[Pre-randomisation in study designs: getting past the taboo]. / Prerandomisatie bij wetenschappelijk onderzoek: een taboe doorbroken.

In October 2006 the Dutch Ministry of Health, Welfare and Sport announced that the use of pre-randomisation in study designs is admissible and not in conflict with the Dutch Medical Research in Human Subjects Act. With pre-randomisation, the conventional sequence of obtaining informed consent followed by randomisation is reversed. According to the original pre-randomisation design (Zelen design), participants are randomised before they are asked to consent; after randomisation, only participants in the experimental group are asked to consent to treatment and effect measurement. In the past, pre-randomisation has seldom been used, and when it was, it was often under the wrong circumstances. Awareness regarding the ethical, legal and methodological objections to pre-randomisation is increasing. About a decade ago, we illustrated the applicability and acceptability of pre-randomisation by means of a fictitious heroin provision trial. In general, pre-randomisation is justified if valid evaluation of the effects of an intervention is impossible using a conventional randomised design, e.g., if knowledge of the intervention may lead to non-compliance or drop-out in the control group, or when the intervention is an educational programme. Other requirements for pre-randomisation include the following: the study has a clinically relevant objective, it is likely that the study will lead to important new insights, the informed consent procedure bears no potential harm to participants, at least standard care is offered to participants in the control group, and the approval of an independent research ethics committee is obtained.

WITHDRAWN: Injection therapy for subacute and chronic benign low-back pain.

BACKGROUND: Injection with anaesthetics and/or steroids is one of the treatment modalities used in patients with chronic low back pain which needs evaluation with respect to the effectiveness on short and long term pain relief. OBJECTIVES: To evaluate the effectiveness of injection therapy in patients with low back pain lasting longer than one month. We distinguished between three injection sites: facet joint, epidural or local injections. SEARCH STRATEGY: We searched the Medline and Embase databases up to 1996 and other search methods as advocated by the Back Review Group search strategy. Abstracts and unpublished studies were not included. SELECTION CRITERIA: Randomized controlled trials of injection therapy for pain relief (although additional treatments were allowed) in patients with benign low back pain lasting longer than one month and not originating from cancer. DATA COLLECTION AND ANALYSIS: Two authors independently assessed the trials for methodological quality. Subgroup analyses were made between trials with different control groups (placebo and active injections), with different injection site (facet joint, epidural and local injection), and timing of outcome measurement (short and long term). Within the resulting 12 subcategories of studies (2*3*2), the overall relative risks and corresponding 95% confidence intervals were estimated, using a random effects model (DerSimonian and Laird). In the case of trials in which control groups were active injections, we refrained from pooling the results. MAIN RESULTS: Twenty-one randomized trials were included in this review. All studies involved patients with low back pain lasting longer than one month. Only 11 studies compared injection therapy with placebo injections (explanatory trials). The methodologic quality of many studies was low: only 8 studies had a methodologic score of 50 or more points. There were only three well designed explanatory clinical trials: one on injections into the facet joints with a short-term RR of 0.89 (95% CI: 0.65-1.21) and a long-term RR of 0.90 (95% CI: 0.69-1.17); one on epidural injections with a short-term RR of 0.94 (95% CI: 0.76-1.15) and a long-term RR of 1.00 (95% CI: 0.71-1.41); and one on local injections with a long-term RR of 0.79 (95% CI: 0.65-0.96). Within the 6 subcategories of explanatory studies the pooled RRs with 95% confidence intervals were: facet joint, short-term: RR=0.89 (0.65-1.21); facet joint, long-term: RR=0.90 (0.69-1.17); epidural, short-term: RR=0.93 (0.79-1.09); epidural, long-term: RR=0.92 (0.76-1.11); local, short-term: RR=0.80 (0.40-1.59); local, long-term: RR=0.79 (0.65-0.96). AUTHORS' CONCLUSIONS: Convincing evidence is lacking on the effects of injection therapies for low back pain. There is a need for more, well designed explanatory trials in this field.

