- Email: [email protected]
Dietary assessment and the reliability of nutritional epidemiology reports
COMMENTARY
7 8
Taylor HR, Rapoza P, West SK, et al. The epidemiology of infection in trachoma. Invest Ophthal Visual Sci 1989; 30: 1823–33. Thylefors B, Dawson CR, Jones BR, Wesk SK, Taylor HR. A simple system for the assessment of trachoma and its complications. Bull World Health Organ 1987; 65: 447–83.
Dietary assessment and the reliability of nutritional epidemiology reports See page 212 In today’s Lancet, Sheila Bingham and colleagues report data from the Norfolk component of the EPIC study, on the relation between total and saturated fat consumption and breast cancer risk. They showed a noteworthy association when consumption was assessed with a 7-day food diary, but the association was modest and not statistically significant when consumption was assessed with a food frequency questionnaire. For reasons of cost and logistics, food frequency questionnaires have been the dominant method in nutritional epidemiology for the self-reporting of food consumption for the past 20 or so years. It would therefore be of considerable interest if the ability to study associations between diet and nutrition and cancer or other chronic diseases had been seriously impaired by the use of food frequency questionnaires, and could be improved by the use of the more burdensome and costly, but still practical, food diary. Nutritional epidemiology research has great publichealth importance, but is not easy. Cohort studies and other observational approaches have important confounding issues, since people adhering to a low-fat diet, or to other dietary recommendations,1,2 are likely to differ from those who do not in many behavioural characteristics. It may not be possible to fully ascertain or fully acknowledge these differences in data analysis. Equally important, nutrient consumption is notoriously difficult to measure accurately, even over a short time period, and measurement issues are likely to be influential for nutritional and non-nutritional (eg, physical activity) potential confounding variables as well. Dietary intervention trials use a research design that largely avoids these issues, but such trials typically need to be so large and of such long duration that only a few can be undertaken, and maintenance of a demanding dietary difference between intervention and control groups may be required for a sufficiently powerful trial. Other possible nutrition and chronic disease research designs include international comparisons, time-trend studies, and migrant studies, but these studies, as typically conducted, are only hypothesis generating. Thus many nutrition and chronic disease reports may be of uncertain reliability and, moreover, there is little consensus on a preferred research agenda for obtaining information that is sufficiently reliable for publichealth purposes. Investigators should look for ways to strengthen the conduct of analytical epidemiology studies as a key step towards such a research agenda. Compared with intervention trials, cohort and case-control studies are inexpensive, at least when done using self-reported data for food consumption and for confounding factors. However, repeated use of available self-reporting instruments by individual study participants reveals a noteworthy random error component of the estimate of consumption for most nutrients.3 Thus the distributions of nutrient intake for total or saturated fat in Bingham and colleagues’ study are likely to have been artificially widened by such random measurement error. The fact that the fat and saturated fat distributions are considerably wider for the food frequency 182
questionnaire than for the 7-day food diary may follow from a larger random error component for the food frequency questionnaire than for the food diary.4 Random error that is independent of the underlying true intake tends to attenuate relative risk estimates, providing a possible explanation for the different breast cancer associations with the food frequency questionnaire and the food diary assessments of total and saturated fat, as noted by Bingham and colleagues. Nearly all attempts to accommodate measurement error in nutritional epidemiology have assumed that the measurement error for an individual’s nutrient consumption is additive and is independent of both that person’s actual consumption and their other characteristics. If, on the other hand, the measurement error distribution depends, for example, on an individual’s age, sex, ethnicity, body mass,5 or other so-called social desirability factors,6 distortions other than simple attenuation might arise in estimation of relative risks. To cite an extreme example, if postmenopausal obese women have an increased risk of breast cancer and consume more fat than other postmenopausal women, but systematically tend to report intermediate levels of consumption, a relative risk that is