Attention to sex-related factors in the development of clinical practice guidelines.

BACKGROUND: Clinical practice guidelines describe optimal strategies for disease prevention, diagnosis, or treatment. Increasing evidence indicates that sex-related factors may have an impact on these strategies. We examined the way in which two Dutch guideline organizations address evidence on sex factors in their guideline development methodologies. We then determined whether attention to these factors could be improved and, if so, how this could be done. METHODS: We selected seven recent guidelines on four conditions: hypertension, depression, osteoporosis, and rheumatoid arthritis. We studied information obtained from interviews with members of the guideline committees and analyzed the content of the guideline documents themselves. Our findings were discussed at an expert meeting. RESULTS: We found that all the guideline committees concerned applied an internationally accepted framework for guideline development. The proportion of male members ranged from 67% to 100%. None of the guidelines included a question (or subquestion) focusing on sex-related factors. In the literature searches no sex-specific search terms were used. Critical appraisals did not include any systematic focus on sex-related factors or effects. The number of sex-specific recommendations (relative to the total number of recommendations) ranged from 0 of 82 and 0 of 148 in the guidelines on depression to 16 of 84 in one of the guidelines on osteoporosis. CONCLUSIONS: We found that when developing guidelines, none of the committees systematically focused on sex-related factors that might be relevant to the way in which evidence is identified, appraised, or described. A number of recommendations were made with the aim to facilitate greater attention to sex-related factors in the current methods of guideline development.

Gender equality in the work of local research ethics committees in Europe: a study of practice in five countries.

BACKGROUND: Funding organisations and research ethics committees (RECs) should play a part in strengthening attention to gender equality in clinical research. In the research policy of European Union (EU), funding measures have been taken to realise this, but such measures are lacking in the EU policy regarding RECs. OBJECTIVE: To explore how RECs in Austria, Germany, Ireland, The Netherlands and Sweden deal with gender equality issues by asking two questions: (1) Do existing procedures promote representation of women and gender expertise in the committee? (2) How are sex and gender issues dealt with in protocol evaluation? METHODS: Two RECs were selected from each country. Data were obtained through interviews with key informants and content analysis of relevant documents (regulations, guidelines and review tools in use in 2003). RESULTS: All countries have rules (mostly informal) to ensure the presence of women on RECs; gender expertise is not required. Drug study protocols are carefully evaluated, sometimes on a formal basis, as regards the inclusion of women of childbearing age. The reason for excluding either one of the sexes or including specific groups of women or making a gender-specific risk-benefit analysis are investigated by some RECs. Such measures are, however, neither defined in the regulations nor integrated in review tools. CONCLUSIONS: The RECs investigated in five European member states are found to pay limited attention to gender equality in their working methods and, in particular in protocol evaluation. Policy and regulations of EU are needed to strengthen attention to gender equality in the work of RECs.

Postmenopausal hormone therapy: less favourable risk-benefit ratios in healthy Dutch women.

OBJECTIVES: To estimate the health effects of postmenopausal hormone therapy used for 10 or 20 years in a population of intermediate cardiovascular risk. DESIGN: Using existing estimates of the effect of hormone therapy on rates of myocardial infarction, hip fracture and breast cancer, a proportional multistage life table was generated to calculate the effects of use for 10 and 20 years in a synthetic cohort of Dutch women aged 55 with an average and a high-risk profile for cardiovascular disease. RESULTS: A woman of the general population who starts hormone therapy at age 55 for 10 years can prolong her life by 1 month and may postpone the occurrence of first incidence of one of the diseases under consideration by 2.4 months. One excess breast cancer case is likely to occur per 5-6 averted cases of first myocardial infarction or hip fracture. If she prolongs her use to 20 years, the gain of life expectancy and disease-free life expectancy is doubled. The risk-benefit ratio worsens to one extra breast cancer per 3-4 averted cases of the preventable diseases. For a woman with a high-risk profile, the gains in health are about twice as high as for her counterpart in the general population, and her risk-benefit ratio is also more favourable. Yet, the risk-benefit ratio still worsens for 20 as compared with 10 years of use. CONCLUSIONS: Women from the general population in the Netherlands and similar populations can achieve only a modest gain in life expectancy by using hormones during 10 or 20 years following menopause. This is a consequence of the low incidence of myocardial infarction and hip fracture and the relatively high incidence of breast cancer before the age of 75. Women at increased cardiovascular risk can benefit more from hormone therapy. But even amongst these women, the risk of breast cancer incurred with long-term use offsets much of the benefit that could accrue from changing the risk of heart disease and hip fracture.