A prospective cohort study on toenail selenium levels and risk of gastrointestinal cancer.

BACKGROUND: Various animal studies and ecologic studies suggest an inverse association between low dietary selenium intake and risk of various types of cancer. PURPOSE: The goal of this prospective cohort study was to investigate the association between toenail selenium levels and risks of stomach cancer and colorectal cancer. METHODS: Our cohort study on diet and cancer started in The Netherlands in 1986 with enrollment of 120,852 subjects aged 55-69 years. Of this number, 58,279 were men and 62,573 were women. Following the case-cohort approach for analysis of the data, we randomly selected from the cohort a subcohort of 3500 subjects (1688 men and 1812 women). After 3.3 years of follow-up, 155 incident cases of microscopically confirmed stomach cancer, 313 cases of colon cancer, and 166 cases of rectal cancer had been detected in the cohort. Toenail selenium data were available for 104 patients with stomach cancer, 234 with colon cancer, and 113 with rectal cancer and for 2459 subjects from the subcohort. RESULTS: In a multivariate analysis, the relative rates (RRs) of stomach cancer for subjects in increasing quintiles of toenail selenium level were 1.00, 0.44, 0.59, 0.84, and 0.64 (trend, P = .491). For men, there was some evidence for an inverse association between toenail selenium levels and stomach cancer: The RR for those in the highest compared with the lowest quintile of toenail selenium was 0.40 (95% confidence interval = 0.17-0.96), but the trend was not statistically significant (P = .136). For stomach cancer in women, there was no negative association with toenail selenium levels. Toenail selenium level was not associated with the risk of colon or rectal cancer. After exclusion of cases diagnosed in the 1st year of follow-up, the RRs of colon cancer for increasing quintiles of toenail selenium were 1.00, 1.27, 1.17, 0.75, and 1.07 (trend, P = .544); for rectal cancer, RR estimates were 1.00, 1.73, 0.83, 1.58, and 1.12 (trend, P = .890). CONCLUSIONS: These data support a suggestive but inconsistent inverse association between selenium levels and risk of stomach cancer. Our findings, like those of other studies, do not suggest an inverse association with risk of colorectal cancer.

Consumption of fermented milk products and breast cancer: a case-control study in The Netherlands.

In a case-control study in The Netherlands, we observed a significantly lower consumption of fermented milk products (predominantly yogurt and buttermilk) among 133 incident breast cancer cases as compared to 289 population controls (mean +/- SD among users only, 116 +/- 100 versus 157 +/- 144 g/day; P less than 0.01). The age-adjusted odds ratio of daily consumption of 1.5 glasses (greater than or equal to 225 g) of fermented milk versus none was 0.50 (95% confidence interval, 0.23-1.08). When fermented milk was entered as a continuous variable (per g) in either age-adjusted or multivariate analysis, the odds ratio expressed per 225 g was 0.63 (multivariate-adjusted 95% confidence interval, 0.41-0.96). After multivariate adjustment for intake of fat and other confounders, a statistically significant decrease in breast cancer risk was also observed for increasing intake of Gouda cheese. The multivariate-adjusted odds ratio expressed per 60 g of this fermented product was 0.56 (95% confidence interval, 0.33-0.95). For daily intake of milk, no statistically significant differences were observed between cases and controls. These results support the hypothesis that high consumption of fermented milk products may protect against breast cancer.

A prospective cohort study on the relation between meat consumption and the risk of colon cancer.

