1. Measures of Disease Association Measuring occurrence of new outcome events can be an aim by itself, but usually we want to look at the relationship between an exposure (risk factor, predictor) and the outcome The type of measure showing an association between an exposure and an outcome event is linked to the study design

2. Main points to be covered Measures of association compare measures of disease between levels of a predictor variable Prevalence ratio versus risk ratio Probability and odds The 2 X 2 table Properties of the odds ratio Absolute risk versus relative risk Disease incidence and risk in a cohort study

3. Cross-Sectional Study Design: A Prevalent Sample

4. Measures of Association in a Cross-Sectional Study Simplest case is to have a dichotomous outcome and dichotomous exposure variable Everyone in the sample is classified as diseased or not and having the exposure or not, making a 2 x 2 table The proportions with disease are compared among those with and without the exposure NB: Exposure=risk factor=predictor

5. 2 x 2 table for association of disease and exposure Disease Yes No Exposure Yes No a b cd a + b c + d a + cb + d N = a+b+c+d Note: data may not always come to you arranged as above. STATA puts exposure across the top, disease on the side.

6. Prevalence ratio of disease in exposed and unexposed Disease Yes No Exposure Yes No a b cd a + b c + d c a PR =

7. Prevalence Ratio Text refers to Point Prevalence Rate Ratio in setting of cross-sectional studies We like to keep the concepts of rate and prevalence separate, and so prefer to use prevalence ratio

8. Exposed Unexposed | Total --------------------------------------------------- Cases | 14 388 | 402 Noncases | 17 248 | 265 --------------------------------------------------- Total | 31 636 | 667 | | Risk |.4516129.6100629 |.6026987 Point estimate [95% Conf. Interval] --------------------------------------------- Risk ratio.7402727 |.4997794 1.096491 ----------------------------------------------- chi2(1) = 3.10 Pr>chi2 = 0.0783 Prevalence ratio (STATA output) STATA calls it a risk ratio by default

9. Prevalence ratio of disease in exposed and unexposed Disease Yes No Exposure Yes No a b cd a + b c + d c a PR = So a/a+b and c/c+d = probabilities of disease and PR is ratio of two probabilities

10. Probability and Odds Odds another way to express probability of an event Odds = # events # non-events Probability = # events # events + # non-events = # events # subjects

11. Probability and Odds Probability = # events # subjects Odds = # events # subjects = probability # non-events (1 – probability) # subjects Odds = p / (1 - p) [ratio of two probabilities]

12. Probability and Odds If event occurs 1 of 5 times, probability = 0.2. Out of the 5 times, 1 time will be the event and 4 times will be the non-event, odds = 0.25 To calculate probability given the odds: probability = odds / 1+ odds

13. Odds versus Probability Less intuitive than probability (probably wouldn’t say “my odds of dying are 1/4”) No less legitimate mathematically, just not so easily understood Used in epidemiology because the measure of association available in case-control design is the odds ratio Also important because the log odds of the outcome is given by the coefficient of a predictor in a logistic regression

14. Odds ratio As odds are just an alternative way of expressing the probability of an outcome, odds ratio (OR), is an alternative to the ratio of two probabilities (prevalence or risk ratios) Odds ratio = ratio of two odds

15. Probability and odds in a 2 x 2 table Disease Yes No Exposure Yes No 2 3 14 5 5 10 3 7 What is p of disease in exposed? What are odds of disease in exposed? And the same for the un-exposed?

16. Probability and odds ratios in a 2 x 2 table Disease Yes No Exposure Yes No 23 14 5 5 10 3 7 PR = 2/51/5 = 2 0R = 2/31/4 = 2.67

17. Odds ratio of disease in exposed and unexposed Disease YesNo Exposure Yes No ab c d a + b c + d c a OR = a a + b 1 - c c + d 1 - Formula of p / 1-p in exposed / p / 1-p in unexposed

18. Odds ratio of disease in exposed and unexposed a + b c + d c a OR = a a + b 1 - c c + d 1 - = a a + b b a + b c c + d d c + d a b c d == ad bc

19. Important Property of Odds Ratio #1 The odds ratio of disease in the exposed and unexposed equals the odds ratio of exposure in the diseased and the not diseased –Important in case-control design

20. Odds ratio of exposure in diseased and not diseased Disease YesNo Exposure Yes No ab c d a + c b + d b a OR = a a + c 1 - b b + d 1 -

