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Dr.

Robert Chapman PH 501, Academic Year 2010-11 REVIEW MATERIAL FOR EPIDEMIOLOGY IN PH 501, HEALTH PROBLEMS, DETERMINANTS, AND TRENDS MEASURES OF DISEASE RISK AND ASSOCIATION OF DISEASE WITH RISK FACTORS (ASSOCIATION OF DEPENDENT VARIABLES WITH INDEPENDENT VARIABLES) Prevalence = the proportion of the population with disease, or any other characteristic, at a single point in time. Note that prevalence does not apply just to disease. We can also measure the prevalence of non-disease characteristics, such as underweight, overweight, and poverty. We can regard prevalence as the probability of a disease, or other characteristic, existing in the population at a point in time. Incidence = the proportion of the population that gets new cases of disease over a specified period of time, usually 1 year. For example, if 10% of the population gets the disease during 1 year. we say that the annual incidence of this disease is 10%, or that the incidence is 10% per year. If the time period is not specified, it usually means annual incidence (incidence in one year). Prevalence = Incidence x Duration. Example: Assume that the annual incidence of disease A is 30%, and that the annual incidence of disease B is also 30%. The average duration of disease A is 0.05 years, and the duration of disease B is 0.6 years. Prevalence of disease A = (0.3/year)(0.05 year) = 0.015 = 1.5%. Prevalence of disease B = (0.3/year) (0.6 year) = 0.18 = 18%. Relative Risk (RR) = the ratio of disease risk (probability, such as prevalence) in exposed and unexposed groups. (Probability can also be expressed by incidence, but NOT by odds). Example: The prevalence of a disease in overweight people is 20%. The prevalence of the same disease in normal-weight people is 5%. The RR of overweight for this disease is 20% / 5% = 4. Note that relative risk does not have units. Attributable Risk (AR, also called Risk Difference) = the difference between disease risk in exposed and unexposed groups. In the example above, the AR of overweight for the disease is 20% - 5% = 15%. We can interpret this to mean that 15% of the overweight group has the disease specifically because of overweight. (5% of both the overweight and normal-weight groups have the disease for reasons other than overweight). Population-Attributable Risk Proportion (PARP), also called Population-Attributable Risk Fraction (PARF), also called the population-attributable fraction (PAF) = the proportion of all disease cases that are specifically attributable to the risk factor that we are studying. Consider the following example, presented in a 2 x 2 table.

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Disease No Yes Total

No

Overweight Yes 9500 3500 500 1500 10000 5000

Total 13000 2000 15000

Disease risk in the non-overweight group is 500/10000 = 5%. Disease risk in the overweight group is 1500 / 5000 = 30%. Thus, RR of overweight for disease is 30% / 5% = 6, and AR of overweight for disease is 30% - 5% = 25%. This means that 25% of the overweight group has the disease specifically attributable to overweight. That is, 0.25 X 5000 = 1250 people have the disease specifically attributable to overweight. The total number of disease cases is 500 + 1500 = 2000. Thus, 1250 / 2000 = 62.5% of all disease cases can be attributed specifically to overweight, so the PARP for overweight is 62.5%. Odds and odds ratio: Please see below. STUDY DESIGNS 1. Cross-sectional study In the cross-sectional study, the population is sampled at a single time. Thus, exposure and disease are measured at the same time, so it can be difficult to be sure that the exposure really occurred before the disease. In analysis, the data are first organized according to exposure status. Then disease frequency is compared at the different exposure levels. Exposure is the independent variable and disease is the dependent variable. (The dependent variable is also known as the outcome variable.) I prefer putting the indepenent variable in the columns, and the dependent variable in the rows, but this is not required. (It is required to understand which is the independent variable and which is the dependent variable). Example: We want to find out whether there is an association of smoking with COPD. We first choose smokers and non-smokers. Then we compare COPD prevalence in smokers and non-smokers. Here is a 2 by 2 table (2 x 2 table) of results. Non-smokers 9500 500 10000 Smokers 1500 500 2000 Total 11000 1000 12000

