JAGS
DECEMBER 2014–VOL. 62, NO. 12
Author Contributions: Dr. Wayne McCormick is responsible for the entire content of this paper. Sponsor’s Role: None.
LETTERS TO THE EDITOR
2467
Author Contributions: Kawada: study concept and design, acquisition of subjects and data, data analysis and interpretation, preparation of manuscript. Sponsor’s Role: N/A.
REFERENCE 1. Berger MS. Misuse of Beers Criteria. J Am Geriar Soc 2014;62:1411.
DIETARY FACTORS AND INCIDENCE OF DEMENTIA: COX REGRESSION ANALYSIS WITH SPECIAL EMPHASIS ON THE NUMBER OF EVENTS To the Editor: I read with interest the paper by Ozawa and colleagues,1 who followed 1,081 individuals aged 60 and older without dementia for 17 years, 303 of whom developed dementia (n = 166 Alzheimer’s disease (AD), n = 95 vascular dementia (VaD)). Their survey was precisely conducted using valid procedures, and being in the second (hazard ratio (HR) = 0.64, 95% confidence interval (CI) = 0.41–0.99), third (HR = 0.57, 95% CI = 0.37– 0.87), and fourth (HR = 0.63, 95% CI = 0.41–0.98) quartiles of milk and dairy intake was significantly protective against AD. The authors used 15 potential confounders for the adjustment of Cox regression analysis. I fundamentally agree their results except for the number of events in their analysis. The number of events per independent variable in Cox regression analysis should be kept at 10 or larger to keep estimates stable.2,3 Because milk and dairy intake was classified into four groups, three variables were statistically used for this main independent variable. By summing the number of independent variable, 180 events are needed for AD incident. The lack of statistical power may explain why there was no statistically significant effect of milk and dairy intake on the incidence of VaD. Further follow-up is needed to confirm the results. It could be that dietary patterns rather than specific foods contribute to the risk of dementia, and the assertion that milk and dairy intake has a direct effect on the incidence of dementia should be approached with caution. The authors conducted a follow-up study for longer than 17 years, and there is a possibility that the risk of dementia had been established at the baseline study. In addition, some confounding factors changed during follow-up. To address this problem, time-dependent Cox regression analysis for the risk assessment of dementia should be conducted.4–6 In any case, sensitivity analysis to verify the effect of milk and dairy intake on each type of dementia should be conducted after summing the number of events. Tomoyuki Kawada, MD Department of Hygiene and Public Health, Nippon Medical School, Bunkyo-Ku, Tokyo, Japan
ACKNOWLEDGMENTS Conflict of Interest: There is no conflict of interest in this study. The author has indicated no financial support.
REFERENCES 1. Ozawa M, Ohara T, Ninomiya T et al. Milk and dairy consumption and risk of dementia in an elderly Japanese population: The Hisayama Study. J Am Geriatr Soc 2014;62:1224–1230. 2. Concato J, Peduzzi P, Holford TR et al. Importance of events per independent variable in proportional hazards analysis. I. Background, goals, and general strategy. J Clin Epidemiol 1995;48:1495–1501. 3. Peduzzi P, Concato J, Feinstein AR et al. Importance of events per independent variable in proportional hazards regression analysis. II. Accuracy and precision of regression estimates. J Clin Epidemiol 1995;48:1503–1510. 4. Nordstr€ om P, Micha€elsson K, Gustafson Y et al. Traumatic brain injury and young onset dementia: A nationwide cohort study. Ann Neurol 2014;75: 374–381. 5. Mielke MM, Zandi PP, Shao H et al. The 32-year relationship between cholesterol and dementia from midlife to late life. Neurology 2010;75: 1888–1895. 6. Norton MC, Smith KR, Østbye T et al. Greater risk of dementia when spouse has dementia? The Cache County Study. J Am Geriatr Soc 2010;58:895–900.