The epidemiology of gallbladder cancer: lifestyle related risk factors and limited surgical possibilities for prevention.

Cancer of the gallbladder is a rare cancer with a poor prognosis. Most patients die within 1 year. The incidence shows large geographic variation and is higher in females and in certain ethnic groups. Gallstones are closely related to this type of cancer. Studying risk factors such as lifestyle is hampered by the generally small size of the case-series. Nevertheless, the studies conducted so far provide some indication that cigarette smoking, alcohol consumption, obesity and specific dietary habits might affect the risk. In women, reproductive history seems to affect the risk as well. Incidence may be lowered by identifying high risk groups and offering preventive measures. Although gallstones are associated with higher risk, most people with untreated gallstones are at low risk of developing the cancer. Moreover, the cancer occurs at such an old age that prophylactic removal of a stone-containing gallbladder is not an appropriate measure for the prevention of gallbladder cancer. Probably at a higher risk are those who are exposed to stones for longer periods. An indicator of duration of exposure is not presently available; whether stone size can be such an indicator in specific conditions and populations needs to be studied further.

Sex differences in illness beliefs and illness behavior in patients with suspected coronary artery disease.

The aim of this study was to explore sex differences in illness beliefs and behavior in patients with suspected coronary artery disease (CAD). Twenty-eight patients, 16 women and 12 men, were interviewed. The results show that both men and women think of CAD as a 'men's disease' and have equal knowledge of CAD risk factors. However, especially the men considered their own risk of developing CAD lower than their estimated probability of their own sex and as low as their estimated risk for women. Both men and women did not attribute their symptoms indicative of CAD to their heart. Women, especially those who did not attribute their symptoms to their heart, had a longer patient delay than men, although their symptoms were indicative of CAD. To conclude, men as well as women should be made more aware of their own risk of developing CAD and of the manifestation of CAD symptoms. Physicians could be encouraged to ask patients more explicitly and thoroughly about their illness beliefs, to check their knowledge and inform them about CAD.

Epidemiologic aspects of gallbladder cancer: a case-control study of the SEARCH Program of the International Agency for Research on Cancer.

BACKGROUND: There are few previous epidemiologic studies of gallbladder cancer, a rare but nearly always lethal gastrointestinal cancer with a demonstrated greater frequency in adult women and older subjects of both sexes, and also in the members of populations throughout central and eastern Europe and certain racial groups such as native American Indians. Unfortunately, the prospects for the prevention of this form of cancer are poor. PURPOSE: Our purpose in conducting this study was to investigate possible new risk factors for gallbladder cancer and to strengthen our understanding of established causal agents that may be involved in this disease. METHODS: A large, collaborative, multicenter, case-control study of cancer of the gallbladder was conducted in five centers located in Australia (Adelaide), Canada (Montreal and Toronto), The Netherlands (Utrecht), and Poland (Opole) from January 1983 through July 1988. Case subjects with gallbladder cancer were accrued by the centers from hospital pathology records and from reports to regional cancer registries. Cancer diagnosis was confirmed by either biopsy, cholecystectomy, or at the time of autopsy. Control subjects were randomly assigned at each center from the population. The pooled analysis included 196 case subjects and 1515 control subjects (who did not report previous cholecystectomy). Ninety-eight percent of the subjects were white. Personal interviews of case subjects, control subjects, and surrogates (spouse or next of kin) were conducted by trained personnel. RESULTS: After adjusting for potential confounding factors (age, sex, center, type of interview, years of schooling, alcohol intake, and lifetime cigarette smoking), a history of gallbladder symptoms requiring medical attention (e.g., reduced bile secretion from the gallbladder into the small intestine due to obstructions of the common bile or cystic ducts) was the major risk factor associated with this form of cancer (odds ratio [OR] = 4.4; 95% confidence interval [CI] = 2.6-7.5). This association was present even in subjects who had their first gallbladder examination because of symptoms present more than 20 years earlier (OR = 6.2; 95% CI = 2.8-13.4). Other variables associated with gallbladder cancer risk included an elevated body mass index, high total energy intake, high carbohydrate intake (after adjustment for total energy intake), and chronic diarrhea. All of these risk factors have been previously associated with gallstone disease. CONCLUSIONS: These findings are consistent with a major role of gallstones, or risk factors for gallstones, in the cause of gallbladder cancer. Additional information on whether or not screening high-risk subjects for gallstones or gallbladder cancer is needed.