Without COPD With COPD Total

The prevalence of COPD in smokers is 500 / 2000 = 0.25 = 25%. The prevalence of COPD in non-smokers is 500 / 10000 = 0.05 = 5%. The relative risk (RR) of smoking for COPD is [(500 / 2000) / (500 / 10000)] = 0.25 / 0.05 = 5. Because 5 is considerably larger than 1, we say that smoking is associated with increased risk of COPD compared to not smoking. (Separate tests are required to say whether this association is "statistically significant.") There are often more than 2 exposure levels in cross-sectional studies and in other kinds of studies. An example is given in the table below. This is not a 2 x 2 table because now there are 3 levels of exposure, no exposure, light exposure, and heavy exposure. Note that the basic reasoning and calculation methods are very similar to those for the 2 x 2 table.
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Without COPD With COPD Total

Non-smokers 9500 500 10000

Light Smokers 850 150 1000

Heavy Smokers 650 350 1000

Total 11000 1000 12000

COPD prevalence in non-smokers is 500 / 10000 = 0.05 = 5%. Prevalence in light smokers is 150 / 1000 = 0.15 = 15%. Prevalence in heavy smokers is 350 / 1000 = 0.35 = 35%. Note that this shows a biological gradient (dose-response relationship) of smoking for COPD, because COPD frequency increases with each successive level of exposure. In this example it is possible to calculate the following 3 types of RR of smoking for COPD: (a) RR in light smokers compared to non-smokers (0.15 / 0.05 = 3); (b) RR in heavy smokers compared to non-smokers (0.35 / 0.05 = 7); and (c) RR in heavy smokers compared to light smokers (0.35 / 0.15 = 2.33). We can also calculate the RR of any smoking, compared to no smoking, for COPD. First we combine the data for light and heavy smokers. There are 500 cases of COPD in a total of 2000 smokers, so COPD prevalence in smokers is 500 / 2000 = 0.25. RR of any smoking for COPD is 0.25 / 0.05 = 5. Odds and odds ratio Here again is the 2 x 2 table given above, with table cells indicated by both numbers and letters.. Non-smokers 9500 a 500 c 10000 a+c Smokers 1500 b 500 d 2000 b+d Total 11000 a+b 1000 c+d 12000 a+b+c+d

