Epidemiology & Evidence Based Medicine. Patrick Linden & Matthew McCall

Transcription

1 Epidemiology & Evidence Based Medicine Patrick Linden & Matthew McCall

2 Areas Covered in this Talk Bradford Hill Criteria Bias and confounding Study designs, advantages and disadvantages Basic definitions Basic stats Screening

3 Association & Causation Not the same (obviously) An associated factor is one frequently found in the presence of a certain disease or outcome A causal factor is involved in the pathophysiology of a disease or outcome

4 Bradford Hill Criteria (Remember ACCESS DTP) Analogy Consistency Coherence Experimental evidence Strength Specificity Dose response Temporality Key principle Plausibility (Reversibility)

5 A YES C YES C YES E YES * S YES S No D YES T YES P YES Smoking & Lung Ca.

6 Causes of Apparent Association Chance Bias Confounding True causality Reverse causality

7 PPQ There is some evidence from cohort studies that people with high educational attainment have a lower risk of dementia and suggest a use it or lose it explanation. Q3 Describe two other possible explanations for such findings. (2 marks)

8 Bias Deviation from the truth due to systematic error in study design May be arise due to Selection bias Information bias

9 Selection Bias Due to difference(s) between the study pop. and the theoretically eligible pop. Sampling bias Influenced by sampling method Participation bias Differences in those agreeing to participate Referral/admission bias Selective referral by study staff Healthy worker effect Employed generally healthier Healthy volunteer effect Volunteers usually health conscious Survivor bias Survivors of disease may be unique

10 Information Bias Systematic measurement or misclassification error Recall bias Patients with disease remember differently Observer bias Data collection differs between groups Detection bias One group followed up more rigorously Loss to follow up Greater attrition of on arm of study

11 Does drinking coffee cause CVD?

12 Confounding A 3 rd factor associated with both exposure and outcome Confounders are independent RFs for the outcome Confounders are not on the causal pathway Leads to 1. Underestimation of assoc 2. Overestimation of assoc 3. Reversal of direction of assoc (Simpson s paradox)

13 Controlling for Confounding Through study design (*Discussed later) Randomisation * Restriction Matching * Using statistical analysis Stratification Standardisation Multivariate analysis

14 Types of Study Meta analysis/systematic review RCT Cohort Case Control Cross sectional/ecological Case report Expert opinion

15 Case Control Study Comparison of participants with a disease ( cases ) to those without ( controls ) Criteria defined for what will be a case Incident (new) cases preferred Matching of controls to cases Matched on variables to reduce confounding Potential for introducing selection bias

16 Case Control cont. Advantages Good for rare diseases Minimises loss to follow up Quick, no waiting time Cheap Can examine multiple variables Disadvantages Retrospective (no temporal info) Cannot demonstrate causality Cannot estimate incidence, Odds ratio not RR *** Risk of bias esp. recall bias

17 Cohort Study Prospective study following a selected pop. over time Exposure status is determined at the study outset The frequency of diseases of interest is recorded Comparison of Exposed and Unexposed groups Unexposed group acts as an internal control group Used to estimate Prevalence Incidence Relative Risk (RR)

18 Cohort cont. Advantages Temporal info Causality can be investigated Incidence can be estimated Can be used to estimate multiple outcomes Can minimise the biases of a case control study Disadvantages Timely Costly Require a large sample Loss to follow up Drift phenomena affecting comparison of earlier and later results

19 Nested Case Control Study Case control study within an already existing cohort Cases are those that develop outcome of interest Controls randomly selected from the remaining outcome negative cohort pop.

20 Randomised Control Trial (RCT) Participants are randomised to receive different interventions aiming to minimise potential bias Outcome data is collected for each treatment arm and the groups are compared Usually, New treatment vs. Placebo/old treatment

21 Randomisation Avoids conscious and unconscious bias Balances groups for confounders There is a concurrent comparison group

22 Blinding Single Participant OR observer blind to intervention Double Participant AND observer blinded Minimises biases due to Preferential participant allocation Preferential intervention delivery Use of co interventions Data collection

23 Intention to treat analysis Participants are analysed according to the group they are allocated to rather than the treatment they receive Accurately compares the intervention strategies Eg. Trial of PCI (stents) vs. CABG (bypass surgery) for cardiac risk reduction, patients allocated to surgery who are ineligible (unfit for surgery, waiting lists, etc) who proceed to PCI are still allocated as a within surgery arm of RCT Sequential analysis Continuous analysis if expected benefits or AE s are high (can stop trial early)

