Relative Risk of Mortality in the Physically Inactive Is Underestimated Because of Real Changes in Exposure Level during Follow-up

Lars Bo Andersen1,2 

1 Norwegian University of Sport and Physical Education, Oslo, Norway.
2 Institute for Exercise and Sport Sciences, University of Copenhagen, Copenhagen, Denmark.

Received for publication May 22, 2003; accepted for publication February 27, 2004.


    ABSTRACT
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Relative risk among exposure groups in prospective cohort studies is based on the assumption that all subjects are exposed at the level recorded at baseline throughout the study. Changes in risk behavior during follow-up will dilute the relative risk. This prospective cohort study in Copenhagen, Denmark, between 1964 and 1994 included 30,640 men and women; 19,149 were examined twice, with an interval of 6.7 (standard deviation, 3.4) years. Relative risks calculated from baseline measurements for moderately active and sedentary groups compared with the highly active group were 1.11 (95% confidence interval: 1.05, 1.18) and 1.64 (95% confidence interval: 1.53, 1.75), respectively. The relative risk between the highly active group and the sedentary group decreased with increasing follow-up time. When intraindividual changes in physical activity level during follow-up were taken into account, the relative risk of physical inactivity was 24–59% higher compared with the relative risk estimated from baseline measurements. The risk of a sedentary lifestyle is underestimated when it is calculated from one baseline measurement in prospective studies, because subjects change behavior during follow-up.

behavior; exercise; follow-up studies; mortality

Abbreviations: Abbreviation: SD, standard deviation.


    INTRODUCTION
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Leisure time physical activity is a complex behavior that is difficult to assess. Powell et al. (1) found that better studies were more likely than poorer studies to report an inverse association between leisure time physical activity and the incidence of cardiovascular disease. A poor assessment method will dilute the estimated relative risk because of misclassification of subjects. Another very important source of invalidity is real changes in behavior during the follow-up. Some studies have used two examinations of exposure level and found that those who increased their physical activity level between the examinations had a subsequent lower risk of disease, and that subjects who decreased their physical activity level had a higher risk (27). In all of these studies, it was possible to calculate the effect of a change in physical activity level, which was possible because a substantial number of subjects changed behavior between the two examinations. Further, the changes in physical activity level were related to changed risk of disease, which means that at least part of the observed changes was not due to assessment error. In the studies by Lissner et al. (3) and Wannamethee et al. (6), almost half of the population changed exposure level during 6 years and during 13 years, respectively. In the study by Paffenbarger et al. (8), even more reported changes, but they used quite narrow physical activity definitions. Therefore, it seems that physical activity is a behavior that changes over time in many persons. In most prospective studies where the level of leisure time physical activity has been related to subsequent disease or death, only one baseline measurement of exposure has been used, and the period after the baseline, when the changes in behavior found in the former studies occurred, is part of the follow-up period.

The aim of this study was to analyze the effect of changes in exposure level during follow-up on the estimated relative risk for leisure time physical activity calculated from the baseline measurement. To elucidate this problem, relative risk was calculated from 1) baseline levels of exposure (leisure time physical activity level), 2) baseline levels of exposure but with decreasing follow-up time, 3) changed exposure from the first to the second examination, and 4) stable exposure at both examinations. The estimated relative risk of leisure time physical activity was used to calculate population attributable risk with and without dilution.


    MATERIALS AND METHODS
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Study populations
This study is based on pooled data from three epidemiologic surveys of the population of Copenhagen, Denmark: the Copenhagen City Heart Study, the Glostrup Population Studies, and the Copenhagen Male Study. In both the Glostrup Population Studies and the Copenhagen City Heart Study, subjects were randomly selected from the Danish Central Population Registry. The Copenhagen Male Study included all middle-aged male employees in 14 public and private companies. Data were collected from 1964 through 1994, and the participation rates in the different cohorts were between 78 percent and 87 percent. A description of key variables in relation to physical activity levels is given in table 1 (9).