The high incidence of colon cancer in affluent societies has often been attributed to a high fat diet and, more in particular, the consumption of meat. The association of the consumption of meat and the intake of fat with risk of colon cancer was investigated in a prospective cohort study on diet and cancer, which is being conducted in the Netherlands since 1986 among 120,852 men and women, aged 55-69. The analysis was based on 215 incident cases of colon cancer (105 men and 110 women) accumulated in 3.3 years of follow-up, excluding cases diagnosed in the first year of follow-up. Dietary habits were assessed at baseline with a 150-item semiquantitative food frequency questionnaire. No trends in relative rates of colon cancer were detected for intake of energy or for the energy-adjusted intake of fats, protein, fat from meat, and protein from meat. Consumption of total fresh meat, beef, pork, minced meat, chicken, and fish was not associated with risk of colon cancer either. Processed meats, however, were associated with an increased risk in men and women (relative rate, 1.17 per increment of 15 g/day; 95% confidence interval, 1.03-1.33). The increased risk appeared to be attributable to one of the five questionnaire items on processed meat, which comprised mainly sausages. This study does not support a role of fresh meat and dietary fat in the etiology of colon cancer in this population. As an exception, some processed meats may increase the risk, but the mechanism is not yet clear.

A prospective cohort study on dietary fat and the risk of postmenopausal breast cancer.

In 1986 a prospective cohort study on diet and cancer was started in the Netherlands among 62,573 women ages 55-69 years. Baseline information on diet and other risk factors was collected with a questionnaire. Cancer incidence was measured by record linkage with cancer registries and a pathology register. A case-cohort approach was used, in which the accumulated person time in the cohort was estimated by follow-up of a randomly selected subcohort (n = 1812). After 3.3 years of follow-up, 471 incident breast cancer cases were available for analysis. Questionnaire data for these cases and the 1716 female subcohort members without a history of cancer other than skin cancer were analyzed. In a multivariate analysis, controlling for traditional risk factors, the relative rates for breast cancer in increasing quintiles of energy-adjusted total fat intake were 1.00, 1.00, 1.34, 1.22, 1.08 (P-trend, 0.32). For saturated fat there was some evidence for a weak positive association when quintiles were used (relative rates in quintiles 1-5, 1.00, 1.22, 1.22, 1.38, 1.39; P-trend, 0.049). The 95% confidence interval (CI) for the top quintile was 0.94-2.06, however; and when saturated fat was used as a continuous variable, the effect was no longer significant (P = 0.20). Relative rate estimates for the highest versus lowest quintiles of monounsaturated fat, polyunsaturated fat, and cholesterol intake were 0.75 (95% CI, 0.50-1.12), 0.95 (95% CI, 0.64-1.40) and 1.09 (95% CI, 0.74-1.61), respectively, with no evidence for significant trends. This prospective study does not support a major role of dietary fat in the etiology of postmenopausal breast cancer.

A prospective cohort study on selenium status and the risk of lung cancer.

Selenium has been suggested to be anticarcinogenic and to play a role in the cellular defense against oxidative stress. The association between toenail selenium (a marker of long-term selenium status) and lung cancer was investigated in a cohort study of diet and cancer that started in 1986 among 120,852 Dutch men and women aged 55-69 years. After 3.3 years of follow-up, 550 incident cases of lung carcinoma were detected. Toenail selenium data were available for 370 lung cancer cases and 2459 members of a randomly selected subcohort. The rate ratio of lung cancer for subjects in the highest compared to the lowest quintile of toenail selenium, after controlling for age, gender, smoking, and education, was 0.50 (95% confidence interval, 0.30-0.81), with a significant inverse trend across quintiles (P = 0.006). The protective effect of selenium was concentrated in subjects with a relatively low dietary intake of beta-carotene or vitamin C. The rate ratio in the highest compared to the lowest quintile of selenium was 0.45 in the low beta-carotene group (95% confidence interval, 0.22-0.92; trend P = 0.028) and 0.36 in the low vitamin C group (95% confidence interval, 0.17-0.75; trend P < 0.001). The results of this study support an inverse association between selenium status and lung cancer and suggest a modification of the effect of selenium by the antioxidants beta-carotene and vitamin C.

Benzodiazepines and the risk of falling leading to femur fractures. Dosage more important than elimination half-life.