RESPONSE LETTER To the Editor: We appreciate Dr. Kawada’s interest and comments1 about our recent study of the relationship between milk and dairy intake and risk of dementia.2 Fifteen potential confounders (age; sex; low education; history of stroke; hypertension; diabetes mellitus; total cholesterol; body mass index; smoking habits; regular exercise; and intake of energy, vegetables, fruit, fish, and meat) were originally used, but the number of events of Alzheimer’s disease (AD) and vascular dementia (VaD) did not satisfy the rule of 10 events per covariate.3 In line with the suggestion, the number of covariates was reduced using a backward selection method; there were seven, six, and six selected covariates in the analysis of all-cause dementia, AD, and VaD, respectively. When the data were reanalyzed using multivariable adjustment using these covariates, the findings remained substantially unchanged (all-cause dementia: adjusted hazard ratio (aHR) = 0.87, 95% confidence interval (CI) = 0.63–1.20 for the second quartile of milk and dairy intake; aHR = 0.68, 95% CI = 0.49–0.94 for the third quartile; aHR = 0.78, 95% CI = 0.57–1.08 for the fourth quartile; AD: aHR = 0.65, 95% CI = 0.42–0.996 for the second quartile; aHR = 0.58, 95% CI = 0.38–0.90 for the third quartile; aHR = 0.65, 95% CI = 0.42–0.98 for the fourth quartile; VaD: aHR = 1.12, 95% CI = 0.66–1.87 for the second quartile; aHR = 0.72, 95% CI = 0.41–1.28 for the third quartile; aHR = 0.73, 95% CI = 0.40–1.33 for the fourth quartile). We previously reported that greater adherence to a dietary pattern characterized by high intake of milk and dairy products, soybeans and soybean products, vegetables, and algae and low intake of rice significantly reduced the risk of dementia.4 Of these foods, only milk and dairy intake was significantly associated with lower risk of dementia. Although lifestyle in early life, in addition to genetic factors,
2468
LETTERS TO THE EDITOR
could largely influence the risk of dementia in elderly adults, clinical and epidemiological evidence, including the results of the current study, indicates that the risk of dementia could be modified in late life. Further cohort studies and intervention trials will be necessary to clarify the protective role of milk and dairy intake in the development of dementia. As requested, an analysis was conducted using a timedependent Cox proportional hazards model. An attempt was made to follow up with more than 80% of the study participants in health examinations every 5 years. Of the aforementioned covariates, selected time-dependent covariates were hypertension, diabetes mellitus, total cholesterol, body mass index, smoking habits, and regular exercise. As a result, the findings were substantially unchanged (data not shown because of word-count limitations).
DECEMBER 2014–VOL. 62, NO. 12
JAGS
Center for Cohort Studies, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan Yutaka Kiyohara, MD, PhD Department of Environmental Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
ACKNOWLEDGMENTS Conflict of Interest: None. Author Contributions: All authors contributed to this paper. Sponsor’s Role: None.
REFERENCES Mio Ozawa, PhD Department of Environmental Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan Tomoyuki Ohara, MD, PhD Department of Environmental Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan Department of Neuropsychiatry, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan Toshiharu Ninomiya, MD, PhD Department of Environmental Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
1. Kawada T. Dietary factors and incidence of dementia: Cox regression analysis with special emphasis on the number of events. J Am Geriatr Soc 2014;62:2467. 2. Ozawa M, Ohara T, Ninomiya T et al. Milk and dairy consumption and risk of dementia in an elderly Japanese population: The Hisayama Study. J Am Geriatr Soc 2014;62:1224–1230. 3. Vittinghoff E, McCulloch CE. Relaxing the rule of ten events per variable in logistic and Cox regression. Am J Epidemiol 2007;165:710–718. 4. Ozawa M, Ninomiya T, Ohara T et al. Dietary patterns and risk of dementia in an elderly Japanese population: The Hisayama Study. Am J Clin Nutr 2013;97:1076–1082.
Copyright of Journal of the American Geriatrics Society is the property of Wiley-Blackwell and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.