Cigarette smoking and pancreas cancer: a case control study of the search programme of the IARC.

A multi-centre case-control study of pancreas cancer, designed to be population-based, to use a random sample of local populations as controls and to use a common protocol and core questionnaire, was conducted as the first study of the SEARCH programme of the International Agency for Research on Cancer. "Ever-smokers" were found to be at increased risk for pancreas cancer compared with "never-smokers" consistently in all strata of gender, response status and centre. Risk of pancreas cancer was found to increase with increasing lifetime consumption of cigarettes, the relative risk rising to 2.70 (95% C.I. 1.95 to 3.74) in the highest intake category. The overall trend in risk was highly significant and the association was found consistently in each stratum of gender, response status and centre. Fifteen years had to pass from quitting cigarette smoking until the risk fell to a level compatible with that in never-smokers among the heaviest group of smokers; among the 2 lowest tertiles this happened within 5 years. Further, reported smoking habits more than 15 years before diagnosis appeared to have no influence on pancreas-cancer risk, irrespective of amount smoked. The results are consistent with a causal role for cigarette smoking in the aetiology of pancreas cancer and illustrate that ceasing to smoke cigarettes can lead to reductions in the elevated risk of pancreas cancer produced by this habit.

Consumption of foods and micronutrients and the risk of cancer of the biliary tract.

BACKGROUND: Gallstones and obesity have been suggested as risk factors for cancer of the biliary tract. Since both factors are related to diet, we studied the relationship between dietary intake and the cancer of interest in a population-based case-control study. METHODS: The study population comprised 111 patients and 480 controls. Food intake was assessed by means of a semiquantitative food frequency questionnaire. Estimates of the intake of foods and micronutrients were obtained from cases and controls themselves (direct respondents) or from relatives (indirect respondents). Participants were categorized into tertiles of intake. Risk ratios were estimated by logistic regression analysis. RESULTS: The major findings are a monotonic decrease in risk associated with the consumption of vegetables (ORs 1.0, 0.7, 0.4, P value trend < 0.01) and a monotonic increase in risk associated with sugar added to drinks and desserts (ORs 1.0, 1.3, 2.5; P value trend < 0.01). CONCLUSIONS: The finding on added sugar corresponds to our earlier report that the group monosaccharides and disaccharides is a potential risk factor for this cancer. Sugar may influence bile composition through lipoprotein metabolism. The protective effect of vegetables is in accordance with the reported inverse relationship between vegetables and many epithelial cancers of the alimentary tract.

Smoking, alcohol consumption and the risk of cancer of the biliary tract; a population-based case-control study in The Netherlands.

Although cancer of the biliary tract is a highly fatal disease, the relationship with modifiable, life style-related factors is hardly studied. Between 1984 and 1987 we conducted a case-control study of 114 patients and 487 controls from the general population. An interviewer-administered questionnaire was used to collect information on life-time smoking habits and life-time alcohol consumption. The information was obtained either from the subjects themselves (direct response) of from relatives (indirect response). Results show that neither smoking at the time of interview (odds ratio (OR) 1.5; 95% confidence interval (CI) 0.9-2.4) nor smoking 2, 5 or 10 years before were associated significantly with the cancer. Alcohol consumption at the time of interview (OR 1.0; 95% CI 0.6-1.5) or drinking 2, 5 or 10 years before were not significantly associated either. Among current alcohol drinkers, long-term consumers had a reduced risk (duration of use > 38 years vs < 25 years: OR 0.4; 95% CI 0.1-0.9) and late starters an elevated risk (starting age > 38 years vs < 21 years: OR 2.7, 95% CI 1.0-7.5). A modifying effect of alcohol consumption on the smoking-cancer relationship was observed: the risk for current smokers was increased only when they did not drink alcohol at that point in time (OR 3.4, 95% CI 1.3-8.5). Our results indicate that long-term moderate alcohol use might be protective against cancer of the biliary tract, whereas smoking might be a risk factor for this cancer.

Regional fat distribution as risk factor for clinically diagnosed gallstones in middle-aged men: a 25-year follow-up study (the Zutphen Study).