BACKGROUND: In the past decade, the use of benzodiazepines has been identified as a major independent risk factor for accidental falls. OBJECTIVE: To study the role of dosing, timing, elimination half-life, and type of benzodiazepine in relation to the occurrence of accidental falls leading to hospitalization for femur fractures. METHODS: A 1:3 age-, sex-, and pharmacy-matched case-control study was performed using data from a Dutch record linkage system (PHARMO) (N = 300,000). Cases included 493 patients (55 years and older), newly admitted to the hospital for a femur fracture resulting from an accidental fall (between 1986 and 1992). Relative risk estimates were calculated using conditional logistic regression analyses to control for the potential confounding effects of concomitant drug use and presence of a wide range of underlying diseases. RESULTS: Falls were significantly associated with current use of benzodiazepines (odds ratio, 1.6; 95% confidence interval, 1.2 to 2.1) and in particular with short half-life benzodiazepines (odds ratio, 1.5; 95% confidence interval, 1.1 to 2.0), sudden dose increases (odds ratio, 3.4; 95% confidence interval, 1.0 to 11.5), and concomitant use of several benzodiazepines (odds ratio, 2.5; 95% confidence interval, 1.3 to 4.9). A strong dose-response relationship (P < .0001) and dose-response relations among users of either short or long half-life benzodiazepines suggests that these increased risks are explained primarily by dose. CONCLUSIONS: Benzodiazepines are a major, independent risk factor for falls leading to femur fractures, and the increased risk is probably explained by prescribing too-high doses to the elderly.

A prospective cohort study on antioxidant and folate intake and male lung cancer risk.

Many studies have reported inverse associations between vegetable and fruit consumption and lung cancer risk. The aim of the present study was to elucidate the role of several antioxidants and folate in this relationship. In the Netherlands Cohort Study on Diet and Cancer, 58,279 men of ages 55-69 years at baseline in 1986 returned a questionnaire including a 150-item food frequency questionnaire. After 6.3 years of follow-up, 939 male lung cancer cases were registered. A new Dutch carotenoid database was used to estimate intake of alpha-carotene, beta-carotene, lutein + zeaxanthin, beta-cryptoxanthin, and lycopene, completed with the antioxidant vitamins C and E and folate. Using case-cohort analysis, rate ratios were calculated, adjusted for age, smoking, educational level, and family history of lung cancer. Protective effects on lung cancer incidence were found for lutein + zeaxanthin, beta-cryptoxanthin, folate, and vitamin C. Other carotenoids (alpha-carotene, beta-carotene, and lycopene) and vitamin E did not show significant associations. After adjustment for vitamin C, only folate remained inversely associated, and after adjustment for folate, only beta-cryptoxanthin and vitamin C remained significantly associated. Inverse associations were strongest among current smokers and weaker for former smokers at baseline. Inverse associations with carotenes, lutein + zeaxanthin, and beta-cryptoxanthin seemed to be limited to small cell and squamous cell carcinomas. Only folate and vitamin C intake appeared to be inversely related to small cell and squamous cell carcinomas and adenocarcinomas. Folate, vitamin C, and beta-cryptoxanthin might be better protective agents against lung cancer in smokers than alpha-carotene, beta-carotene, lutein + zeaxanthin, and lycopene.

Predictors of toenail selenium levels in men and women.

Potential predictors of toenail selenium levels were studied in 1211 men and 1248 women aged 55-69 years. These subjects were randomly selected cohort members without prevalent cancer (other than skin) participating in a prospective study on diet and cancer in the Netherlands. Information on the considered potential predictors (gender, age, smoking, intake of dietary selenium and alcohol, Quetelet index) was collected together with toenail specimens in 1986. The average toenail selenium concentration was significantly (P < 0.001) lower in men than in women: 0.547 +/- 0.126 microgram/g (mean +/- SD) and 0.575 +/- 0.109 microgram/g, respectively. The gender difference remained significant after adjustment for the other variables in multiple regression analyses. Age was not associated with toenail selenium levels in men or women. An inverse association was observed with current smoking but not with past smoking. The average toenail selenium values for male current smokers were 0.513 +/- 0.106 microgram/g (mean +/- SD) versus 0.571 +/- 0.133 microgram/g for male never- or ex-smokers (P < 0.001). For women these values were 0.548 +/- 0.101 and 0.581 +/- 0.109 microgram/g, respectively (P < 0.001). Dietary selenium intake was positively associated with toenail selenium levels in multivariate analyses (P < 0.001), but the association was weak (partial r = 0.09). Alcohol intake and Quetelet index were not significant independent predictors of toenail selenium. The observed associations had similar directions in men and women but were stronger in men.