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TABLE 1. Association of baseline characteristics with level of leisure time physical activity, Copenhagen, Denmark, 1964–1994*
 
At baseline, 13,375 females and 17,265 males were examined. The relative risk of physical inactivity among these subjects was used as the referent to evaluate dilution. At the second examination, 9,969 males were eligible for calculations, with 527 males excluded because of a diagnosis of cardiovascular disease. Female participants at the second examination numbered 8,426, and 194 were excluded because of cardiovascular disease prior to the second examination. The age at the first examination was 20–93 years, with a mean of 47.6 (standard deviation (SD), 10.0) years. The time between the first and second examinations was 6.7 (SD, 3.4) years, and the subjects who participated in the two examinations were followed for another 10.2 (SD, 3.8) years after the second examination. Knowledge of chronic diseases before the first examination was available from the questionnaires, the examination by the physician, and hospital records for 6,919 subjects. Baseline analyses were conducted with these subjects both included and excluded. No difference was found, and we decided to include subjects with chronic disease in the baseline calculation. In the analysis where changes in physical activity were used, subjects with cardiovascular disease (International Classification of Diseases diagnosis codes 410–414) prior to the second examination were excluded, because the disease may have caused the behavioral change. Other diseases also may cause behavioral changes, but the analyses were similar whether they were included or not.

Assessment
At baseline, self-report questionnaires were used to assess the subjects’ leisure time physical activity and educational status. The subjects’ height, weight, and blood pressure were measured, and a venous blood sample was drawn for analysis of serum cholesterol and triglyceride.

Physical activity during leisure time was classified into four categories by means of questions originally constructed and evaluated by Saltin and Grimby (10). Some differences existed in the phrasing of the questions among the cohorts, but four categories were used in all the cohorts, and no difference was found in the age-specific distributions of leisure time physical activity among cohorts. However, as few subjects belonged to the highest category of leisure time physical activity, analyses were performed with levels three and four combined as one group. The three groups are referred to as sedentary, moderately active, and highly active.

Blood pressure was measured on the upper arm with the use of a mercury sphygmomanometer with subjects in the sitting position having rested for at least 5 minutes. The venous blood sample was drawn following a 12-hour fast and analyzed for total serum cholesterol by conventional methods (11). In the Copenhagen City Heart Study, subjects were nonfasting, and blood lipids were analyzed from plasma.

Endpoints
Information on mortality between the second examination and December 31, 1994, was obtained. All subjects were traced by means of the Danish Central Population Registry. Person-years were calculated from the date of the first examination until December 31, 1994, or to the date of emigration, death, or disappearance.

Statistics
All data were analyzed using Intercooled Stata version 5 software (Stata Corporation, College Station, Texas). Relative risks were calculated from Cox proportional hazards models. The date of the first examination was used as the entry time in the baseline model, but in all models where two examinations were used, the date of the second examination was used. Categorized risk factors were entered into the Cox models for adjustment since a nonlinear relation was found between mortality and the risk factors body mass index and serum cholesterol. All analyses were done both as crude analyses (age adjusted) for each sex separately and afterwards with adjustment for other risk factors, but these adjustments did not alter any comparisons among the different methods used to calculate dilution caused by intraindividual variation during follow-up. Therefore, it was decided to present age- and sex-adjusted calculations, except for the original baseline estimates where all data are presented.

In figure 1, the relative risk among exposure groups is plotted as a function of follow-up time. The relative risk was calculated first using a maximum of 30 years of follow-up. Subjects were censored when one of the following events occurred: 1) death, 2) emigration, 3) 30 years of follow-up, and 4) December 31, 1994. In the next calculation, subjects were censored after death, emigration, 25 years of follow-up, or December 31, 1994, and so on. This means that the same subjects are included in all the calculations, but the calculation after 30 years of follow-up includes subjects who have been followed less. This approach was chosen, because it gives the most conservative result and the best estimation of the effect of follow-up time. In the figure, data are included only until 20 years of follow-up, because no further change in relative risk was found.