24 RCT s cont Advantages Gold standard, minimises bias Can compare interventions Can be used in meta analysis Disadvantages Time consuming Expensive Resource intensive Ethical issues Risk of selection bias Risk of contamination (intervention arms mixing)

25 Cluster RCT Allocation by cluster Eg. GP practice, village, workplace Used in situations were contamination is expected Used if participants within a cluster are expected to be similar Improves adherence and is easier to administrate Requires larger sample for analysis (for intra class correlation)

26 Evidence Based Medicine Advantages Guides best practice Aids decision making Develops guidelines Disadvantages Time consuming The evidence base may be biased or wrong Ignores patient choice Ignores value of clinical experience

27 Meta Analysis Compilation of relevant RCT s and/or cohort studies Used to calculate a pooled effect estimate Provide a clearer idea of the true picture (theoretically)

28 Forest Plot Differential weighting of each study Effect estimates (squares) + 95% CI (lines) Pooled effect estimate calculated

29 Funnel Plot Used to check for publication bias Trend to suppress studies suggesting no effect or negative findings Paucity of values around the null (usually 0 or 1) suggests bias Absent white study findings

30 Meta analysis cont. Advantages Clearer idea of the truth (potentially) Larger sample pop = Greater statistical power Weighting in favour of more rigorous studies Disadvantages May be publication bias Inclusion criteria strict Studies may not be similar enough to pool Differences in methods Differences in outcomes Differences in follow up

31 Prevalence The number of affected persons (cases) in a pop. at risk at a specific time Measure of chronic disease levels Point prevalence Prevalence at a single point in time Period prevalence Number affected at any time during a specific time period = (No. of cases / No. within pop. at risk) x1000

32 Incidence The number of new cases occurring during a specified time period in a pop. at risk Uses Predict the expected number of new cases Predict rise and fall in disease levels Measure of absolute risk = (No. of new cases / No. at risk) x1000

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34 Relative Risk (RR) The risk of developing an outcome/disease after an exposure vs. the risk without the exposure RR = Incidence in exposed / Incidence in nonexposed Outcome Status +ve ve Exposure +ve A B Status ve C D RR = (A / A+B) / (C / C+D)

35 Odds Ratio (OR) Calculated from case control studies (incidence cannot be calculated) May provide an approximation to RR if the incidence is low Outcome Status +ve ve Exposure +ve A B Status ve C D OR = (A/B) / (C/D) = AD / BC

36 Attributable Risk (AR) The difference in the rates of disease occurring in the exposed pop vs. the unexposed pop ie. the number of cases attributable to the exposure Eg. Cases of lung ca attributable to smoking AR = Incidence Exposed Incidence Unexposed

37 In this trial, for instance, 22 of 40 patients given ibuprofen had adequate pain relief compared with only 7 of 40 given placebo. Exposure Outcome Positive + Negative Positive Negative 7 33 OR = ad/bc = 22x33/18x7 = 726/126 = 5.76 Therefore ibuprofen is much better than placebo at pain relief or Exposure positive is better than exposure negative

38 A recent meta analysis study of the benefits of stroke units reviewed the outcome of 2000 patients randomised to supportive care in a general medical ward and 2000 patients randomised to a specialised stroke unit where they received a patient specific treatment programme. By the end of scheduled follow up the numbers who had died or were in institutional care overall were 500 in the stroke units and 600 in the conventional wards. Q6 Based on these findings how many patients need to be treated in a stroke unit rather than in a conventional ward to result in one extra non institutionalised survivor? Show your calculation (2.5 marks)

39 Number needed to treat = reciprocal of Absolute Risk Reduction (ARR) Outcome Status + live - death Intervention Group + special general ARR =a/(a+b) c/(c+d ) NNT = 1/ARR = 1500/ /2000 = 20 people = 1/20

40 PPQ There is some dispute about whether the relative risk of lung cancer from smoking is more important than its population attributable risk (PAR). Explain the terms relative risk and population attributable risk.