Without COPD With COPD Total

Odds = [probability / (1 - probability)] = (p / (1-p)). Thus, when probability = 0.01, odds = 0.01 / 0.99 = 1/99 or 1 to 9 or 0.0101, almost exactly the same as the probability. When probability = 0.4, odds = 0.4 / 0.6 = 2 to 3 or 0.67, quite different from the probability. Note that odds and probability are more nearly equal when the disease is rare than when the disease is frequent. When the disease is frequent, odds can differ considerably from probability. In the 2 x 2 table above, probability (p) of COPD in non-smokers = (c / (a+c)). Odds of COPD in non-smokers = p / 1 - p = (c / (a+c)) / [1 (c / (a+c))] = (c / (a+c)) / [(a+c) / (a+c) - (c / (a+c))] = [(c / (a+c)) / (a / (a+c))] = c / a. Similarly, probability of COPD in smokers = (d / (b+d)), and odds of COPD in smokers = d / b. Thus, the probability of disease is the ratio of the number of people with the disease to the total number of people at the exposure level, and the odds of disease is the ratio of the number with the disease to the number without the disease. In this example, what are the probability and odds of disease in the total population? Recall that relative risk (RR) equals the prevalence (probability) in the exposed group divided by that in the unexposed group. The odds ratio (OR) equals the odds in the exposed group divided by that in the unexposed group. When the disease is rare, OR is close to RR. When the disease is frequent, OR can differ considerably from RR. When
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RR=1 or OR=1, there is no association of the risk factor with the disease. When RR and OR do not equal 1, OR is further from 1 than is OR. In the 2 x 2 table above, the prevalence (probability) of COPD is 500 / 10000 = 5% in nonsmokers, and 500 / 2000 = 25% in smokers. The RR of smoking for COPD = 25% / 5% = 5. The odds of COPD are 500 / 9500 in non-smokers and 500 / 1500 in smokers. The OR of smoking for COPD is therefore (500 / 1500) / (500 / 9500) = 6.33. This is the same as (d / b) / (c / a) = ad / bc. Now we will look at it another way. We have just calculated the odds ratio of smoking for COPD. What is the odds ratio of COPD for smoking? The odds of smoking in people with COPD = d / c. The odds of smoking in people without COPD = b / a. Thus, the odds ratio of COPD for smoking is (d / c) / (b / a) = ad / bc, exactly the same as the OR of smoking for COPD. In other words, the OR of exposure for disease is exactly the same as the OR of disease for exposure. This is why it is possible to calculate a valid OR in case-control studies (please see below). (As mentioned above, odds = [probability / (1 - probability)]. Therefore probability = [odds / (1 + odds)].) 2. Case-control studies when cases and controls ARE NOT matched (unmatched casecontrol studies) Case-control studies are especially useful for studying diseases that are rare, such as many types of cancer. In the case control study, we first sample on disease status. That is, we first choose subjects with and without disease. Then we compare the exposure situation in subjects with and without disease. Subjects with disease are often called cases, and subjects without disease are often called controls. Because we sample on disease status, we do not know the probabilities or the odds of disease in people with and without exposure. Therefore, it is not possible to calculate RR from case-control data. It is also not possible to directly calculate the OR of exposure for disease from case-control data. However, we do know the odds of exposure in subjects with and without disease. This enables us to calculate the OR of disease for exposure. As we have seen, this is equal to the OR of exposure for disease. Again, this is why we can calculate a valid OR from case-control data. Unmatched case-control example: We want to find out whether there is an association of smoking with lung cancer. We do this with a case-control study. First we choose subjects with and without lung cancer. Then we compare the distributions of smoking in these 2 groups. Here is a 2 x 2 table of our case-control data. Without lung cancer 150 a 50 c 200 With lung cancer 20 b 180 d 200 Total 170 230 400

Non-smokers Smokers Total

In this table, cells a and d are called concordant cells, because the disease and exposure status of subjects in each of these cells is the same. In cell a, subjects do not have the exposure and do not have the disease. In cell d, subjects have both the exposure and the disease. Cells b and c are called discordant cells, because the disease and exposure status of subjects is different. In cell b, subjects do not have the exposure but have the disease. In cell c, subjects have the exposure but do not have the disease.
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The odds of exposure (smoking) in cases is 180 / 20 = 9. The odds of exposure in controls is 50 / 150 = 1 / 3 = 0.33. Thus, the OR of exposure for disease = 9 / 0.33 = 27. This is the same as the product of the concordant cells divided by the product of the discordant cells. In this example the concordant cells are a and d, and the discordant cells are b and c, so the OR = ad / bc = (150 x 180) / (20 x 50) = 27. IMPORTANT: Do not simply memorize the formula for OR as ad / bc. Instead, remember that the OR is the product of concordant cells divided by the product of discordant cells. In the table below, the OR = bc / ad, not ad / bc. Without lung cancer 150 c 50 d 200 With lung cancer 20 a 180 b 200 Total 170 230 400

Non-smokers Smokers Total

Case-control studies can also have more than 2 exposure levels, for example nonsmokers, light smokers, and heavy smokers. Here are the data above, divided into 3 exposure levels. Without lung cancer 150 25 25 200 With lung cancer 20 60 120 200 Total 170 85 145 400