The Zelen design may be the best choice for a heroin-provision experiment.

Recently, the Dutch Parliament agreed upon the conduct of a randomized clinical trial on the effects on heroin provision on general health and psychosocial and criminal behavior in long-term addicts. Previous studies failed to establish the effects beyond reasonable doubt. The main reasons why previous trials failed are massive dropout or noncompliance in the control group. Designing a new heroin-provision trial, we concluded that the Zelen design provides the best guarantee for obtaining valid study results. Compared with the traditional design, the Zelen design probably reduces noncompliance and dropout considerably, thus increasing validity. Depending on the study population, the Zelen design may reduce study precision. However, in a trial aimed at badly integrated addicts, the Zelen design can be conducted without loss of precision because baseline measurements will only weakly correlate with effect measurements. The arguments favoring the Zelen design may be generalized to trials in which the experimental treatment is highly attractive to the study participants. However, the use of the Zelen design precludes blinding of participants who receive the experimental treatment. We argue that the conduct of studies that predictably tend to produce invalid results is ethically dubious. The ethical problem of studying participants without their consent can be solved by a slight modification of the Zelen design in which the sampling of a control group is postponed. Both the traditional and the Zelen design can imply ethical problems. Both designs can be ethically justifiable and should not be rejected on a priori grounds.

The effect of beta-carotene on the regression and progression of cervical dysplasia: a clinical experiment.

In order to gain insight into the causality of the relation between beta-carotene and cancer, we performed a randomized placebo-controlled trial in which the effect of beta-carotene on the regression and progression rates of cervical dysplasia were examined. The experimental group (n = 137) received a supplemental dose of 10 mg of beta-carotene daily for 3 months. The control group (n = 141) received placebo capsules. As the outcome parameter, two definitions of regression and progression were used, which were based on the degree of dysplasia before and after the medication period. The number of patients who showed progression was too small to allow conclusions. No effect of beta-carotene on the regression percentages was observed: OR = 0.68 (95% CI: 0.28-1.60) using the broad definition; and OR = 1.22 (95% CI: 0.43-3.41) with the strict definition. A secondary analysis, in which the effect of the total intake of beta-carotene (diet + medication) on the regression percentages of cervical dysplasia was studied, did not show a positive effect either. The paper discusses to what extent issues in the study design may have masked a potential effect and how our results affect the evidence for a causal relation between beta-carotene and cancer.

Current use of thiazide diuretics and prevention of femur fractures.

A case control study of a defined population from The Netherlands was performed to evaluate the risk of femur fractures associated with the use of thiazide diuretics. Included were 386 patients hospitalized for femur fractures between 1986 and 1990 who were residents and 45 years of age and older. Per case, one age-, sex-, pharmacy-, and general practitioner-matched control was chosen from the general population. Drug use was ascertained from computerized pharmacy records. The adjusted odds ratio of current use of thiazide diuretics was 0.5 (95% confidence interval, 0.3-0.9). The protective effect of thiazide diuretics was greatest for use of 1 year or longer at relatively high doses of thiazides (odds ratio, 0.3; 95% confidence interval, 0.1-0.9). We also found that patients who discontinued thiazide use longer than 2 months were not protected against femur fractures. These results support the hypothesis that use of thiazide diuretics protects against femur fractures.

