Study Subjects

Between June 1994 and October 1998, 24,540 participants were recruited in the EPIC-Heidelberg cohort, contributing to the European Prospective Investigation into Cancer and Nutrition (EPIC) [18]. Subjects were recruited from the general population [19]. For the present analysis participants younger than 50 years at the end of follow-up (N = 10,759) were excluded. Thus, the analytic cohort comprised 13,781 participants aged between 50 and 75 years at the end of a mean follow-up of 8.7 years.

The baseline assessment included a self–administered food frequency questionnaire (FFQ) and standardized anthropometric measurements including height and weight. Nutrient intake data were calculated from the food consumption data by means of the German Food Composition Tables. The participants were also asked to provide detailed information about their smoking history, physical activity and medical history. The investigation was approved by the ethics committee at the Heidelberg University.

Follow-up and outcome

Follow-up of the cohort began at the date of recruitment and ended at either death or date of the last contact, whichever came first. Prevalent chronic diseases at recruitment were assessed during face-to-face interview. Incident cases of cancer and other chronic diseases were identified by active follow-up. The follow-up consisted of a questionnaire on physician diagnosed chronic conditions and the year of diagnosis. Chronic diseases were regrouped into cancer (all except non-melanoma skin cancer), diabetes mellitus, thyroid disease, stroke, myocardial infarction (MI), heart diseases (except MI), lung diseases (asthma, chronic obstructive pulmonary disease), gastrointestinal diseases (reflux esophagitis, chronic gastritis, gastric ulcer, Crohn's disease, ulcerative colitis, chronic diverticulitis), liver/kidney diseases, pancreatitis, muscle/bone diseases (rheumatic disease, osteoporosis), diseases of the central nervous system (multiple sclerosis, Alzheimer disease, Parkinson's disease), hypertension, dyslipidemia, and hyperuricemia. All self-reports on incident cases of cancer were verified by comparison with the medical records. However, medical verification of other chronic diseases has not been done, except for a few small validation/pilot studies on incident cases of myocardial infarction, stroke, asthma [20], and diabetes. During follow-up, 800 decedents (576 men and 224 women) were registered, confirmed by death certificates, and all-cause mortality was determined. Participation rate was over 90% in each follow-up round. At the end of the 3^rd follow-up, 5.8% of the study participants were lost for follow-up.

The number of concurrent chronic conditions was counted to compute a score of morbidity (0 to ≥ 6). Multimorbidity (yes/no) was defined as two or more concurrent chronic conditions. In addition, multiple metabolic diseases is defined as the concomitant occurrence of metabolic diseases (0, 1, 2, ≥ 3) including diabetes, hypertension, dyslipidemia and hyperuricemia; the dichotomous variable 'metabolic diseases' (yes/no) reflects the existence of any metabolic disease.

Predictors

Educational attainment was used to characterise a participant's SEP. The highest education achieved was measured by questionnaire at recruitment and summarized according to the German schooling system with three degrees: primary school or less (low), secondary school (middle), and grammar school (high). Subjects without school graduation (N = 113) were assigned to the lowest educational level. The highest category of educational attainment was used as the reference group.

As covariates known or potential risk factors of multimorbidity were considered. Smoking status was categorized as never smoker, ex-smoker or current smoker. Body mass index (BMI) was calculated as weight (kg)/height² (m²). Alcohol consumption (g/day), fruit and vegetable intake (g/day) were included in the models as continuous variables. Physical activity was classified as inactive, moderately inactive, moderately active and active based on occupational activity, cycling, and sports [21].

Statistical analysis

This is a cross-sectional analysis of multi-morbidity, using all available information on prevalent chronic diseases collected at recruitment of the cohort and during follow-up rounds. Information on lifestyle factors, diet, and anthropometric data (measurements) was collected at recruitment. The prevalence of chronic conditions was analyzed in relation to educational attainment stratified by sex, because the association between educational level and health outcome could vary by sex as former reports have shown [2, 3, 22]. Age-adjusted logistic regression models were calculated to examine predictors of multimorbidity and Cox proportional hazard models (HR) for mortality, respectively. In order to explore mediating effects we introduced smoking status and increasing BMI (per increments of 5 kg/m²) in the age-adjusted models. Adjusted odds ratios (OR_adj) and 95% confidence intervals (95% CI) for morbidity were calculated by inclusion of age (continuous, year), BMI (continuous, kg/m²), fruit intake (continuous, g/day), vegetable intake (continuous, g/day), alcohol consumption (continuous, g/day), smoking habits, and total physical activity in the models. Whether the associations differed by sex or age was assessed by including a cross-product term in the logistic regression equitation, and p for interaction was calculated with the log-likelihood test. For evaluation of the impact of the single multimorbidity scores, multinomial logistic regression models applying the generalized logit function (glogit) in PROC LOGISTIC were calculated. SAS statistical software 9.13 (SAS institute Inc, Cary, NC) was used for all calculations. A p-value < 0.05 was used to determine statistical significance.

