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

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Presentation on theme: "Clinical Epidemiology – the basics. What do the terms relative risk and absolute risk mean? What are the advantages and disadvantages of each? A new screening."— Presentation transcript:

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 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 EFFECTIVESAFE COST PATIENT FACTORS

7 QUALITY OF CARE SYSTEMATIC APPLICATION OF THERAPY 100% 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 dont 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 TOMORROWS 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 isnt 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 CasesControls EXPOSURE Yes a b EXPOSURE No c d Odds Ratio = ad/bc (1 = no association, > 1 = possible association, < 1 = protective effect) DISEASE CasesControls (lung cancer) EXPOSUREYes (smoking)No The odds ratio would therefore be 56 x 246 = = x

21 TYPES OF STUDY - HYPOTHESIS TESTING COHORT STUDIES

22 OUTCOME YesNo 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) YesNo Exposed ( on oral contraceptive ) Not exposed (not on o.c.) 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 OUTCOME YesNo 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 RRR A 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 detail 4S 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) Experimental intervention (simvastatin) The ARR is (256/2223) - (182/2221) = = 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) Experimental intervention (simvastatin) Prevalence of event in control group = 256/2223x100=11.5% RRR = 29%

30 Now thats 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:

34 Odds ratios or relative risks? Macfarlane J et al. BMJ 2002; 13: Patients who took antibiotics Patients who did not take antibiotics TOTAL Patients who were given a leaflet Patients not given a leaflet TOTAL

35 Patients who took antibiotics Patients who did not take antibiotics TOTAL Patients who were given a leaflet Patients not given a leaflet TOTAL Relative risk: (49/104) / (63/101) = 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 Patients who took antibiotics Patients who did not take antibiotics TOTAL Patients who were given a leaflet Patients not given a leaflet TOTAL Odds ratio: (49/55) / (63/38) = 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 Patients who took antibiotics Patients who did not take antibiotics TOTAL Patients who were given a leaflet Patients not given a leaflet TOTAL Absolute risk reduction: (49/104) – (63/101) = 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 Patients who took antibiotics Patients who did not take antibiotics TOTAL Patients who were given a leaflet Patients not given a leaflet TOTAL 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:

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 aint what they used to be Joseph Heller Catch 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 No Disease AB Percent of population No Disease No Disease VALUE Arbitrary Units Set cut off at AA lot of people who do not have the disease are labeled as having it (false positives) Set cut off at B A lot of people who do have the disease are labeled as not having it (false negatives) Disease C

44 DISEASE Present Absent TEST Positive Negative a b cd

45 Measure the usefulness of the TEST by.. Positive Negative a b c d TEST PresentAbsent DISEASE SensitivitySpecificity Sensitivity = a = 45 = 90%high sens y = a + c 50few false negatives Specificity = d = 45 = 90%high spec y = b + d 50few 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:- 1.How good (or bad) the test was at detecting true positives and true negatives 2.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 TEST Positive Negative a b cd Present Absent DISEASE Positive predictive value a = 45 = 90% a+b 50 Prevalence = 50% Negative predictive value d = 45 = 90% c+d 50 Sens = 45/50 i.e. 90% Spec = 45/50 i.e. 90% The Impact of Prevalence on Predictive Value (Bayes Theorem)

50 DISEASE PresentAbsent ab cd TEST POSITIVE NEGATIVE PPV = 9 = 50% 18 NPV = 81 = 99% 82 Sensitivity =9 = 90%Specificity = 81 = 90% Watch what happens when the prevalence drops to 10%…….

51 Likelihood ratios express how many more times (or less times) a test result is to be found in diseased people compared with non-diseased people. TEST Positive Negative Present Absent a c b d DISEASE LR +ve = aLR -ve = ca + c b db + d This change can be described arithmetically by likelihood ratios.

52 Likelihood ratios - EXAMPLE TEST POSITIVE NEGATIVE DISEASE PRESENT ABSENT ab cd LR +ve =0.9 = 10LR -ve =0.1 =

53 New non-invasive tests for H. Pylori Gastritis. Comparison with tissue-based gold standard. Douglas O, et al. Digestive Diseases and Sciences 1996; 41:740-8 Urea Breath Test Sens. Spec. LR +ve LR -ve Serum Anti-bodies Here comes another (different) magic nomogram!

54 +ve-ve PrevalencePTPPTP UBT20%85%2% 40%95%5% Sab20%60%5% 40%80%12% PTP - Post-test probability UBT - urea breath test Sab - serum antibody test

55 +ve-ve PrevalencePTPPTP UBT20%85%2% 40%95%5% Sab20%60%5% 40%80%12% PTP - Post-test probability UBT - urea breath test Sab - serum antibody test

56 H Pylori infection in a population with a 25% prevalence MeReC Bulletin 2001; 12 (1): Near-patient serological tests Laboratory serological tests Breath test ( 14 C) Breath test ( 13 C) False Negative results (%) False positive results (%) Negative predictive value (%) Positive predictive value (%) Specificity (%) Sensitivity (%)

57 SUMMARY

58 EVIDENCE BASED MEDICINE FORMULATE QUESTION EFFICIENTLY TRACK DOWN BEST AVAILABLE EVIDENCE CRITICALLY REVIEW THE VALIDITY AND USEFULNESS OF THE EVIDENCE IMPLEMENT CHANGES IN CLINICAL PRACTICE EVALUATE PERFORMANCE

59 The evidence isnt there (whinge, moan) OR I dont have the time (whine, complain) Clinical Evidence Cochrane DTB, MeReC Bulletin PRODIGY Evidence Based Medicine

60 LIMITATIONS STILL LOTS OF ROOM FOR DEBATE ABOUT THE EVIDENCE BASE EBM = WHAT IS BEST FOR AN INDIVIDUAL PATIENT (patient utility) EVIDENCE BASED PURCHASING = BEST USE OF HEALTH CARE RESOURCES FOR THE LOCAL POPULATION (cost utility). i.e. knowledge of local needs, priorities and constraints WHAT IF THESE CONFLICT? (Anybody want to mention beta interferon and MS?!)

61 EBM VISION FROM 1996


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