Interobserver variation in histopathological grading of cervical dysplasia.

In order to assess the variability among histopathologists in grading cervical dysplasia, four experienced histopathologists examined the same set of 106 biopsy specimens and assigned them to one of five diagnostic categories. These were: no dysplasia, mild dysplasia, moderate dysplasia, severe dysplasia and carcinoma in situ. The histopathologists did not discuss the grading criteria beforehand. There was considerable disagreement among the pathologists: unweighted group kappa 0.28, weighted group kappa 0.56. It appeared that all grades of dysplasia were equally difficult to distinguish from adjacent categories. Various explanations for this interobserver variation are put forward.

A large-scale prospective cohort study on diet and cancer in The Netherlands.

In 1986, a prospective cohort study on diet and cancer was started in The Netherlands. The cohort (n = 120, 852) of 55-69 year old men (48.2%) and women (51.8%) originates from 204 computerized municipal population registries. At baseline, participants completed a self-administered questionnaire on diet and potential confounding variables. In addition, about 67% of the participants provided toenail clippings. Cancer follow-up consists of record linkage to a pathology registry and to cancer registries. The initial interest is in stomach, colorectal, breast and lung tumors. A case-cohort approach is applied, in which detailed follow-up information of a random subcohort (n = 5000) provides an estimate of the person-time experience of the cohort. Exposure data of the subcohort will be combined with those of incident cases, yielding exposure-specific incidence rate ratios. The intraindividual variation in determinants is estimated by annually repeated measurements (n = 250) within the subcohort. The rationale, efficiency aspects and study characteristics are discussed.

Sources of interobserver variation in histopathological grading of cervical dysplasia.

The present study aimed to assess where the interobserver variation in grading cervical dysplasia stems from. Four experienced pathologists examined 93 histological slides, after they agreed on which morphological characteristics should be considered relevant for grading. They scored 6 morphological characteristics for each slide and assigned it to a degree of dysplasia. Compared to a previous study, the interobserver variation showed a statistically significant improvement: the weighted group kappa value increased from 0.55 to 0.69. For the scores of the individual characteristics considerable interobserver variation was observed: weighted group kappa values ranged from 0.28 to 0.49. The pathologists slightly differed in which characteristics they considered most important for their grading. The agreement on the degree of dysplasia turned out to be better than the agreement on the morphological characteristics on which this diagnosis is based. In the discussion, a few explanations for this paradoxical finding are put forward.

The role of sexual factors in the aetiology of cervical dysplasia.

The effect of sexual behavior on the risk for cervical dysplasia was evaluated in a case-control study. Cases (n = 257) had a histologically confirmed diagnosis of cervical dysplasia. Controls (n = 705) were sampled from the general population. A postal questionnaire was used to obtain information about, among other things, age at first sexual intercourse, number of sexual partners, current frequency of intercourse and contraceptive use. Information was also collected about other risk factors for cervical dysplasia, in order to adjust for possible confounding. We observed higher risks for cervical dysplasia (mild, moderate and severe) with increasing number of sexual partners. This effect appeared to be dependent on smoking behaviour. For women who reported more than six sexual partners, the adjusted odds ratio (aOR) was 9.1 (95% CI: 3.5-23.7) for non-smokers, and 26.4 (95% CI: 11.8-58.8) for women who smoked > or = 20 cigarettes per day. The effects of age at first sexual intercourse and current frequency of intercourse disappeared after adjustment for other risk factors. Use of oral contraceptives for > 10 years increased the risk (aOR = 2.3; 95% CI: 1.2-4.6). Thus, the number of sexual partners, especially in combination with smoking behaviour, appeared to be the most important risk factor for cervical dysplasia.

Differences in mortality and coronary heart disease between Lithuania and The Netherlands: results from the WHO Kaunas-Rotterdam Intervention Study (KRIS).