roughly linear as a function of actual fat intake may be distorted to a nonmonotone shape similar to that shown for the relative risk estimates for energy-adjusted saturated fat obtained with the food frequency questionnaire in the table in Bingham and colleagues’ report. Thus understanding and accommodating any systematic component to measurement error seems vital to measuring associations reliably, at least if self-reported data are to be the principal method of dietary assessment. Measurement of biomarkers of nutrient consumption provides a potential way of accommodating both systematic and random components of measurement error in dietary self-reporting, to the extent that measurements of a specific biomarker follow a simple additive measurementerror model. In these circumstances, biomarker data from a subset of the study cohort, or from the control group in a case-control study, allows the self-reported estimates of consumption to be recalibrated accounting for random and systematic components of error, including so-called subject-specific biases (correlations among errors when a self-reporting instrument is administered multiple times to an individual in a study). However, suitable biomarkers currently exist for only a few nutrients or nutrient combinations (eg, short-term total energy, protein, sodium, and potassium).4,7,8 Therefore the identification of suitable biomarkers for various other nutrients is an important research goal for nutritional epidemiology. Bingham and colleagues’ report highlights the importance of these methodological issues in nutrition and chronic disease research by providing an example in which two valuable dietary self-reporting instruments give qualitatively different results. Their report will help to move the debate about measurement error in dietary assessment, which has been ongoing for several years, into a more practical arena. However, it will be useful to compare disease-risk associations with food diary and food frequency assessments of fat intake in additional cohort studies, as the Norfolk-EPIC study is based on a modest number of cases of breast cancer—and especially because the estimated relative risks across fat intake quintiles (whether based on food diaries or food frequency questionnaires) seem larger than would be expected9 from the international correlational analyses that provided much of the stimulus for the fat and breast cancer hypothesis. More generally, the reliability and interpretation of cohortTHE LANCET • Vol 362 • July 19, 2003 • www.thelancet.com
For personal use. Only reproduce with permission from The Lancet.
COMMENTARY
study data on the controversial topic of an association between dietary fat and breast cancer10,11 will unfortunately remain unclear until further objective information becomes available about the measurement properties of the dietary assessment methods used. Ross L Prentice Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA 98109-1024, USA (e-mail: [email protected]) 1
US Department of Health and Human Services. Healthy People 2010 Objectives: secretary’s council draft. Washington, DC: US Department of Health and Human Services, Office of Public Health and Science, 1999; April 23. 2 The American Cancer Society 1996 Advisory Committee on Diet, Nutrition, and Cancer Prevention. Guidelines on diet, nutrition, and cancer prevention: reducing the risk of cancer with healthy food choices and physical activity. CA Cancer J Clin 1996; 46: 325–41. 3 Willett WC, Sampson L, Stampfer MJ, et al. Reproducibility and validity of a semiquantitative food frequency questionnaire. Am J Epidemiol 1985; 122: 51–65. 4 Day NE, McKeown N, Wong MY, Welch A, Bingham SA. Epidemiological assessment of diet: a comparison of a 7-day diary with a food frequency questionnaire using urinary markers of nitrogen, potassium and sodium. Int J Epidemiol 2001; 30: 309–17. 5 Heitmann BL, Lissner L. Dietary underreporting by obese individuals: is it specific or non-specific? BMJ 1995; 311: 986–89. 6 Hebert JR, Clemow L, Pbert L, Ockene IS, Ockene JK. Social desirability bias in dietary self-report may compromise the validity of dietary intake measures. Int J Epidemiol 1995; 24: 389–98. 7 Schoeller DA. Recent advances from application of doubly labeled water to measurement of human energy expenditure. J Nutr 1999; 129: 1765–68. 8 Bingham SA, Cummings JH. Urine nitrogen as an independent validatory measure of dietary intake: a study of nitrogen balance in individuals consuming their normal diet. Am J Clin Nutr 1985; 42: 1276–89. 9 Prentice RL. Future possibilities in the prevention of breast cancer: fat and fiber and breast cancer research. Breast Cancer Res 2000; 2: 268–76. 10 Greenwald P. Role of dietary fat in the causation of breast cancer: point. Cancer Epidemiol Biomarkers Prev 1999; 8: 3–7. 11 Hunter DJ. Role of dietary fat in the causation of breast cancer: counterpoint. Cancer Epidemiol Biomarkers Prev 1999; 8: 9–13.