21. OR for disease = OR for exposure a + c b + d b a OR exp = a a + c 1 - b b + d 1 - = a a + c c a + c b b + d d b + d a c b d == ad bc Important characteristic of odds ratio

22. Measures of Association Using Disease Incidence With cross-sectional data we can calculate a ratio of the probability or of the odds of prevalent disease in two groups, but we cannot measure incidence A cohort study allows us to calculate the incidence of disease in two groups

23. Measuring Association in a Cohort Following two groups by exposure status within a cohort: Equivalent to following two cohorts defined by exposure

24. Analysis of Disease Incidence in a Cohort Measure occurrence of new disease separately in a sub-cohort of exposed and a sub-cohort of unexposed individuals Compare incidence in each sub-cohort How compare incidence in the sub-cohorts?

25. Relative Risk vs. Relative Rate Risk is based on proportion of persons with disease = cumulative incidence Risk ratio = ratio of 2 cumulative incidence estimates = relative risk Rate is based on events per person-time = incidence rate Rate ratio = ratio of 2 incidence rates = relative rate We prefer risk ratio, rate ratio, odds ratio

26. A Note on RR or “Relative Risk” Relative risk or RR is very common in the literature, but may represent a risk ratio, a rate ratio, a prevalence ratio, or even an odds ratio We will try to be explicit about the measure and distinguish the different types of ratios There can be substantial difference in the association of a risk factor with prevalent versus incident disease

27. Difference vs. Ratio Measures Two basic ways to compare measures: –difference: subtract one from the other –ratio: form a ratio of one over the other Can take the difference of either an incidence or a prevalence measure but rare with prevalence Example using incidence: cumulative incidence 26% in exposed and 15% in unexposed, –risk difference = 26% - 15% = 11% –risk ratio = 0.26 / 0.15 = 1.7

28. Summary of Measures of Association RatioDifference Cross-sectional prevalence ratioprevalence difference odds ratioodds difference Cohortrisk ratiorisk difference rate ratiorate difference odds ratioodds difference

29. Why use difference vs. ratio? Risk difference gives an absolute measure of the association between exposure and disease occurrence –public health implication is clearer with absolute measure: how much disease might eliminating the exposure prevent? Risk ratio gives a relative measure –relative measure gives better sense of strength of an association between exposure and disease for inferences about causes of disease

30. Relative Measures and Strength of Association with a Risk Factor In practice many risk factors have a relative measure (prevalence, risk, rate, or odds ratio) in the range of 2 to 5 Some very strong risk factors may have a relative measure in the range of 10 or more –Asbestos and lung cancer Relative measures < 2.0 may still be valid but are more likely to be the result of bias –Second-hand smoke relative risk < 1.5

31. Example of Absolute vs. Relative Measure of Risk TB recurrence No TB recurrence Total Treated > 6 mos 14 986 1000 Treated < 3 mos 40 960 1000 Risk ratio = 0.04/0.014 = 2.9 Risk difference = 0.04 – 0.014 = 2.6% If incidence is very low, relative measure can be large but difference measure small

32. Reciprocal of Absolute Difference ( 1/difference) Number needed to treat to prevent one case of disease Number needed to treat to harm one person Number needed to protect from exposure to prevent one case of disease TB rifampin example: 1/0.026 = 38.5, means that you have to treat 38.5 persons for 6 mos vs. 3 mos. to prevent one case of TB recurrence

33. Table 2. Survival and Functional Outcomes from the Two Study Phases Study Phase Return of Spontaneous Circulation Risk Difference (95% CI) p-value Rapid Defibrillation ( N=1391) 12.9% -- Advanced Life Support (N=4247) 18.0% 5.1% (3.0-7.2) <0.001 Stiel et al., NEJM, 2004 Example of study reporting risk difference Risk difference = 0.051; number needed to treat = 1/0.051 = 20

34. Risk Ratio Diarrheal Disease Yes No Total Ate potato salad 54 16 70 Did not eat potato salad 2 26 28 Total 56 42 98 Probability of disease, ate salad = 54/70 = 0.77 Probability of disease, no salad = 2/28 = 0.07 Risk ratio = 0.77/0.07 = 11 Illustrates risk ratio in cohort with complete follow-up

35. Risk Ratio in a Cohort with Censoring Choose a time point for comparing two cumulative incidences: At 6 years, % dead in low CD4 group = 0.70 and in high CD4 group = 0.26. Risk ratio at 6 years = 0.70/0.26 = 2.69

36. Comparing two K-M Curves Risk ratio would be different for different follow-up Times. Entire curves are compared using log rank test (or other similar tests).