Non-smokers Light smokers Heavy smokers Total

The OR for lung cancer in light smokers, relative to non-smokers, is (150 x 60) / (20 x 25) = 18. The OR for lung cancer in heavy smokers, relative to non-smokers, is (150 x 120) / (20 x 25) = 36. The OR for lung cancer in heavy smolkers, relative to light smokers, is (25 x 120) / (60 x 25) = 2. 3. Case-control study when cases and controls ARE matched: one case to one control (matched case-control pairs) In many case-control studies, cases and controls are matched on one or more factors such as age and gender. This increases the efficiency of the study to assess risk factors of interest, but prevents assessment of the matching factors. The reason for this is that when we match, we force the distribution of the matching factors to be the same in cases and controls. Therefore, we cannot make a fair test of matching factor effects. To calculate odds ratio in a matched case-control studies, we organize the data differently from the unmatched study. Here is an example in which cases and controls are matched for age, and there is 1 control per case. That is, the total numbers of cases and controls are equal. We choose 100 cases and 100 age-matched controls (total 200 subjects, total 100 case-control pairs). We organize the data into numbers of case-control pairs with and without the exposure factor of interest, as follows: Controls (no lung cancer) Smokes Cases (with lung cancer) Smokes Does not smoke 5 10 Total 15

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Does not smoke Total

70 75

15 25

85 Total 100 pairs

The OR of smoking for lung cancer is the ratio of numbers of case-control pairs that are discordant for exposure status. There are 70 pairs in which the case smokes but the control does not, and 10 pairs in which the control smokes but the case does not. Thus the OR of smoking for lung cancer = 70 / 10 = 7. We ignore the concordant case-control pairs when calculating OR from matched case-control data. What (incorrect) OR would we calculate if we treated these data as unmatched? We can break down the table above into a usual 2 x 2 table, with 200 individual subjects instead of 100 case-control pairs. Do not smoke Smoke Total Controls 70 + 15 = 85 5 + 10 = 15 100 Cases 10 + 15 = 25 5 + 70 = 75 100 Total 110 90 Total 200 subjects

The (incorrect) OR calculated from this table is [(85 x 75) / (25 x 15)] = 17. Note that this is very different from the correct OR, which is 7. In a matched case-control study, we cannot test the effect of the matching factor(s). This is because when we match, we force the distribution of the matching factor to be the same in cases and controls. This guarantees an odds ratio = 1, and this is not a fair test of the effect of the matching factor. In case-control studies, it is very important to choose controls in a way that will give a fair test of the factor(s) of interest. For example, in a case-control study of smoking and lung cancer, we would generally want to find the effect of smoking in lung cancer patients as compared to the general population. In this situation we would not want to choose controls with COPD, because COPD, like lung cancer, is positively associated with smoking. Thus, selection of controls with COPD would give an underestimate of the true effect of smoking on lung cancer. (If we wanted to find the effect of smoking in lung cancer as compared to COPD, then it would be appropriate to choose controls with COPD.) 4. Cohort study when the outcome is a discrete event (e.g., death, new case of cancer, new case of other disease) The word "cohort" means a group of people with similar characteristics, or simply a group of people. In epidemiology, the term "cohort study" is reserved for a study in which we select subjects with different levels of exposure (that is, we sample on exposure status). At the start of a cohort study, no subjects yet have the disease of interest. Then we measure occurrence of disease over time in the different exposure groups. The time period is known as the follow-up period. Then we compare the occurrence of disease in subjects in the different exposure groups. If higher rates of disease are associated with higher exposure, we have evidence that this type of exposure may be a cause of this disease. If not, we have evidence that this type of exposure does not cause this disease. In a cohort study, we first sample on exposure status. A subject is considered to leave the study when he or she gets the disease of interest, when the study ends, or when the subject is lost to follow-up for any reason. We record how many subjects get the disease at each exposure level, and WHEN each subject gets the disease.

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In each exposure group, we can divide the number of disease cases by the total number of subjects in the group. We can also divide the number of cases by the total time that the members of that group were in the study. This quantity, cases divided by time, is called the hazard of disease. Then we compare the disease rates in the different exposure groups. We can do this in 2 ways. In the first way, we divide the number of subjects with disease by the total number of subjects in each group, similar to a cross-sectional study. This gives the relative risk (RR) of disease, similar to a cross-sectional study. This way is usually not desirable, because it ignores the time that subjects are in the study. The second way compares the disease hazards in the different exposure groups, and gives us the hazard ratio (HR) for disease This is usually the desirable method, because it takes time into account. Example: We want to find out whether there is a relationship of household stove improvement with COPD risk reduction. (In this example, we are finding out whether stove improvement is a protective factor.) Therefore, we are testing whether RR and HR of stove improvement for COPD are less than 1. First we sample on stove improvement status. Then we compare incidence of COPD with and without stove improvement. Then we divide incidence with stove improvement by incidence without stove improvement. Here is a table of our cohort data.
Without stove improvement 400 100 500 2500 With stove improvement 900 100 1000 10000 Total 1300 200 1500 12500