Breast-cancer prevention: is the riskbenefit ratio in favour of tamoxifen? Breast cancer is the most common malignancy in the world among women: over a million women are diagnosed every year, and 370 000 will die due to breast cancer.1 Breast cancer incidence and mortality has marked regional and country differences. Unknown western lifestyle factors and the hormonal environment are strongly related to the risk of developing sporadic breast cancer, the most common form. Treatment of early breast cancer with tamoxifen and chemotherapy gives clinically meaningful and long-lasting survival improvements.2,3 The beneficial effects of adjuvant tamoxifen on oestrogen-receptor-positive breast cancers and the reduction in contralateral breast cancers, combined with the high incidence of breast cancer, stimulated investigators on both sides of the Atlantic to investigate whether the development of breast cancer could be prevented in at-risk women. Four randomised studies with tamoxifen and one with raloxifene have investigated the potential preventive effect of these drugs; raloxifene was actually tested for osteoporosis prevention (breast cancer prevention was a secondary endpoint). The women included in the trials had calculated risks of breast cancer varying from normal (a woman in the USA and other countries in the western world has a lifetime
risk of around 1 in 8 and up to 1 in 10, respectively) to different increased levels of risk, according to predefined risk-level strategies.4–9 The reduction of new breast cancers tended to be highest in the largest study. 36 111 women (28 406 in the four tamoxifen studies) were included in these prospective studies with active drug or placebo.9 In total, 289 patients were diagnosed with breast cancer in the tamoxifen-treated groups; the corresponding figure was 465 for those not receiving tamoxifen, including in-situ cancers. In the tamoxifen groups, 1 in 49 women developed breast cancer; in the placebo groups, 1 in 31 did so. The calculated reduction in breast cancer was 38% (48% for invasive oestrogen-receptor-positive breast cancers) after treating with tamoxifen for 5 years. Thus, by treating 14 192 women at different risk levels, 5 years of tamoxifen prevented, or deferred, 132 oestrogen-receptor-positive and invasive breast cancers. The gain also had an expense; 53 versus 22 women developed an endometrial carcinoma and 118 versus 62 had a thromboembolic event (tamoxifen versus untreated, respectively). 59 and 39 women, respectively, had a recorded diagnosis of a cerebrovascular accident or stroke. The opposite was found for transient ischaemic attacks. The other drug tested, the selective oestrogen-receptor modulator, raloxifene, was associated with a potentially larger reduction of breast cancer incidence and no increased risk for endometrial carcinoma, and raloxifene is being tested head to head with tamoxifen in the ongoing STAR (Study of Tamoxifen and Raloxifene) study.9 Using the prevention data from the largest study, NSABP-P1,10 Fisher estimated that 700 000 invasive and non-invasive breast cancers could be avoided over 5 years by giving tamoxifen prevention to 29 million women. Andrew Freedman and colleagues11 recently recalculated the potential impact using the data from the P1 study, modulated on almost 66 million US women aged 35–79 years. These investigators used a modified Gail model and estimated that 15·5% would be potentially eligible for prevention with tamoxifen, although with marked between-race differences (18·7% for white women, 5·7% for black women, and 2·9% for Hispanic women). The calculated risk-estimates will, in some other high-risk countries in the world, be almost as high as for the high-risk group of white women in the USA. However, when benefitrisk ratios for tamoxifen are applied, only 4·9%, instead of 18·7%, of white women in the USA would be potential candidates for tamoxifen prevention, according to Freedman and colleagues. For black women the corresponding figure is 0·6%; similar data cannot be properly estimated for Hispanic women. The health-economic consequences of this type of strategy must also be analysed. In almost all countries, the health sector has limited resources. We must therefore strive to increase resources, but also to make the best priorities and medical decisions, and include health-economic modelling. On such a basis, plus the current data on prevention, it is by no means obvious that prevention with present drugs is the way forward. However, with present knowledge, doctors can carefully discuss with women at risk for breast cancer the potential benefits and risks in relation to each individual’s risk level for breast cancer, other illnesses, and individual preferences.11 The lack of a benefit in overall survival in the prevention studies to date, with complicated benefit-risk relations and the fact that only oestrogen-receptor-positive tumours can be prevented or deferred, means that the task today is to find early oestrogen-receptor-positive breast cancers by surveillance strategies, including mammography. Modern
THE LANCET • Vol 362 • July 19, 2003 • www.thelancet.com
For personal use. Only reproduce with permission from The Lancet.