BACKGROUND: A 9.5-year follow-up of the Kaunas-Rotterdam Intervention Study (KRIS) provided an opportunity to compare mortality patterns and rates in a population from Lithuania, one of the former republics of the Soviet Union, with a population from the Netherlands. These populations consisted of 2452 and 3365 males, respectively, aged 45-60 years. In 1972-1974, these males were extensively screened for cardiovascular risk factors, using uniform methods. METHODS AND RESULTS: During the follow-up, 303 males in Kaunas (Lithuania) and 350 males in Rotterdam (the Netherlands) died. Using Cox proportional hazards and logistic regression analysis, it was found that all-cause mortality rates during follow-up were 30% higher in Kaunas; this was mainly due to higher mortality rates from external causes (relative risk = 6.69), stomach cancer (RR = 2.78), stroke (RR = 2.30) and infectious diseases (RR = 12.43). The risk of fatal and non-fatal coronary heart disease (CHD) was, however, smaller in Kaunas (RR = 0.72). This lower risk closely corresponded with the Lithuanian risk profile which could be described by less smoking, lower cholesterol levels, and higher physical activity. As Lithuanians had a more advantageous cardiovascular risk profile, the higher Lithuanian all-cause mortality rates could not be explained by this risk profile. CONCLUSIONS: The results provide evidence for geographical differences in mortality and morbidity between Lithuania and the Netherlands. Population-specific health behaviours were shown to be involved in differences in the risk of CHD. The lower CHD rates in Eastern European communities in the 1970s, in this study confirmed for Lithuania, suggests that the apex of the CHD epidemic had not yet reached the Lithuanian population.

Educational level of spouses and risk of mortality: the WHO Kaunas-Rotterdam Intervention Study (KRIS).

BACKGROUND: A 9.5-year follow-up of the Kaunas-Rotterdam Intervention Study (KRIS) provided the opportunity of investigating whether the educational level of wives was associated with their husbands' risk of mortality and coronary heart disease (CHD), independently of the educational level of the husbands themselves. METHODS: The data represent populations consisting of 2452 Lithuanian men and 3365 Dutch men. These men were extensively screened for cardiovascular risk factors in the period 1972-1974. During the follow-up 303 Kaunasians and 350 Rotterdammers died. We used the Cox proportional hazards and the logistic regression models to analyse the data. RESULTS: We found that men whose spouses had little education apparently had an increased risk of all-cause mortality, even when their own educational level was taken into account. The relative risks (RR) were 1.57 in Kaunas and 2.15 in Rotterdam. The results for fatal and non-fatal myocardial infarctions were compatible with this finding, especially in Rotterdam. The prevalence of smoking was higher among men whose wives had primary schooling only. Nonetheless, adjusting the effect of the wife's educational level on her husband's mortality risk for all coronary risk factors in the husband only partially explained the association. CONCLUSIONS: The spouse's educational level appears to have independent effects on a man's risk of mortality in both eastern and western European communities. The results strongly suggest that including characteristics of the socioeconomic status of an individual's spouse would improve studies of socioeconomic differences in health.

The role of beta-carotene and other dietary factors in the aetiology of cervical dysplasia: results of a case-control study.

The effects of beta-carotene and several other dietary factors on the risk of cervical dysplasia were evaluated in a case-control study. Cases (n = 257) were the participants of a randomized trial assessing the effect of beta-carotene on cervical dysplasia. Controls (n = 705) were sampled from the general population. A postal questionnaire was used to obtain information about the frequency of consumption of several food items containing beta-carotene, retinol, vitamin C and dietary fibre. Information was also collected about other risk factors for cervical dysplasia, in order to adjust for possible confounding. To our surprise, we observed an increased risk of cervical dysplasia for women with a high intake of beta-carotene (odds ratio (OR) = 2.31; 95% confidence interval (CI): 1.27-4.19). No relationship was found with the intake of retinol, while both vitamin C and dietary fibre showed a weak and not statistically significant inverse relationship with cervical dysplasia. These findings do not support the hypothesis that beta-carotene protects against cervical dysplasia.