Subjects without COPD Subjects with COPD Total Subjects Person-years

If we use the first method above, RR of stove improvement for COPD = [(100 / 1000) / (100 / 500)] = 0.5. Note that this less than 1, suggesting a protective effect of stove improvement. Note that this method ignores time. If we use the second method, HR of stove improvement for COPD = [(100 / 10000) / (100 / 2500)] = 0.25. This is generally a better measure of association than the RR, because it takes time into account. In this example, the RR underestimates the protective effect of stove improvement. Also, the average numbers of person-years for subjects with and without stove improvement are 10 person-years and 5 person-years, respectively. Therefore, on average, subjects with stove improvement were followed longer than were subjects without stove improvement. 5. Cohort study when the outcome is a continuous variable (e.g., blood pressure, body weight, body mass index) In some cohort studies, the outcome is a continuous variable, not a discrete event. In this type of study, as in the study of a discrete event, we follow subjects over time. However, in this type of study, we compare the mean of the outcome before and after the intervention or exposure. To deal with confounding, it is best to include groups with and without the intervention or exposure (treatment group and control group). In this design we can compare the change in the outcome in the groups with and without the intervention or exposure.

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6. Some advantages and disadvantages of the basic study designs Design Cross-sectional Advantages 1. Possible to calculate prevalence and relative risk (can also calculate odds and odds ratio). 2. Relatively quick and inexpensive. 1. Feasible for rare diseases. 2. Efficient for studying some disease outbreaks, e.g., diarrhea outbreak on a cruise ship. 2. Relatively quick and inexpensive. Advantages 1. Can measure and compare time to events. 2. Exposure is known to precede outcome. 3. Can evaluate factors that change over time.. Disadvantages 1. Exposure and disease measured at the same time, so cannot directly determine time relationship between exposure and disease. 2. Subject to bias. 3. Not feasible for rare diseases. 1. Cannot calculate relative risk. Can only calculate odds ratio. 2. Subject to bias.

Case-control

Design Cohort

Disadvantages 1. Usually time-consuming and expensive.

7. There are other study designs, for example ecological, case-crossover, nested casecontrol, case-cohort, time series (repeated measures), and randomized controlled trial. These are not discussed in this review, and you are not responsible for them in this course. MATHEMATICAL FORMULAS FOR CALCULATING POPULATION-ATTRIBUTABLE RISK PROPORTION (PARP, SAME AS POPULATION-ATTRIBUTABLE RISK FRACTION (PARF)) NOTE ON NOTATION: In this review Pe is the proportion of the population that has exposure. In the PH 501 PowerPoint presentation Pe is the disease prevalence in the exposed group, and PrevE is the proportion of the population that has exposure.. Recall that the population-attributable risk proportion (PARP) is the proportion of all disease cases that can be attributed specifically to the risk factor of interest. Here again is the 2 x 2 table for smoking and COPD. Non-smokers 9500 500 10000 Smokers 1500 500 2000 Total 11000 1000 12000