183
7 8
Taylor HR, Rapoza P, West SK, et al. The epidemiology of infection in trachoma. Invest Ophthal Visual Sci 1989; 30: 1823–33. Thylefors B, Dawson CR, Jones BR, Wesk SK, Taylor HR. A simple system for the assessment of trachoma and its complications. Bull World Health Organ 1987; 65: 447–83.
Dietary assessment and the reliability of nutritional epidemiology reports See page 212 In today’s Lancet, Sheila Bingham and colleagues report data from the Norfolk component of the EPIC study, on the relation between total and saturated fat consumption and breast cancer risk. They showed a noteworthy association when consumption was assessed with a 7-day food diary, but the association was modest and not statistically significant when consumption was assessed with a food frequency questionnaire. For reasons of cost and logistics, food frequency questionnaires have been the dominant method in nutritional epidemiology for the self-reporting of food consumption for the past 20 or so years. It would therefore be of considerable interest if the ability to study associations between diet and nutrition and cancer or other chronic diseases had been seriously impaired by the use of food frequency questionnaires, and could be improved by the use of the more burdensome and costly, but still practical, food diary. Nutritional epidemiology research has great publichealth importance, but is not easy. Cohort studies and other observational approaches have important confounding issues, since people adhering to a low-fat diet, or to other dietary recommendations,1,2 are likely to differ from those who do not in many behavioural characteristics. It may not be possible to fully ascertain or fully acknowledge these differences in data analysis. Equally important, nutrient consumption is notoriously difficult to measure accurately, even over a short time period, and measurement issues are likely to be influential for nutritional and non-nutritional (eg, physical activity) potential confounding variables as well. Dietary intervention trials use a research design that largely avoids these issues, but such trials typically need to be so large and of such long duration that only a few can be undertaken, and maintenance of a demanding dietary difference between intervention and control groups may be required for a sufficiently powerful trial. Other possible nutrition and chronic disease research designs include international comparisons, time-trend studies, and migrant studies, but these studies, as typically conducted, are only hypothesis generating. Thus many nutrition and chronic disease reports may be of uncertain reliability and, moreover, there is little consensus on a preferred research agenda for obtaining information that is sufficiently reliable for publichealth purposes. Investigators should look for ways to strengthen the conduct of analytical epidemiology studies as a key step towards such a research agenda. Compared with intervention trials, cohort and case-control studies are inexpensive, at least when done using self-reported data for food consumption and for confounding factors. However, repeated use of available self-reporting instruments by individual study participants reveals a noteworthy random error component of the estimate of consumption for most nutrients.3 Thus the distributions of nutrient intake for total or saturated fat in Bingham and colleagues’ study are likely to have been artificially widened by such random measurement error. The fact that the fat and saturated fat distributions are considerably wider for the food frequency 182
questionnaire than for the 7-day food diary may follow from a larger random error component for the food frequency questionnaire than for the food diary.4 Random error that is independent of the underlying true intake tends to attenuate relative risk estimates, providing a possible explanation for the different breast cancer associations with the food frequency questionnaire and the food diary assessments of total and saturated fat, as noted by Bingham and colleagues. Nearly all attempts to accommodate measurement error in nutritional epidemiology have assumed that the measurement error for an individual’s nutrient consumption is additive and is independent of both that person’s actual consumption and their other characteristics. If, on the other hand, the measurement error distribution depends, for example, on an individual’s age, sex, ethnicity, body mass,5 or other so-called social desirability factors,6 distortions other than simple attenuation might arise in estimation of relative risks. To cite an extreme example, if postmenopausal obese women have an increased risk of breast cancer and consume more fat than other postmenopausal women, but systematically tend to report intermediate levels of consumption, a relative risk that is roughly linear as a function of actual fat intake may