41 Test Characteristics Sensitivity Ability of a test to identify an individual with a disease A sensitive test has few false Negatives Rules a disease out SNout Sensitivity = ( A / A + C ) Specificity Ability of a test to identify an individual without a disease A specific test has few false Positives Rules a disease in SPin Specificity = ( B / B + D ) Test Status Disease Status +ve ve +ve A B ve C D

42 Test Characteristics cont. Positive Predictive Value (PPV) Proportion of test +ve individuals that are truly disease +ve PPV = ( A / A + B ) Negative Predictive Value (NPV) Proportion of test ve individuals that are truly disease ve NPV = ( D / C + D ) Disease Status +ve ve Test +ve A B Status ve C D

43 Statistics P value The probability of obtaining results as or more extreme if the null hypothesis is true Significance (usually) set at p < 0.05 (or p < 0.001) Type 1 error The incorrect rejection of an true null hypothesis Making an association were there isn t one Type 2 error The failure to reject a false null hypothesis Failing to recognise that there is an association

44 95% Confidence Limits The likelihood that if a sample was repeated 100 times the mean would lie within the interval values 95 times Narrow CL s suggest accurate results Significant results will not include 1

45 PPQ Following the high profile death of a couple of young sportsmen, some sporting associations and local charities have advocated the screening of young athletes for occult cardiomyopathy. Q6 What criteria should guide the decision to implement any public health screening programme? (4 marks)

46 Screening Wilson Jungner Criteria 1. The condition should be an important health problem 2. The disease s natural history should be well understood 3. There should be a detectable early stage 4. There should be a benefit of earlier treatment 5. A suitable screening test should be in place 6. The test should be acceptable 7. Intervals for repeating the test should be determined 8. There should be service provision to handle the workload created by screening 9. The benefits must outweigh the risks 10. It should be cost effective

47 Screening cont. Lead time bias The time between disease detection on screening and the time when the disease would have presented clinically Occurs when earlier detection does not improve prognosis Eg. PSA and prostate cancer Lag time bias Screening picks up indolent, clinically non significant disease Misses quickly developing, aggressive disease Skews survival data and leads to unnecessary treatment Eg. Breast screening Interval cancer/disease Disease diagnosed during the screening interval

48 Questions?

49 Some More Past Paper Questions

50 PPQ In a longitudinal study of newborn infants born between 1980 and 1984, 1035 children were followed up until they were 13 years old. Information was collected (from the parents) about whether that had attended day care nurseries when they were young. The relative risk of asthma for those children who regularly attended day care nurseries before they were 6 months old, (compared to those who didn t) was 0.4 ( ). Q5. What statistical interpretation do you give to the relative risk (and its confidence limits) (2 marks) Q6. Aside from taking account of potential confounders, in general what additional information is required to calculate a Population Attributable Fraction (formula not required) and what information does this PAF convey?

51 PPQ You wonder if there is an association between alcohol consumption and the development of gout. Q7. How would you set up a study to determine the incidence of alcohol related gouty episodes? (2 marks) You find a relative risk of gout in males who consume more than 30 units of alcohol per week of 2.5. Q8. What does a relative risk of 2.5 mean?

52 PPQ Screening tests are used in the neonatal period to detect certain types of deafness in children Q7 Describe 6 (six) of the GENERAL criteria that are used to judge the worth and validity of any screening programme. (3 marks)

53 PPQ A recent study has shown that the relative risk of heart disease among regular users of non steroidal antiinflammatory drugs is 1.7 (95% confidence limits ). When trying to explain this finding, epidemiologists will try to decide between chance, bias, confounding and causality. Q7 With regard to the above study findings, EXPLAIN the terms: (a) Chance (b) Bias (c) Confounding (d) Causality (4 marks)

54 PPQ A Large prospective cohort study has demonstrated that the relative risk of stroke, over five years of follow up for men with hypertension ( as described above) is of the order of 2 (95% confidence limits ) Q9 Explain the terms relative risk and confidence limits (2 marks)

55 PPQ Q9 Although herd immunity has little bearing in TB, explain what herd immunity is? (2 marks)

56 PPQ Across the countries in the European Union, there is a positive correlation between the rate of mortality caused by cirrhosis of the liver and the average per capita consumption of alcohol. Q6 With the use of diagrams, explain the terms correlation and regression with regard to alcohol consumption and cirrhosis mortality rates described above. (2 marks) Q7 Over 20 years ago the late Sir Geoffrey Rose suggested that we might reduce the harm from alcohol related morbidity if we all drank less rather than getting the really heavy drinkers to stop. Explain his logic. (2 marks)

57 A successful vaccination programme requires coverage to exceed a critical percentage of the population. Why might 100% coverage not be necessary? (2 marks)

58 PPQ The health service badly needs more dialysis capacity but many of the additional new patients being put on dialysis are in their 80 s. Q9 Describe one way in which a health economist might help us determine the right number of additional dialysis stations. (1 mark)