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FIGURE 1. Relative risks and confidence intervals of mortality in the sedentary group compared with those in the highly active group, Copenhagen, Denmark, 1964–1994. Relative risks are shown as a function of length of follow-up. In the analyses with long follow-up times, cohorts examined so late that they could not fulfill the required follow-up time were included.

 
Population attributable risk (PAR) is the percentage of deaths that theoretically can be prevented if all subjects were at the lowest level of risk. It was calculated as follows:

PAR = {Sigma}Pexp(i) x (RRi – 1) x 100/1 + {Sigma}Pexp(i) x (RRi 1),

where RRi was the relative risk in group i compared with the group having the lowest risk, and Pexp(i) was the proportion of subjects belonging to group i.


    RESULTS
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Four methods were used to calculate the relative risk of leisure time physical activity.

Method 1: analysis using baseline levels of exposure
If the knowledge from the second examination had not existed, the relative risk of mortality related to exposure (leisure time physical activity level) would be calculated using all subjects who participated in the first baseline measurements. Data for each sex are presented in table 2.


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TABLE 2. Baseline analysis with full follow-up time, displaying age-adjusted and multivariate-adjusted relative risks of mortality in relation to leisure time physical activity, with the highly active as referent group, Copenhagen, Denmark, 1964–1994*
 
Method 2: analysis using baseline levels of exposure but with decreasing follow-up time
The number of subjects changing exposure level is supposed to increase with increasing follow-up time. The relative risk among exposure groups may therefore depend on the length of follow-up, because more subjects may be misclassified when the follow-up time is long. The relative risks were calculated for leisure time physical activity and with decreasing follow-up time starting with 30 years (figure 1). All subjects were followed for the specific number of years or until censoring by death, emigration, or December 31, 1994. As seen from figure 1, the relative risk of the sedentary group compared with the highly active group decreases with increasing follow-up time.

Method 3: analysis using changed exposure from the first to the second examination
Leisure time physical activity was assessed twice, with an interval of 5.5 (SD, 1.4) years, for 7,154 females. During 10.8 (SD, 2.8) years of follow-up after the second examination, 932 females died, and 194 females were excluded from the analysis because of cardiovascular disease prior to the second examination. Leisure time physical activity was also assessed twice, with an interval of 7.8 (SD, 4.2) years, for 7,666 males who were followed for another 9.6 (SD, 4.4) years, resulting in 1,490 deaths (527 males were excluded because of cardiovascular disease). Changes in leisure time physical activity from the first to the second examination are described in table 3. The Spearman correlation coefficient between leisure time physical activity at the first and the second examination was 0.34.


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TABLE 3. Leisure time physical activity levels in women and men participating in two examinations, Copenhagen, Denmark, 1964–1994
 
The mortality rates were calculated for the subjects who changed behavior between the two examinations (table 4). From the prevalence of subjects who changed behavior and their actual mortality rate, we calculated that the combined rate for all sedentary subjects at the first examination was only 0.85 of those who stayed sedentary. For the highly active group from the first examination, a combined rate of 1.20 was found compared with those who were highly active at both examinations.


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TABLE 4. Age- and sex-adjusted relative risk of mortality in those who changed leisure time physical activity between the two examinations related to those who stayed at the same level, Copenhagen, Denmark, 1964–1994
 
This means that the relative risk calculated from baseline measurements is underestimated 1.20/0.85 times (40 percent) between the sedentary group and the highly active group and 1.20/1.02 times (18 percent) between the moderately active group and the highly active group. Therefore, instead of the calculated relative risk of 1.64 for the sedentary group in relation to the highly active group, a more realistic estimate of the real difference in mortality would be 1.64 x 1.40 = 2.30. Instead of a relative risk of 1.11 for the moderately active group compared with the highly active group, a more realistic difference would be 1.31.