be distorted to a nonmonotone shape similar to that shown for the relative risk estimates for energy-adjusted saturated fat obtained with the food frequency questionnaire in the table in Bingham and colleagues’ report. Thus understanding and accommodating any systematic component to measurement error seems vital to measuring associations reliably, at least if self-reported data are to be the principal method of dietary assessment. Measurement of biomarkers of nutrient consumption provides a potential way of accommodating both systematic and random components of measurement error in dietary self-reporting, to the extent that measurements of a specific biomarker follow a simple additive measurementerror model. In these circumstances, biomarker data from a subset of the study cohort, or from the control group in a case-control study, allows the self-reported estimates of consumption to be recalibrated accounting for random and systematic components of error, including so-called subject-specific biases (correlations among errors when a self-reporting instrument is administered multiple times to an individual in a study). However, suitable biomarkers currently exist for only a few nutrients or nutrient combinations (eg, short-term total energy, protein, sodium, and potassium).4,7,8 Therefore the identification of suitable biomarkers for various other nutrients is an important research goal for nutritional epidemiology. Bingham and colleagues’ report highlights the importance of these methodological issues in nutrition and chronic disease research by providing an example in which two valuable dietary self-reporting instruments give qualitatively different results. Their report will help to move the debate about measurement error in dietary assessment, which has been ongoing for several years, into a more practical arena. However, it will be useful to compare disease-risk associations with food diary and food frequency assessments of fat intake in additional cohort studies, as the Norfolk-EPIC study is based on a modest number of cases of breast cancer—and especially because the estimated relative risks across fat intake quintiles (whether based on food diaries or food frequency questionnaires) seem larger than would be expected9 from the international correlational analyses that provided much of the stimulus for the fat and breast cancer hypothesis. More generally, the reliability and interpretation of cohortTHE LANCET • Vol 362 • July 19, 2003 • www.thelancet.com
For personal use. Only reproduce with permission from The Lancet.
COMMENTARY
study data on the controversial topic of an association between dietary fat and breast cancer10,11 will unfortunately remain unclear until further objective information becomes available about the measurement properties of the dietary assessment methods used. Ross L Prentice Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA 98109-1024, USA (e-mail: [email protected]) 1
US Department of Health and Human Services. Healthy People 2010 Objectives: secretary’s council draft. Washington, DC: US Department of Health and Human Services, Office of Public Health and Science, 1999; April 23. 2 The American Cancer Society 1996 Advisory Committee on Diet, Nutrition, and Cancer Prevention. Guidelines on diet, nutrition, and cancer prevention: reducing the risk of cancer with healthy food choices and physical activity. CA Cancer J Clin 1996; 46: 325–41. 3 Willett WC, Sampson L, Stampfer MJ, et al. Reproducibility and validity of a semiquantitative food frequency questionnaire. Am J Epidemiol 1985; 122: 51–65. 4 Day NE, McKeown N, Wong MY, Welch A, Bingham SA. Epidemiological assessment of diet: a comparison of a 7-day diary with a food frequency questionnaire using urinary markers of nitrogen, potassium and sodium. Int J Epidemiol 2001; 30: 309–17. 5 Heitmann BL, Lissner L. Dietary underreporting by obese individuals: is it specific or non-specific? BMJ 1995; 311: 986–89. 6 Hebert JR, Clemow L, Pbert L, Ockene IS, Ockene JK. Social desirability bias in dietary self-report may compromise the validity of dietary intake measures. Int J Epidemiol 1995; 24: 389–98. 7 Schoeller DA. Recent advances from application of doubly labeled water to measurement of human energy expenditure. J Nutr 1999; 129: 1765–68. 8 Bingham SA, Cummings JH. Urine nitrogen as an independent validatory measure of dietary intake: a study of nitrogen balance in individuals consuming their normal diet. Am J Clin Nutr 1985; 42: 1276–89. 9 Prentice RL. Future possibilities in the prevention of breast cancer: fat and fiber and breast cancer research. Breast Cancer Res 2000; 2: 268–76. 10 Greenwald P. Role of dietary fat in the causation of breast cancer: point. Cancer Epidemiol Biomarkers Prev 1999; 8: 3–7. 11 Hunter DJ. Role of dietary fat in the causation of breast cancer: counterpoint. Cancer Epidemiol Biomarkers Prev 1999; 8: 9–13.