37. OR compared to Risk Ratio 0 1∞ Stronger effect OR Risk Ratio Stronger effect Risk Ratio OR If Risk Ratio = 1.0, OR = 1.0; otherwise OR farther from 1.0

38. Risk ratio and Odds ratio If Risk Ratio > 1, then OR farther from 1 than Risk Ratio: RR = 0.4 = 2 0.2 OR = 0.4 0.6 = 0.67 = 2.7 0.2 0.25 0.8

39. Risk ratio and Odds ratio If Risk Ratio < 1, then OR farther from 1 than RR: RR = 0.2 = 0.67 0.3 OR = 0.2 0.8 = 0.25 = 0.58 0.3 0.43 0.7

40. Exposed Unexposed | Total --------------------------------------------------- Cases | 14 388 | 402 Noncases | 17 248 | 265 --------------------------------------------------- Total | 31 636 | 667 | | Risk |.4516129.6100629 |.6026987 Point estimate [95% Conf. Interval] --------------------------------------------- Risk ratio.7402727 |.4997794 1.096491 Odds ratio.5263796 |.2583209 1.072801 ----------------------------------------------- chi2(1) = 3.10 Pr>chi2 = 0.0783 Odds ratio (STATA output)

41. Important property of odds ratio #2 OR approximates Risk Ratio only if disease incidence is low in both the exposed and the unexposed group

42. Risk ratio and Odds ratio If risk of disease is low in both exposed and unexposed, RR and OR approximately equal. Text example: incidence of MI risk in high bp group is 0.018 and in low bp group is 0.003: Risk Ratio = 0.018/0.003 = 6.0 OR = 0.01833/0.00301 = 6.09

43. Risk ratio and Odds ratio If risk of disease is high in either or both exposed and unexposed, Risk Ratio and OR differ Example, if risk in exposed is 0.6 and 0.1 in unexposed: RR = 0.6/0.1 = 6.0 OR = 0.6/0.4 / 0.1/0.9 = 13.5 OR approximates Risk Ratio only if incidence is low in both exposed and unexposed group

44. “Bias” in OR as estimate of RR Text refers to “bias” in OR as estimate of RR (OR = RR x (1-incid. unexp )/(1-incid. exp )) –not “bias” in usual sense because both OR and RR are mathematically valid and use the same numbers Simply that OR cannot be thought of as a surrogate for the RR unless incidence is low

45. Important property of odds ratio #3 Unlike Risk Ratio, OR is symmetrical: OR of event = 1 / OR of non-event

46. Symmetry of odds ratio versus non-symmetry of risk ratio OR of non-event is 1/OR of event RR of non-event = 1/RR of event Example: If cum. inc. in exp. = 0.25 and cum. inc. in unexp. = 0.07, then RR (event) = 0.25 / 0.07 = 3.6 RR ( non-event ) = 0.75 / 0.93 = 0.8 Not reciprocal: 1/3.6 = 0.28 = 0.8

47. Symmetry of OR Example continued: OR (event) = 0.25 (1- 0.25) = 4.4 0.07 (1- 0.07) OR (non-event) = 0.07 (1- 0.07) = 0.23 0.25 (1- 0.25) Reciprocal: 1/4.46 = 0.23

48. Important property of odds ratio #4 Coefficient of a predictor variable in logistic regression is the log odds of the outcome (e to the power of the coefficient = OR) –Logistic regression is the method of multivariable analysis used most often in cross-sectional and case-control studies

49. 3 Useful Properties of Odds Ratios Odds ratio of disease equals odds ratio of exposure –Important in case-control studies Odds ratio of non-event is the reciprocal of the odds ratio of the event (symmetrical) Regression coefficient in logistic regression equals the log of the odds ratio

50. Summary points Cross-sectional study gives a prevalence ratio Risk ratio should refer to incident disease Relative ratios show strength of association Risk difference gives absolute difference indicating number to treat/prevent exposure Properties of the OR important in case-control studies –OR for disease = OR for exposure –Logistic regression coefficient gives OR