Method 4: analysis using stable exposure at both examinations
Many subjects have not been exposed to the amount of leisure time physical activity that they reported at the first examination during the whole period of follow-up since the first examination, and they were therefore misclassified if only baseline data were used. Some of the misclassification caused by true change in exposure level can be excluded if the relative risk between activity groups is calculated including only the subjects who reported the same leisure time physical activity level in the questionnaire at both examinations. In this analysis, only 54 percent of those who participated in the first examination were included. The difference in mortality rates between groups increased after exclusion of subjects who were misclassified (table 5).


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TABLE 5. Calculation of population attributable risk using four different methods of estimating the relative risk of mortality among leisure time physical activity groups, Copenhagen, Denmark, 1964–1994*
 
Population attributable risk
Population attributable risk was calculated using all four methods of estimating the relative risk among leisure time physical activity groups (table 5). As the mortality rate of the highly active group was the lowest, rates of the sedentary and moderately active groups were expressed in relation to this group (table 5). Population attributable risk is highly dependent on the mortality rate in the referent group (highly active), and using the rate of the combined leisure time physical activity groups 3 and 4 will underestimate population attributable risk but narrow the confidence interval considerably.


    DISCUSSION
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
The present study analyzes a methodological problem related especially to physical activity and inherited in all published prospective studies estimating the benefit of physical activity from one baseline assessment and subsequent follow-up. All the studies we are aware of in the literature, where physical activity level has been assessed more than once with some years between, have found changes similar to those of the present study. The fact that physical activity levels change in many subjects during the study causes an underestimation, which can be quantified, but only a few studies have data to do it. A decrease in physical activity level could be caused by disease, which could increase mortality and therefore introduce bias. However, all subjects were examined by a physician at both the first and the second examinations, and complete hospital records were available. Those who had cardiovascular disease, which might affect their participation in physical activity, were excluded from the analysis. In addition, half of the dilution was caused by subjects who increased their physical activity level, and this part of the dilution cannot be a bias.

Most prospective cohort studies have only one baseline measurement of leisure time physical activity, and they can therefore calculate mortality rates based on only this measurement, often with a follow-up time of 10 or more years. In the present study, we compared the estimated relative risk calculated from one baseline measurement of leisure time physical activity and from the knowledge of changes in exposure between two measurements with an interval of 6.7 (SD, 3.4) years. Spearman correlation coefficients between the first and second measurements were 0.34 for leisure time physical activity. In both the first and the second assessments of the individual leisure time physical activity level, some misclassification may exist caused by an inaccurate assessment method and variation about the true mean. The analyses were not corrected for this type of variability, and the dilution found from the different methods is therefore an underestimation of the real dilution. We have treated both assessments of leisure time physical activity as if they were the true means of habitual leisure time physical activity levels in the individual at two different times of his or her life, and the dilution may be more severe than these calculations suggest. The lower mortality rates in subjects who increased their leisure time physical activity level and the higher rates in those who decreased their physical activity level, compared with those who stayed at the same level (table 4), were evidence of true changes, even if it was not possible to quantify the true changes compared with the error variation from assessment error.

Calculated dilution
The present study calculated the relative risks of leisure time physical activity levels using four different methods in order to evaluate the influence of changes in behavior after the first baseline assessment of the relative risk. The relative risk calculated from a usual baseline measurement was compared with the relative risk estimated with a short follow-up period, where fewer changes in true behavior occur, and with two methods taking changes into account. Calculations after 2 years of follow-up were possible because more than 500 deaths occurred within the first 2 years.

Baseline
An estimation of the relative risk of mortality from all subjects participating in the first examination was calculated as a referent value. It could be argued that the referent calculation should be conducted with values from the first examination but including only the subjects participating in both examinations. However, this analysis increased the dilution considerably, and we chose the former for comparison as the more conservative solution and because these data would have been used if a second examination had not existed. In the analysis of the complete baseline group, a relative risk of 1.11 was found for the moderately active group, and a relative risk of 1.64 was found for the sedentary group compared with the most active group. These values are comparable with those of most other studies using one baseline measurement of leisure time physical activity related to subsequent all-cause mortality with a long follow-up time (1215). Subsequently, follow-up time was gradually shortened by censoring subjects after 20 years, 15 years, etc., until a follow-up time of 2 years. Below this level, the number of endpoints became critical. The reason for the inclusion of subjects examined so late that they could not fulfill a longer follow-up time was to include the same subjects in all the analyses included in figure 1, and this inclusion made the difference in relative risk only less between long and short follow-up times. The calculated population attributable risk was surprisingly high, and physical inactivity accounted for more than 40 percent of all deaths.