Breast-cancer prevention: is the riskbenefit ratio in favour of tamoxifen? Breast cancer is the most common malignancy in the world among women: over a million women are diagnosed every year, and 370 000 will die due to breast cancer.1 Breast cancer incidence and mortality has marked regional and country differences. Unknown western lifestyle factors and the hormonal environment are strongly related to the risk of developing sporadic breast cancer, the most common form. Treatment of early breast cancer with tamoxifen and chemotherapy gives clinically meaningful and long-lasting survival improvements.2,3 The beneficial effects of adjuvant tamoxifen on oestrogen-receptor-positive breast cancers and the reduction in contralateral breast cancers, combined with the high incidence of breast cancer, stimulated investigators on both sides of the Atlantic to investigate whether the development of breast cancer could be prevented in at-risk women. Four randomised studies with tamoxifen and one with raloxifene have investigated the potential preventive effect of these drugs; raloxifene was actually tested for osteoporosis prevention (breast cancer prevention was a secondary endpoint). The women included in the trials had calculated risks of breast cancer varying from normal (a woman in the USA and other countries in the western world has a lifetime
risk of around 1 in 8 and up to 1 in 10, respectively) to different increased levels of risk, according to predefined risk-level strategies.4–9 The reduction of new breast cancers tended to be highest in the largest study. 36 111 women (28 406 in the four tamoxifen studies) were included in these prospective studies with active drug or placebo.9 In total, 289 patients were diagnosed with breast cancer in the tamoxifen-treated groups; the corresponding figure was 465 for those not receiving tamoxifen, including in-situ cancers. In the tamoxifen groups, 1 in 49 women developed breast cancer; in the placebo groups, 1 in 31 did so. The calculated reduction in breast cancer was 38% (48% for invasive oestrogen-receptor-positive breast cancers) after treating with tamoxifen for 5 years. Thus, by treating 14 192 women at different risk levels, 5 years of tamoxifen prevented, or deferred, 132 oestrogen-receptor-positive and invasive breast cancers. The gain also had an expense; 53 versus 22 women developed an endometrial carcinoma and 118 versus 62 had a thromboembolic event (tamoxifen versus untreated, respectively). 59 and 39 women, respectively, had a recorded diagnosis of a cerebrovascular accident or stroke. The opposite was found for transient ischaemic attacks. The other drug tested, the selective oestrogen-receptor modulator, raloxifene, was associated with a potentially larger reduction of breast cancer incidence and no increased risk for endometrial carcinoma, and raloxifene is being tested head to head with tamoxifen in the ongoing STAR (Study of Tamoxifen and Raloxifene) study.9 Using the prevention data from the largest study, NSABP-P1,10 Fisher estimated that 700 000 invasive and non-invasive breast cancers could be avoided over 5 years by giving tamoxifen prevention to 29 million women. Andrew Freedman and colleagues11 recently recalculated the potential impact using the data from the P1 study, modulated on almost 66 million US women aged 35–79 years. These investigators used a modified Gail model and estimated that 15·5% would be potentially eligible for prevention with tamoxifen, although with marked between-race differences (18·7% for white women, 5·7% for black women, and 2·9% for Hispanic women). The calculated risk-estimates will, in some other high-risk countries in the world, be almost as high as for the high-risk group of white women in the USA. However, when benefitrisk ratios for tamoxifen are applied, only 4·9%, instead of 18·7%, of white women in the USA would be potential candidates for tamoxifen prevention, according to Freedman and colleagues. For black women the corresponding figure is 0·6%; similar data cannot be properly estimated for Hispanic women. The health-economic consequences of this type of strategy must also be analysed. In almost all countries, the health sector has limited resources. We must therefore strive to increase resources, but also to make the best priorities and medical decisions, and include health-economic modelling. On such a basis, plus the current data on prevention, it is by no means obvious that prevention with present drugs is the way forward. However, with present knowledge, doctors can carefully discuss with women at risk for breast cancer the potential benefits and risks in relation to each individual’s risk level for breast cancer, other illnesses, and individual preferences.11 The lack of a benefit in overall survival in the prevention studies to date, with complicated benefit-risk relations and the fact that only oestrogen-receptor-positive tumours can be prevented or deferred, means that the task today is to find early oestrogen-receptor-positive breast cancers by surveillance strategies, including mammography. Modern
THE LANCET • Vol 362 • July 19, 2003 • www.thelancet.com
For personal use. Only reproduce with permission from The Lancet.
183