DECEMBER 2014–VOL. 62, NO. 12
Author Contributions: Dr. Wayne McCormick is responsible for the entire content of this paper. Sponsor’s Role: None.
LETTERS TO THE EDITOR
2467
Author Contributions: Kawada: study concept and design, acquisition of subjects and data, data analysis and interpretation, preparation of manuscript. Sponsor’s Role: N/A.
REFERENCE 1. Berger MS. Misuse of Beers Criteria. J Am Geriar Soc 2014;62:1411.
DIETARY FACTORS AND INCIDENCE OF DEMENTIA: COX REGRESSION ANALYSIS WITH SPECIAL EMPHASIS ON THE NUMBER OF EVENTS To the Editor: I read with interest the paper by Ozawa and colleagues,1 who followed 1,081 individuals aged 60 and older without dementia for 17 years, 303 of whom developed dementia (n = 166 Alzheimer’s disease (AD), n = 95 vascular dementia (VaD)). Their survey was precisely conducted using valid procedures, and being in the second (hazard ratio (HR) = 0.64, 95% confidence interval (CI) = 0.41–0.99), third (HR = 0.57, 95% CI = 0.37– 0.87), and fourth (HR = 0.63, 95% CI = 0.41–0.98) quartiles of milk and dairy intake was significantly protective against AD. The authors used 15 potential confounders for the adjustment of Cox regression analysis. I fundamentally agree their results except for the number of events in their analysis. The number of events per independent variable in Cox regression analysis should be kept at 10 or larger to keep estimates stable.2,3 Because milk and dairy intake was classified into four groups, three variables were statistically used for this main independent variable. By summing the number of independent variable, 180 events are needed for AD incident. The lack of statistical power may explain why there was no statistically significant effect of milk and dairy intake on the incidence of VaD. Further follow-up is needed to confirm the results. It could be that dietary patterns rather than specific foods contribute to the risk of dementia, and the assertion that milk and dairy intake has a direct effect on the incidence of dementia should be approached with caution. The authors conducted a follow-up study for longer than 17 years, and there is a possibility that the risk of dementia had been established at the baseline study. In addition, some confounding factors changed during follow-up. To address this problem, time-dependent Cox regression analysis for the risk assessment of dementia should be conducted.4–6 In any case, sensitivity analysis to verify the effect of milk and dairy intake on each type of dementia should be conducted after summing the number of events. Tomoyuki Kawada, MD Department of Hygiene and Public Health, Nippon Medical School, Bunkyo-Ku, Tokyo, Japan
ACKNOWLEDGMENTS Conflict of Interest: There is no conflict of interest in this study. The author has indicated no financial support.
REFERENCES 1. Ozawa M, Ohara T, Ninomiya T et al. Milk and dairy consumption and risk of dementia in an elderly Japanese population: The Hisayama Study. J Am Geriatr Soc 2014;62:1224–1230. 2. Concato J, Peduzzi P, Holford TR et al. Importance of events per independent variable in proportional hazards analysis. I. Background, goals, and general strategy. J Clin Epidemiol 1995;48:1495–1501. 3. Peduzzi P, Concato J, Feinstein AR et al. Importance of events per independent variable in proportional hazards regression analysis. II. Accuracy and precision of regression estimates. J Clin Epidemiol 1995;48:1503–1510. 4. Nordstr€ om P, Micha€elsson K, Gustafson Y et al. Traumatic brain injury and young onset dementia: A nationwide cohort study. Ann Neurol 2014;75: 374–381. 5. Mielke MM, Zandi PP, Shao H et al. The 32-year relationship between cholesterol and dementia from midlife to late life. Neurology 2010;75: 1888–1895. 6. Norton MC, Smith KR, Østbye T et al. Greater risk of dementia when spouse has dementia? The Cache County Study. J Am Geriatr Soc 2010;58:895–900.