Obesity is considered to be an important risk factor for the formation of gallstones. The relationship is well established for women but not for men. In a long-term follow-up study of middle-aged men the relationship between various markers of obesity and the incidence of clinically diagnosed gallstones during 25 years of follow-up was studied. Information on the presence of gallstones was obtained by self-report and verified through medical records after death. Of the 860 men who were between 40 and 59 years old at the start of the study, 54 developed gallstones, yielding an incidence rate of 3.1/1000 person-years. Cox proportional hazard models were used to examine the associations between the risk factors and newly diagnosed gallstones. Univariate analysis revealed that the subscapular-to-triceps skinfold thickness ratio (STR) yields a significant positive association (HR upper quartile: 2.5, 95% CI: 1.1-5.7). Subscapular skinfold thickness had a borderline significant, positive association, which became significant after exclusion of subjects who developed symptomatic gallstones within the first 3 years of follow-up (HR upper quartile: 2.5, 95% CI: 1.0-6.2). The multivariate model revealed that the association of STR with clinically diagnosed gallstones was independent of Body Mass Index. Our results indicate that regional fat distribution, as measured by the subscapular-to-triceps skinfold thickness ratio, may play an important role in the formation of gallstones in men, as was previously found for women in other studies.

Dietary risk factors for clinically diagnosed gallstones in middle-aged men. A 25-year follow-up study (the Zutphen Study).

In a long-term follow-up study of middle-aged men, the relation between the intake of energy, nutrients, and foods and the 25-year incidence of clinically diagnosed gallstones was studied. Information on the presence of gallstones was obtained by self-report and verified through medical records after death. Of 860 men, 54 developed symptomatic gallstones, yielding an incidence rate of 3.1/1000 person-years. The present study provides a comprehensive picture of dietary risk factors for clinically diagnosed gallstones based on a long-term follow-up. Calcium intake was inversely associated with gallstone incidence in the univariate and multivariate Cox proportional hazards analyses (hazard ratio (HR) upper tertile: 0.3; 95% CI: 0.1 to 0.7). A positive association with sugars (monosaccharides and disaccharides) appeared after the introduction of age, body mass index, calcium intake, and the intake of energy from nutrients other than sugars into the model (HR upper tertile: 2.3; 95% CI: 1.0 to 4.8). Calcium may alter the composition of bile by preventing the reabsorption of secondary bile acids in the colon, whereas sugars may influence bile composition through lipoprotein metabolism.

Reproductive history and cancer of the biliary tract in women.

Although reproductive factors have been shown to be related to the composition of bile and functioning of the biliary system, their relationship with biliary tract cancer has not been studied in detail. Between 1984 and 1987 we conducted a case-control study of 75 women with cancer of the biliary tract and 252 controls from the general population. An interviewer-administered questionnaire was used to collect information on reproductive history. The information was obtained from the responders themselves (direct response) or from relatives (indirect response). Our results indicate that younger age at menarche, early age at first pregnancy, higher number of pregnancies and prolonged fertility may enhance the risk of cancer of the biliary tract. Overall, increased exposure to endogenous oestrogens and progesterone constitutes a higher risk.

Gallstone size and the risk of gallbladder cancer.

The relation between gallstone size and gallbladder cancer was investigated in a matched hospital-based case-control study of surgical patients in a predominantly white population. Stone size was considered to be an indicator of the damaging effects of gallstones on gallbladder mucosa, which may enhance carcinogenesis. A radiologist determined the size of the largest gallstone within the gallbladder by reviewing hard copies of the ultrasonographic examinations of cases and controls. Between 1983 and 1989, 83 surgical patients with gallbladder cancer were identified in 18 participating hospitals. Hard copies were available for 72 patients and 208 matched controls. For 43 cancer patients and 98 matched controls stone size could be determined. In contrast to two other studies, no relation was found between stone size and gallbladder cancer. The reasons for this discrepancy are discussed.

Dietary sugar intake in the aetiology of biliary tract cancer.

Although gallstones and obesity are important risk factors for biliary tract cancer, the relation between diet and this type of cancer has not been studied in detail. Between 1984 and 1988 we conducted a case-control study of 111 cases of biliary tract cancer and 480 controls from the general population. Food intake was assessed by means of a semiquantitative food frequency questionnaire. Estimates of the total energy intake and the intake of macronutrients were obtained from the patients and controls themselves (direct respondents) or from relatives (indirect respondents). The major finding is that the risk associated with the intake of sugars (i.e. the combined intake of monosaccharides and disaccharides), independent of other sources of energy, is more than doubled for indirect respondents and for both respondent groups combined. A biological explanation for the fact that the intake of sugars may be a risk factor for biliary tract cancer might be based on the relationships between sugar, blood lipids and gallstone formation.

