1. 1 Basic epidemiological study designs and its role in measuring disease exposure association M. A. Yushuf Sharker Assistant Scientist Center for Communicable diseases Icddr,b yushuf@icddrb.org

2. Measures of Disease Exposure Association Does coffee drinking affect the risk of pancreatic cancer? Coffee drinking is the exposure (E) or risk factor measured in binary scale Exposed = E = 1 Not exposed = E ’ = 0 Pancreatic cancer is the disease outcome (D) also measured in binary scale Disease = D = 1 Not Disease = D’ = 0 We are interested in the association between the risk factor and disease 2

3. Data We have collected information from the sampled individuals and arranged in the following table DiseaseNot Disease Exposedaba+b Not Exposedcdc+d a+cb+dN 3

4. Excess Risk (ER) -1 ≤ ER ≤ 1 ER = 0 is the null value, D and E are independent ER > 0 indicates greater risk of disease when exposed than when unexposed ER < 0 is the lower risk of disease ER is the excess number of cases as a fraction of the population size when population members are all exposed compared to them all being unexposed 4

5. Example: Excess Risk (ER) Risk of Pancreatic cancer associated with coffee drinking is.07 Or, We would expect the pancreatic cancer increase by 7% as all people appear as coffee drinker compared to all people being non-coffee drinker Pancreatic Cancer Dnot D Coffee Drinking E75259 not E7134141 14186200 5

6. Relative Risk (RR) RR is always non-negative RR = 1 is the null value RR > 1 indicates greater risk of disease when exposed than when unexposed RR < 1 is the lower risk of disease RR is not symmetric over the role of D and E 6

7. Example: Relative Risk (RR) The risk of having pancreatic cancer is 2.4 time higher among coffee drinkers than non-coffee drinkers Pancreatic Cancer Dnot D Coffee Drinking E75259 not E7134141 14186200 7

8. Odds Ratio (OR) OR is always non-negative OR = 1 is the null value OR > 1 indicates greater risk of disease when exposed than when unexposed OR < 1 is the lower risk of disease OR > RR OR is symmetric over the role of D and E Under rare disease assumption, OR closely approximates RR 8

9. Example: Odds Ratio (OR) Coffee drinkers are 2.6 time more likely to have cancer than non coffee drinkers Pancreatic cancer patients are 2.6 time more likely to be exposed in coffee drinking than non-diseased Pancreatic Cancer Dnot D Coffee Drinking E75259 not E7134141 14186200 9

10. Does associations indicate causal association? Not necessarily 10

11. Why causality assessment is so important in health research? We are interested to identify the risk factors that influence the risk of disease The objective of health research is to develop a sustainable intervention to reduce the risk of disease Interventions are designed to reduce the exposure to the risk factors to control the infection 11

12. Causal Association Association of disease occurrence with the risk factor is said to be causal if 1.The level of exposure is determined before the occurrence of the disease (level of exposure and Chronology) 2.The other conditions for both exposed and unexposed will remain identical 3.The factors which might be the outcome of exposure were not controlled by the identical condition We might require additional criterion to follow to be an association as causal, We are highlighting these three because these are linked with study designs. 12

13. Ideal experiment for causal association An ideal experiment GroupCoffee (E)Not Coffee (E')Number 1DDNp1 2DD'Np2 3D'DNp3 4D' Np4 Think about the causal effect of Coffee drinking (E) and Pancreatic Cancer (D) 13

14. Real world Experiment A real world experiment Unobserved response is called counterfactual Measures of causal effect depends on the distribution of counterfactuals Counterf actual of subject 1 Counterf actual of subject 2 Counterf actual of subject 3 14

15. Real world Experiment Let us consider a specific distribution of counterfactual Group 1 and 3 we observed the response to coffee drinking and 2 and 4 to non coffee drinking GroupCoffee (E)Not Coffee (E')Number 1DNp1 2D'Np2 3D'Np3 4D'Np4 15

16. Real world Experiment Population data on coffee drinking and pancreatic cancer with specific counterfactual distribution GroupDNot DTotal ENp1Np3N(p1+p3) E’0N(p2+p4) TotalNp1N(p2+p3+p4)N We might think of different distribution of counterfactual that might give us different values between 0 to inf. Such specific distribution does not guarantee RR = RR causal 16