RESPONSE LETTER To the Editor: We appreciate Dr. Kawada’s interest and comments1 about our recent study of the relationship between milk and dairy intake and risk of dementia.2 Fifteen potential confounders (age; sex; low education; history of stroke; hypertension; diabetes mellitus; total cholesterol; body mass index; smoking habits; regular exercise; and intake of energy, vegetables, fruit, fish, and meat) were originally used, but the number of events of Alzheimer’s disease (AD) and vascular dementia (VaD) did not satisfy the rule of 10 events per covariate.3 In line with the suggestion, the number of covariates was reduced using a backward selection method; there were seven, six, and six selected covariates in the analysis of all-cause dementia, AD, and VaD, respectively. When the data were reanalyzed using multivariable adjustment using these covariates, the findings remained substantially unchanged (all-cause dementia: adjusted hazard ratio (aHR) = 0.87, 95% confidence interval (CI) = 0.63–1.20 for the second quartile of milk and dairy intake; aHR = 0.68, 95% CI = 0.49–0.94 for the third quartile; aHR = 0.78, 95% CI = 0.57–1.08 for the fourth quartile; AD: aHR = 0.65, 95% CI = 0.42–0.996 for the second quartile; aHR = 0.58, 95% CI = 0.38–0.90 for the third quartile; aHR = 0.65, 95% CI = 0.42–0.98 for the fourth quartile; VaD: aHR = 1.12, 95% CI = 0.66–1.87 for the second quartile; aHR = 0.72, 95% CI = 0.41–1.28 for the third quartile; aHR = 0.73, 95% CI = 0.40–1.33 for the fourth quartile). We previously reported that greater adherence to a dietary pattern characterized by high intake of milk and dairy products, soybeans and soybean products, vegetables, and algae and low intake of rice significantly reduced the risk of dementia.4 Of these foods, only milk and dairy intake was significantly associated with lower risk of dementia. Although lifestyle in early life, in addition to genetic factors,
2468
LETTERS TO THE EDITOR
could largely influence the risk of dementia in elderly adults, clinical and epidemiological evidence, including the results of the current study, indicates that the risk of dementia could be modified in late life. Further cohort studies and intervention trials will be necessary to clarify the protective role of milk and dairy intake in the development of dementia. As requested, an analysis was conducted using a timedependent Cox proportional hazards model. An attempt was made to follow up with more than 80% of the study participants in health examinations every 5 years. Of the aforementioned covariates, selected time-dependent covariates were hypertension, diabetes mellitus, total cholesterol, body mass index, smoking habits, and regular exercise. As a result, the findings were substantially unchanged (data not shown because of word-count limitations).
DECEMBER 2014–VOL. 62, NO. 12
JAGS
Center for Cohort Studies, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan Yutaka Kiyohara, MD, PhD Department of Environmental Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
ACKNOWLEDGMENTS Conflict of Interest: None. Author Contributions: All authors contributed to this paper. Sponsor’s Role: None.
REFERENCES Mio Ozawa, PhD Department of Environmental Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan Tomoyuki Ohara, MD, PhD Department of Environmental Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan Department of Neuropsychiatry, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan Toshiharu Ninomiya, MD, PhD Department of Environmental Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
1. Kawada T. Dietary factors and incidence of dementia: Cox regression analysis with special emphasis on the number of events. J Am Geriatr Soc 2014;62:2467. 2. Ozawa M, Ohara T, Ninomiya T et al. Milk and dairy consumption and risk of dementia in an elderly Japanese population: The Hisayama Study. J Am Geriatr Soc 2014;62:1224–1230. 3. Vittinghoff E, McCulloch CE. Relaxing the rule of ten events per variable in logistic and Cox regression. Am J Epidemiol 2007;165:710–718. 4. Ozawa M, Ninomiya T, Ohara T et al. Dietary patterns and risk of dementia in an elderly Japanese population: The Hisayama Study. Am J Clin Nutr 2013;97:1076–1082.
Copyright of Journal of the American Geriatrics Society is the property of Wiley-Blackwell and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.