Two methods using two examinations
In the analysis of subjects reporting the same leisure time physical activity level at both examinations, the only dilution of the estimates is in the assessment of leisure time physical activity at the two examinations and possible fluctuations between the two examinations. Thus, if the true mean of leisure time physical activity could be assessed, the estimate would be very close to the real difference between the physically active and the sedentary groups, with the exception that changes in leisure time physical activity after the second examination and during the follow-up would not be taken into account. The analysis excluded all subjects who had not participated in two examinations and who had changed leisure time physical activity level, and therefore only one fourth of the original cohort was included (7,806 subjects experiencing 1,199 deaths). The population attributable risk in the analysis of the subjects with a stable leisure time physical activity level was 25.2 percent or 55 percent higher than the referent population attributable risk.

In the second analysis, we used the knowledge of the real mortality rates of all subjects who had participated twice and belonged to a certain leisure time physical activity level at the first examination regardless of whether they had changed leisure time physical activity level or not. As some of the sedentary subjects at the first examination had become active with a decreased mortality rate, the mean rate of the whole group was lower than that in subjects who stayed sedentary. The true difference in mortality rates between the sedentary and the vigorously active groups was 40 percent higher, and the calculated population attributable risk was 191 percent higher than in the referent analysis. This is a substantial difference that should affect preventive strategies. Powell and Blair (16) have estimated that 35 percent of deaths from cardiovascular disease, 32 percent of deaths from colon cancer, and 35 percent of deaths from diabetes could theoretically be prevented if everyone were vigorously active. Haapanen-Niemi et al. (17) calculated that physical inactivity was responsible for between 22 percent and 39 percent of all cardiovascular disease cases. However, these values are calculated from the prevalence of a risk factor in a certain exposure group and the relative risk of disease in this group compared with the group with the lowest risk, and calculations are based on one baseline measurement and subsequent mortality rates in baseline exposure groups. Therefore, these calculations may include a substantial amount of dilution.

It could be argued that unrecognized disease could have caused the changes in exposure level. However, dilution is experienced only with physical activity and not with smoking (data not shown), and completely different approaches to calculate the dilution in physical inactivity estimates gave similar conclusions.

Other studies have used two examinations and estimated the effect of changes in leisure time physical activity on mortality or cardiovascular disease (3, 6, 8, 18). In these studies, the data have not been used to analyze the dilution of the association between leisure time physical activity and mortality caused by changes in leisure time physical activity between the first and second examinations, but just as many subjects changed physical activity level as in the present study. We therefore believe that other prospective studies include as many subjects changing physical activity level after baseline assessment, but they just do not have the data to analyze it. As dilution is a problem primarily in studies analyzing the relation between disease and a complex and unstable health behavior, the problem might be just as important in analyses of nutrition, which also involves a complex health behavior.

We have tried different approaches to elucidate the problem of the analysis of an unstable health behavior. All these approaches pointed in the same direction. Most prospective studies have long follow-up time because the number of cases is the limiting factor in the statistical analyses, and it is more expensive to increase the size of the cohort than to increase follow-up time.


    ACKNOWLEDGMENTS
 
The study was supported with grants from the Danish Heart Foundation and the Danish Medical Research Council.

Many thanks to the Copenhagen Center for Prospective Population Studies for providing raw data.


    NOTES
 
Correspondence to Dr. Lars Bo Andersen, Norwegian University of Sport and Physical Education, Box 4014, Sognsveien 220, Ullevaal Stadion, 0806 Oslo, Norway (e-mail: lars.bo.andersen{at}nih.no). Back


    REFERENCES
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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