Without COPD With COPD Total

There are 1000 cases of COPD in all. 5% of non-smokers have COPD. This is the baseline rate of COPD, or the rate that we would expect apart from any additional risk that might come from smoking. 5% of smokers = 100 subjects. So we expect a baseline
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occurrence of 100 COPD cases in smokers. This leaves 400 cases in smokers that are attributable to smoking. Therefore the PARF due to smoking is 400 / 1000 = 0.4 = 40%. When there are only 2 exposure levels, no exposure and any exposure, the mathematical formula for calculating the PARP is [(RR 1)(Pe)] / [1 + [(RR 1)(Pe)]], where RR is relative risk and Pe is the proportion of subjects with exposure. In this example, the exposure is smoking, and Pe = 2000 / 12000 = 1 / 6 = 0.167. PARP = [(5-1)(.167)] / [1 + (5 1)(.167)] = 0.668 / 1.668 = 0.4 = 40%. Again, we calculate that 40% of all COPD cases come from smoking, so the PARP of COPD due to smoking is 40%. What is the PARP of exposure in the exposed group? In this group, the PARP = (RR - 1) / [1 + (RR - 1)] = [(RR - 1) / RR]. Thus, the PARP in smokers = 4 / 5 = 80%. When there are more than 2 exposure levels, for example no smoking, light smoking, and heavy smoking, we can separately calculate the PARPs for light smoking and heavy smoking in relation to no smoking. Here is the example that we saw previously, with smokers separated into light smokers and heavy smokers. Nonsmokers 9500 500 10000 Light Smokers 850 150 1000 Heavy Smokers 650 350 1000 Total 11000 1000 12000

Without COPD With COPD Total

The baseline COPD rate, with no contribution by smoking, is 5%. There are 1000 light smokers and 1000 heavy smokers. Thus, we expect that 50 COPD cases in light smokers and 50 COPD cases in heavy smokers are not attributable to smoking. We presume that the remaining 100 COPD cases in light smokers, and the remaining 300 COPD cases in heavy smokers, are attributable to smoking. Thus, as before, we see that 400 of the 1000 total COPD cases, or 40%, are attributable to smoking. Therefore, the PARP of COPD due to smoking is 40%, exactly as in the previous example. Here is the mathematical formula for PARP when there are 3 exposure levels. We wish to calculate the PARP of any smoking for COPD, and we are given information separately for light smokers and heavy smokers First, here is the necessary information: RRL = RR of COPD in light smokers relative to non-smokers = 0.15 / 0.05 = 3. PL = the proportion of light smokers in the whole population = 1000 / 12000 = 0.083. RRH = the RR of COPD in heavy smokers relative to non-smokers = 0.35 / 0.05 = 7. PH = the proportion of heavy smokers in the whole population = 1000 / 12000 = 0.083. The formula is: PARP of any smoking for COPD = [(RRL - 1)(PL) + (RRH - 1)(PH)] / [1 + [(RRL - 1)(PL) + (RRH - 1)(PH)]] = [(2 x 0.083) + (6 x 0.083)] / [1 + (2 x 0.083) + (6 x 0.083)] = 0.667 / 1.667 = 0.4 = 40% The PARP of light smoking only for COPD is [(RRL - 1)(PL)] / [1 + [(RRL - 1)(PL) + (RRH - 1)(PH)]] = 0.166 / 1.667 = 0.10 = 10%
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The PARP of heavy smoking only for COPD is [(RRH - 1)(PH)] / [1 + [(RRL - 1)(PL) + (RRH - 1)(PH)]] = 0.5 / 1.667 = 0.30 = 30% Note that PARP of light smoking and the PARP of heavy smoking add to the PARP for any smoking, 40%. In a case-control study, we do not know RR and we do not know the proportion of the population with exposure. We can use OR to approximate RR. Thus, we can estimate PARP by [(OR 1)(estimated Pe)] / [1 + [(OR 1)(estimated Pe)]]. We can often estimate Pe by the proportion of controls with exposure. Also, sometimes we can find a reasonable measurement or estimate of Pe outside our study. VACCINE EFFICACY (Note: I use the word "efficacy" to have the same meaning as "effectiveness.) We can think of the vaccine as the exposure factor. Therefore, subjects with exposure are vaccinated subjects, and subjects without exposure are unvaccinated subjects. FU = disease frequency in unvaccinated subjects. FV = disease frequency in vaccinated subjects. Relative risk = RR = FV / FU. We hope that the vaccine will reduce risk of the disease. That is, we hope that vaccination will be a protective factor, not a risk factor such as smoking. Thus, we hope that the RR of vaccination will be <1. Vaccine efficacy = [(FU - FV) / FU] = [(FU / FU) - (FV / FU)] = (1 - RR) If RR = 1, FV = FU, so the vaccine has no effect. In this situation vaccine efficacy is 0. If RR = 0, FV = 0. That is, the vaccine eliminates all of the disease. In this situation vaccine efficacy is 1, or 100%. Suppose that in a population. illness rates before and after vaccination are 30% and 10%, respectively. FU = 0.3 and FV = 0.1, so RR = 0.1 / 0.3 = 0.33. Vaccine efficacy = 1 - 0.33 = 0.67. That is, the vaccine has eliminated 67% of the disease. DIRECT AND INDIRECT ADJUSTMENT We frequently wish to adjust for one or more potential confounding factors, so that we can get a more fair comparison of 2 or more groups. For example, in comparing mortality rates between 2 populations, we would often wish to adjust for age, because mortality is positively associated with age and because the 2 populations might have different age distributions. That is, one population might be older than the other one. Suppose that we wish to compare overall mortality rates between a wealthy country and a poor country. The unadjusted (crude) mortality rate might be lower in the poor country than the wealthy one. However, comparing unadjusted rates would not be appropriate, because populations in poor countries are usually younger than in wealthy ones, and mortality is positively associated with age. In this situation we should adjust both countries' mortality rates for age before we compare mortalities. There are 2 methods of adjustment, direct and indirect. In both methods, we must have a reference (standard) population. In direct adjustment, we apply observed rates in our comparison groups to numbers (counts) in our reference population. That is, we calculate how many cases would occur in the reference population if it had the same categoryspecific rates as the study population. In indirect adjustment, we apply the categoryspecific numbers in our comparison groups to category-specific rates in the reference population. That is, we calculate how many cases would occur in the study population if it had the same category-specific rates as the reference population. Then we divide the
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observed number of cases in the study population (the observed number) by this calculated number (the expected number). This gives the standard mortality (morbidity) ratio, or SMR. Here is an example with 2 groups, showing age-specific numbers of deaths and mortality rates..
Age Number <35 100 35-54 500 >54 1000 Total 1600 Group 1 Cases 5 30 80 115 Rate 0.05 0.06 0.08 0.072 Number 1000 300 100 1400 Group 2 Cases 60 21 9 90 Rate 0.06 0.07 0.09 0.064 Reference Population Number Cases Rate 1000 60 0.06 1000 70 0.07 1000 80 0.08 3000 210 0.07