Chronic diseases

Consistent with our findings, other authors identified hypertension, dyslipidemia, chronic ischemic heart disease, back pain and diabetes as most prevalent diagnoses among 60 to 70 year old persons in Germany [23]. The higher prevalence of gastrointestinal diseases may be attributed to younger age of the participants in our study. The prevalence of central-nervous system diseases, however, is likely to be underestimated because of the increasing study participants' disability to complete questionnaires.

Our observations are consistent with the well-known paradox that mortality in women is lower than in men of the same age despite higher levels of morbidity among women [24]. In our data, the sex difference of mortality was weaker compared to a previous review [25]. This may be explained by increasing smoking prevalence among women during the past decades [26].

Intermediaries

Differences in socio-economic position are associated with inequalities in health that may be mediated by differences in health-related behaviour [27]. In line with former research [15, 27–30], we observed that participants with a higher educational level were leaner, ate more fruits and vegetables, and were less likely to be smokers at recruitment. Consistent with our results, it was also noted that moderate drinking was not associated with a SEP gradient, while heavy drinking was more prevalent at lower levels [31, 32]. We observed that the smoking prevalence and, in consequence, number of smoking related diseases were higher in low education groups than in their counterparts. This observation is in consistency with other reports [28, 31]. In our study, however, middle and highly educated men were less physically active than less educated men (please see table 2). The combination of physical inactivity and other adverse lifestyle factors could explain the high prevalence of metabolic disease in men at intermediate educational level.

Our observation that low SEP was recognized as a determinant for higher risk of chronic diseases are in line with the literature [5, 6, 31]. We observed that the association of education differed by disease and adjustment attenuated the relationships differentially [6, 33]. Our results suggest that higher BMI, but not smoking status, may act as an intermediate factor of education on multimorbidity. However, smoking status attenuated the estimates for mortality. Potential explanation could be that in the age group 50 to 75 years smoking habits are rather associated with mortality than with multimorbidity.

Research on mortality has shown that the associations with education were partially eliminated after adjustment for covariates [34]. Other authors found that both social class in childhood and adulthood contribute to disease risk applying objective measures in mid-life [35].

Multimorbidity

Consistent with other studies, we observed that low educational level was statistically significantly associated with a higher prevalence of multimorbidity compared to high educational level [2, 6]. Stronger associations between education and multimorbidity were found among the participants aged 50 to 60 years than among elders, which can be explained by premature mortality in low SEP groups [36]. Growing evidence exists that SEP differences are also reflected in biological markers of disease [5, 6]. In a cohort study on cardiovascular risk factors among men in France and Northern Ireland, education was inversely associated with blood pressure and BMI but not with total cholesterol concentration [31]. Our data further suggest that the educational attainment is not only associated with multimorbidity, but that the social gradient is related to the number of diseases. Our observation that education has an impact on multimorbidity is supported by numerous studies on the relationship between low education and high mortality [9, 13, 23]. Further evidence comes from a study on morbidity during the last years of life among US citizens, which revealed lower morbidity and disability in those with higher education [37].

Further unmeasured factors may contribute to the relationship between education and multimorbidity such as psychosocial factors, stress and other environmental factors [7, 38–40]. It has been hypothesized that low control in terms of autonomy and low social participation are likely contributors to health inequalities [41]. Psychosocial variables such as employment, active coping style, high occupational class and an external locus of control were associated with low prevalence of multimorbidity [42].

Sex differences in health were hypothesized to be related to differential exposure and differential vulnerability [43]. In the present study, pancreatitis and hyperuricemia were more frequent in men and stroke was more frequent in women. Higher prevalence of diabetes in women than in men was found by other authors [6, 44]. Our results suggest differential associations between education and multimorbidity by sex, which may be explained by differences in lifestyle [26], however, these differences could also be due to chance variation by stratification. Also behavioural aspects are likely to be linked with the outcome [40, 43].

Some potential limitations of this study should be considered. We analyzed school attainment as indicator of SEP, but no other indicator such as profession or income. However, measures for adulthood SEP such as occupation or income and measures of economic distress have been shown to be in good correlation with each other [45]. Participants of EPIC-Heidelberg were recruited from the general population [19], but the response rate in less educated subjects tends to be lower than in well-educated ones, implying that the real differences may actually be underestimated.

Our study was largely based on the participants' self-reports, which could have introduced some bias. However, all self-reports on cancer were verified by comparison with medical records, and validation studies were conducted for diabetes, myocardial infarction, and stroke. Misreporting could be linked to the respondents' educational levels, resulting in underestimation of educational inequalities in a previous study [46]. Also, non-response is higher in groups of low SEP and of ill-health [47], which may also result in attenuated estimates. Information on habitual diet and lifestyle factors may be affected by morbidity itself since reverse causation can not be excluded. However, dietary habits and other lifestyle factors were found to be relatively stable over time in our cohort [48]. For some chronic diseases it is difficult to determine whether or not they can be considered independently from each other, such as diabetes mellitus, hypertension, and myocardial infarction [49]. From the public health point-of-view, however, this is irrelevant because persons with several diseases are likely to take more medications and to have more medical consultations.

The strengths of this study are the use of prospective data, its population-based approach, and the possibility to adjust for relevant confounding variables.