Aspects of medical history and exocrine carcinoma of the pancreas: a population-based case-control study in The Netherlands.

During 1984-88 a population-based case-control study was carried out in The Netherlands, in collaboration with the International Agency for Research on Cancer, to examine the possible relationship between aspects of medical history and exocrine pancreatic carcinoma in 176 cases and 487 controls. About 58% of patients were interviewed directly. We observed an inverse relationship between medical treatment for allergy-related conditions and the development of pancreatic cancer (30 cases vs. 130 controls, OR 0.57, 95% CI 0.36 to 0.90). A history of gallbladder problems, gallstones, cholecystectomy, stomach or duodenal ulcer, pancreatitis, appendicitis, diabetes or tonsillectomy was not related to risk. In direct responses, compared with once daily, a positive relationship was seen for stool frequency, 10 years ago, of less than once daily (18 cases vs. 40 controls, OR 2.10, 95% CI 1.09 to 4.04). In men, diabetes treated with insulin and diagnosed more than 1 year previously was significantly and positively related to risk (5 cases vs. 1 control, OR 11.66, 95% 1.28 to 105.95). In brief, the results of the present study suggest that a history of allergy-related conditions may protect, whereas a past stool frequency of less than once daily may enhance the risk of cancer of the pancreas. Other elements of the medical history were not consistently related to risk.

Anthropometric and reproductive variables and exocrine carcinoma of the pancreas: a population-based case-control study in The Netherlands.

During 1984-88 a population-based case-control study was carried out in The Netherlands, in collaboration with the International Agency for Research on Cancer, to examine the possible relationship between aspects of medical history and exocrine pancreatic carcinoma in 176 cases and 487 controls. About 58% of patients were interviewed directly. In women, a significant, positive dose-response effect of height was seen (p-value trend less than 0.005). Compared with ages 14 or more, women with an early age at menarche, i.e., 11 years or less, had a 3-fold increase in risk (15 cases vs. 23 controls, OR 3.07, 95% CI 1.35 to 7.00). Other apsects of the reproductive history were not related to risk. In brief, the results of the present study support the hypothesis that, in women, early menarche and greater adult stature may be early predictors of the development of cancer of the pancreas later in life.

Lifetime consumption of alcoholic beverages, tea and coffee and exocrine carcinoma of the pancreas: a population-based case-control study in The Netherlands.

From 1984 to 1988 a population-based case-control study was carried out in the Netherlands, in collaboration with the International Agency for Research on Cancer, to examine the possible relationship between the habitual lifetime consumption of alcohol, coffee and tea and exocrine pancreatic carcinoma in 176 cases and 487 controls. An interviewer-administered questionnaire was used to ascertain major life events and obtain estimates of consumption (ever-never) and frequency of consumption throughout life. Logistic regression analyses yielded odds ratios adjusted for age, sex, response status, smoking, dietary intake of energy and vegetables and of alcoholic or non-alcoholic drinks. When compared with data from non-drinkers, the cumulative lifetime consumption of all types of alcohol in grams of ethanol (ORs 1.00, 0.97, 0.93, 1.25, p trend 0.55), beer, spirits, red wine and fortified wine was not related to risk. The consumption of white wine was inversely associated with risk (OR 0.41, 95% CI 0.24-0.70). The uniformly reduced risk estimates for the lifetime number of drinks of white wine were based on small numbers (ORs 1.00, 0.44, 0.25, 0.40, p trend 0.001). When compared with data from non-drinkers, our findings suggest an inverse dose-response relationship for the lifetime consumption of coffee (ORs 1.00, 0.72, 0.37, 0.58, p trend 0.06), whereas lifetime consumption of tea and of ground, instant and decaffeinated coffee was not associated with risk. The absence of an effect of lifetime consumption of decaffeinated coffee may be due to the small numbers of subjects. These results further strengthen existing evidence against a positive association between consumption as well as lifetime consumption of (sources of) alcohol, tea or coffee and the development of exocrine pancreatic cancer.