Notice that the overall unadjusted mortality rate is higher in group 1 than group 2. Also notice that all age-specific rates are higher in group 2 than group 1. This tells us that comparison of the overall unadjusted rates would be misleading, and that we should adjust for age before we compare mortality rates between the 2 groups. Direct age adjustment Group 1: (.05)(1000) + (.06)(1000) + (.08)(1000) = 190. 190 / 3000 = 6.3% Group 2: (.06)(1000) + (.07)(1000) + (.09)(1000) = 220. 220 / 3000 = 7.3% Indirect age adjustment Group 1 (100)(.06) + (500)(.07) + (1000)(.08) = 121. 121 is the "expected" number of deaths, that is, the number of deaths that would be expected if the age-specific rates of the reference population occurred in group 1. 115 is the observed number of deaths in group 1. Divide the observed by the expected. 115 / 121 = 0.95 = standardized mortality ratio (SMR) for group 1. Group 2 (1000)(.06) + (300)(.07) + (100)(.08) = 89. 89 is the expected number of deaths in group 2. 90 is the observed number of deaths in group 2. Divide observed by expected. 90 / 89 = 1.01 = standardized mortality ratio (SMR) for group 2. After both direct and indirect age adjustment, the overall adjusted rate in group 2 is higher than in group 1. This is consistent with the comparison of the age-specific rates in the 2 groups.

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Sometimes it is difficult to find an appropriate external reference population. We can always construct an "internal" reference population by combining the information from the comparison groups. We can use this internal reference population for adjustment, in the same way as we would use an external reference population. In this example, the internal reference population would be as follows: Age <35 35-54 >54 Total INTERNAL REFERENCE POPULATION Number Cases Rate 1100 65 .059 800 51 .064 1100 89 .081 3000 205 .068

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