the incidence in the exposed divided by the incidence in the non-exposed. This is expressed as a divided by c . a+b c+d

  23. COHORT STUDY EXAMPLE Deep vein thromboses (DVT) in oral contraceptive users. (Hypothetical results). OUTCOME (DVT) Yes No Exposed ( on oral contraceptive ) 41 9998 Not exposed (not on o.c.)7 10009 These results would give a relative risk of 6- significantly large enough numbers to indicate the possibility of a real association between exposure and outcome. However, NB biases.

  24. RANDOMISED CONTROLLED TRIALS

  25. RANDOMISED CONTROLLED TRIALS OUTCOME Yes No Comparison intervention a b Experimental intervention c d Absolute risk reduction: “What is the size of this effect in the population” Control event rate - experimental event rate a/a+b - c/c+d Relative risk reduction: “ How many fewer patients will get the outcome measured if they get active treatment versus comparison intervention” a /a+b - c/c+d a/a+b

  26. ARR and RRRA quick test • In a study lasting 12 months, the death rate on placebo was 10% and the death rate on Marvelicoxib was 5%. • What is the ARR? • What is the RRR?

  27. ARR and RRR in more detail4S STUDY • STABLE ANGINA OR MYOCARDIAL INFARCTION MORE THAN 6 MONTHS PREVIOUSLY • SERUM CHOLESTEROL > 6.2mmol/l • EXCLUDED PATIENTS WITH ARYHTHMIAS AND HEART FAILURE • ALL PATIENTS GIVEN 8 WEEKS OF DIETARY THERAPY • IF CHOLESTEROL STILL RAISED (>5.5) RANDOMISED TO RECEIVE SIMVASTATIN (20mg > 40mg) OR PLACEBO • OUTCOME DEATH OR MYOCARDIAL INFARCTION (LENGTH OF TREATMENT 5.4 YEARS ) WERE THE OUTCOMES

  28. RCT EXAMPLE - 4S STUDY OUTCOME (death) Yes No Comparison intervention (placebo) 256 1967 2223 Experimental intervention (simvastatin) 182 2039 2221 The ARR is (256/2223) - (182/2221) = 0.115 - 0.082 = 0.033. The RRR is 0.033/0.115 = 0.29 or expressed as a percentage 29%. 1/ARR = NUMBER NEEDED TO TREAT. 1/0.033 = 30. i.e. if we treat 30 patients with IHD with simvastatin as per 4S study, in 5.4 years we will have prevented 1 death.

  29. Another way of calculating NNTs OUTCOME (death) Yes No Comparison intervention (placebo) 256 1967 2223 Experimental intervention (simvastatin) 182 2039 2221 Prevalence of event in control group = 256/2223x100=11.5% RRR = 29%

  30. Now that’s magic!

  31. NNT EXAMPLES Intervention Outcome NNT

  32. Why are RCTs the “gold standard”Breast cancer mortality in studies of screening with mammography; women aged 50 and over (55 in Malmo study, 45 in UK)

  33. Egger M et al. Meta-analysis Spurious precision? Meta-analysis of observational studies BMJ 1998;316:140-144

  34. Odds ratios or relative risks?Macfarlane J et al. BMJ 2002; 13: 105-9

  35. Relative risk: (49/104) / (63/101) = 0.76. i.e the relative risk of patients taking an antibiotic if they were given a leaflet is reduced by 24%. Also called risk ratio.

  36. Odds ratio: (49/55) / (63/38) = 0.54. There was a 46% reduction in the ratio of those taking antibiotics who had a leaflet compared with the ratio of those taking antibiotics who did not have a leaflet.

  37. Absolute risk reduction: (49/104) – (63/101) = 0.15. Also known as the risk difference. i.e. the difference in the risk of taking antibiotics depending on whether a leaflet was used or not.

  38. NNT: 1 / 0.15 = 7. i.e. 7 people need to be given a leaflet In order for 1 additional person not to take antibiotics

  39. Jüni P, Rutjes AWS, Dieppe PA.Are selective COX 2 inhibitors superior to traditional non steroidal anti-inflammatory drugs? BMJ 2002; 324: 1287-1288

  40. Screening and Diagnostic Tests

  41. SCREENING - WILSON & JUNGEN (WHO, 1968) • IS THE DISORDER COMMON / IMPORTANT • ARE THERE TREATMENTS FOR THE DISORDER • IS THERE A KNOWN NATURAL HISTORY & “WINDOW OF OPPORTUNITY” WHERE SCREENING CAN DETECT DISEASE EARLY WITH IMPROVED CHANCE OF CURE • IS THE TEST ACCEPTABLE TO PATIENTS • SENSITIVE AND SPECIFIC • GENERALISABLE • CHEAP / COST EFFECTIVE • APPLY TO GROUP AT HIGH RISK

  42. Tests ain’t what they used to beJoseph Heller Catch 22 1962 “Gus and Wes had succeeded in elevating medicine to an exact science. All men reporting on sick call with temperatures above 102 were rushed to hospital. All those except Yossarian reporting on sick call with temperatures below 102 had their gums and toes painted with gentian violet solution and were given a laxative to throwaway in the bushes. All those reporting on sick call with temperatures of exactly 102 were asked to return in an hour to have their temperatures taken again.”

  43. A B No Disease No Disease Disease Disease C No Disease Disease Percent of population 0 10 20 30 VALUE Arbitrary Units Set cut off at A A lot of people who do not have the disease are labeled as having it (false positives) A lot of people who do have the disease are labeled as not having it (false negatives) Set cut off at B

  44. DISEASE Present Absent Positive 50 0 a b TEST c d Negative 0 50

  45. Measure the usefulness of the TEST by.. DISEASE Present Absent 5 Positive 45 b a TEST c d Negative 5 45 Sensitivity Specificity Sensitivity = a = 45 = 90% high sensy = a + c 50 few false negatives Specificity = d = 45 = 90% high specy = b + d 50 few false positives

  46. Test with a high specificity useful to rule in a diagnosis e.g. before cancer chemotherapy Test with high sensitivity useful to rule out a diagnosis e.g. antenatal for syphilis Sensitivity and specificity are properties of the test and are taken into account when deciding whether to test.

  47. But…… (and this is the hard bit so concentrate NOW) • When the test result is available the usefulness of the result depends on:- • How good (or bad) the test was at detecting true positives and true negatives • The pre-test probability of the person being tested actually having the disease for which they are being tested.

  48. What is the pre-test probability of someone with dyspepsia being H pylori positive?What is the pre-test probability of someone with dyspepsia being H pylori negative?

  49. The Impact of Prevalence on Predictive Value (Bayes Theorem) DISEASE Absent Present Positive predictive value a = 45 = 90% a+b 50 5 Positive 45 b a c d TEST 5 45 Negative predictive value d = 45 = 90% c+d 50 Negative Sens = 45/50 i.e. 90% Spec = 45/50 i.e. 90% Prevalence = 50%

  50. Watch what happens when the prevalence drops to 10%……. DISEASE Present Absent PPV = 9 = 50% 18 POSITIVE 9 9 a b TEST NPV = 81 = 99% 82 NEGATIVE 1 81 c d Sensitivity = 9 = 90%Specificity = 81 = 90% 10 90

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