17. Real world Experiment Suppose for each group, the toss of a coin determines whether an individual of a group whether he/she is a coffee drinker or abstainer. We can expect the following 2 X 2 table GroupDNot DTotal EN(p1+p2)/2N(p1+p4)/2N/2 E’N(p1+p3)/2N(p2+p4)/2N/2 TotalN(2p1+p2+p3)/2N(p2+p3+2p4)/2N Even if the distribution of exposure is random, Then on average, the real world experiment might determine the causal association 17

18. Study Designs We design our studies following the basic requirements so that our observed association could translate into causal association. The basic study designs in epidemiological research are as follows Observational Cross Sectional Case-Control study Cohort Study Experimental Randomized control trial 18

19. Select a random sample of size n from the study population Example: Coffee drinking and pancreatic cancer Cross sectional survey Pancreatic Cancer Dnot D Coffee Drinking E75259 not E7134141 14186200 19

20. Choice of an individual (under either exposure) is random This fits with the required condition to be In addition, Joint, marginal and conditional probabilities can be estimated using data from the cross sectional survey which really useful to translate the disease process. Cross sectional survey 20

21. Disease Status Dnot D Coffee Drinking E75259 not E7134141 14186200 Cross sectional survey 21

22. Not suitable for infectious or high fatal disease Exposure and outcome examined simultaneously Cannot infer the temporal sequence of E-D Cross sectional survey 22

23. Case-Control Studies Identify the two sub-group of population of diseased and not diseased Select a random samples from diseased and not diseased group separately Measure subsequently the presence and absence of E of each individuals in the past in both samples 23

24. Case-Control Studies The distribution of exposure condition is random Confirms that exposure happened before disease We can only estimate the conditional probabilities of exposure for given either disease condition We can only estimate the Odds Ratio using the symmetric properties of OR In rare disease condition, OR closely approximates RR 24

25. Case-Control Studies Example: Possible data from a Case-Control study (n d = n d’ = 100) Pancreatic cancer LowNormal Coffee Drinking E502878 not E5072122 100 200 The probability of getting coffee drinker is 2.6 time more likely in diseased group than not diseased group 25

26. Limitations of Case-Control Studies Exposure measurement error Selection bias through inappropriate choice of controls Clear definition of case and control and predefined method of control selection could reduce the chance of bias but we have very few tools to control the exposure measurement error 26

27. Variants of Case-Control Studies Risk set sampling In a dynamic cohort, all disease does not happened at the same time. If a patient was identified at time t, we select controls from the population of individuals who are at risk at time t. Case cohort design In this approach we select a set of diseased individuals within a time interval [0, T] through risk set sampling. m controls are chosen at random from the entire population at risk 27

28. Cohort Studies Identify two sub-groups of the population on the basis of their exposure level and follow-up Take a random sample from each of the two subgroups Measure subsequently the presence or absence of disease of the selected individuals of the both subgroups Sampling is carried out separately for sub populations at different levels of exposure 28

29. Example data from Cohort Studies Pancreatic Cancer Dnot D Coffee Drinking E1288100 not E595100 17183200 Joint and marginal probabilities are not estimable Only conditional probabilities conditioning on exposure are estimable RR, OR and ER are estimable from such study design Possible data from a cohort study (n=200) 29

30. future time Study population Exposure Non-exposure outcome no outcome outcome no outcome baseline RANDOMIZATION Randomized Control Trial (RCT) 30

31. A Randomized Control Trial Provides high degree of validity to establish causality Maintain all the advantage of cohort design Ethical challenges of experimental research Most costly & time consuming – Randomization, blinding… Not feasible for outcomes that are rare or have long lag times Randomized Control Trial (RCT) 31

32. Hierarchy of Epidemiologic Study Designs Tower & Spector, 2007 Case reports Case series Ecologic studies Cross-sectional studies Case-control studies Cohort studies Randomized controlled trials Generates hypotheses Establish causality 32

33. Common Errors and biases in causal association All study design for causal association suffers the following Errors and biases Measurement error of disease and exposures Information bias Selection Bias Confounder 33

34. Take Home Messages Statistical association are not necessarily causal association Study designs provides situations so that the real world experiments close approximate the outcomes to ideal experiments Different study designs provide different levels of confident for causal association 34