PEER REVIEW HISTORY BMJ Open publishes all reviews undertaken for accepted manuscripts. Reviewers are asked to complete a checklist review form (http://bmjopen.bmj.com/site/about/resources/checklist.pdf) and are provided with free text boxes to elaborate on their assessment. These free text comments are reproduced below. ARTICLE DETAILS TITLE (PROVISIONAL) AUTHORS Estimating change in cardiovascular disease and diabetes burdens due to dietary and metabolic transition in Korea 1998-2011: A comparative risk assessment analysis Cho, Yoonsu; Cudhea, Frederick; Park, Ju-Hyun; Lee, Jong-Tae; Mozaffarian, Dariush; Singh, Gitanjali; Shin, Min-Jeong VERSION 1 - REVIEW REVIEWER REVIEW RETURNED Michael Wheeler Baker IDI Heart and Diabetes Institute, Melbourne, Australia 28-Jul-2016 GENERAL COMMENTS Overall: It is an important question that the authors are asking given the rapid change occurring across all sectors of Korean society between 1998 and 2011. There are a few key issues the authors could address which would strengthen the current analysis. If the authors are suggesting that Korea has culturally unique health behaviours to other populations, why have the authors used relative risk values taken from US, European and Asian population to use in their current estimation of attributable risk specific to the Korean population? Could the authors make clear early on in the manuscript the purpose using relative risk in their current analysis? It seems from reading further in the methods section that this relative risk was used to calculate the population attributable fraction and uncertainty level (UI), but this could be made clear early on so as the reader does not think that there are two parallel research questions being asked. Regarding the results section, it is not clear why the authors have not done any statistical analysis to compare the change in the distribution of the presented risk factors between time points. For example stating there was a 6% decrease in systolic blood pressure between 1998-2011, but with no analysis to test weather this difference is significant. Also it is unclear from the current analysis what confounders specifically were controlled for. For example was physical activity controlled for in all the relative risk values used? The authors are to be commended on a balanced discussion with inclusion of strengths and limitations of the study which help put it in context.
Language: The authors are encouraged to scrutinise the manuscript for grammatical errors, which appear frequently. The authors are encouraged to use the term risk factors throughout the manuscript in place of risk or factors alone. For example metabolic risk factors in place of metabolic factors or metabolic risk Specific Comments: Title I suggest the authors remove the s after changes and burdens to make the title read better. Abstract Page 2, line 11: Suggest the authors use the term metabolic risk factors in place of metabolic risks. Page 2, line 11-16: The authors could be specific about what diseases are considered cardiometabolic diseases in this manuscript and clarify whether it is death by disease or disease incidence, or both, that are the outcomes of the study. Page 2, line 20: The authors could be specific about exactly what risk factors are included. Having this information in the abstract will aid the reader. Page 2, line 23: What is the total number of participants included in analysis, n=? Page 2, line 23-24: It may help to clarify what the relative risk is being compared to, for example this measure is used to compare the risk between exposed and unexposed group. Are the authors using relative risk to compare a Korean population to another population? Page 2, line 25-32: Could the authors clarify whether the population attributable risk is being used to compare the optimal versus suboptimal risk exposure level within the Korean population? Page 2, line 34: It would aid the reader to include the definitions of high blood pressure, high intake of sodium, low intake of fruits and wholegrains in the abstract, i.e what are the thresholds that define these exposures? Page 2 line 34-43: It may help clarify results if the results are presented per multiple of the population Introduction Page 4, line 15: Could the authors provide a reference for this statement about CVD
and DM killing 38 million? Page 4, line 26: I think the authors mean to say modifiable risk factors Page 4, line 44: I think the authors mean to say Chinese population Page 4, line 36: The sentence reads clearer with the word that is removed Page 4, line 52: This sentence should read based on the nations please add a the here. Page 5, line 6-11: A reference is needed for this statement about Korea s unique diet compared to western and other Asian diets. Page 5 line 17: I think this should read burden of disease not burden of risk Methods Page 5, line 56-57: Can the authors clarify whether this pertains to the theoretical minimum risk exposure level? Page 6, line 21: Could the authors clarify why sugar and alcohol intake were not included as dietary risk factors? Page 7, table1. The authors are encouraged to provide evidence as rationale for the selection of the theoretical minimum risk exposure level of each dietary and metabolic risk factor? Page 9, line 9: Can the authors clarify what population the Korean population is being compared to in the relative risk analysis? Page 10, line 6: Can the authors clarify how many had no missing data? Page 10, line 11: This should read whose intake Page 10, line 11-13: Are the authors suggesting that reporting eating rice less than once per day is incorrect? This threshold may be too similar to what is normal for the goal of eliminating erroneous data. Page 10, line 15: Can the authors provide the exact sample size? Page 10, line 22: Can the authors provide the reference for this standardised protocol?
Page 10, line 25: Was blood pressure taken as a single measurement, or the average of three serial measurements? Page 10, line 43: The authors are encouraged to provide the references for the evidence mentioned here. Page 11, line 6: The authors are encouraged to provide evidence to support the defined theoretical minimum risk exposure levels. Page 12, line 44: Can the authors test the normality of the exposure distributions? Results Page 13, line 13-44: The authors could clarify for each risk factor what time period the change results pertain to? Discussion The discussion could be enhanced by focusing more on the change in risk factors between 1998 and 2011 and also the change in death attributable to each risk factor between 1998 and 2011. Figure 1: The authors are encouraged to provide details of the non-parametric tests used to test the change across time? Also the graphs appear small and blurry, the authors are encouraged to submit higher quality images. Perhaps the authors could exclude graphs of the dietary and metabolic risk factors that did not differ across time, but mention in the text which risk factors did not change, leaving room for larger graphs of the risk factors that did show significant change across time. Figure 2: This figure could be condensed into one graph showing the change in death attributable to each risk factor between 1998 and 2011 with analysis done to test whether this change is significantly different. REVIEWER REVIEW RETURNED Charumathi Sabanayagam Duke-NUS Medical School, Singapore 03-Aug-2016 GENERAL COMMENTS Cho et al. evaluated the contributions of diet and metabolic factors to death due to cardiometabolic diseases in Korea. It is an interesting article, however some issues need to be addressed. 1. Authors have estimated death due to CVD and diabetes and not the diseases per se. The title should reflect the outcome, i.e. death due to CVD and not just CVD and diabetes. 2. Why was not CVD and diabetes considered? Was this information not available in KHANES? 3. Disease-specific deaths: Authors have included deaths due to
specific CVDs such as stroke, hypertensive, ischemic heart disease etc. How about deaths due to heart diseases that do not fall under specific heart condition? 4. How complete is the death register? Were the outcomes based on principal cause of death? 5. How were those with underweight dealt with? 6. Statistical analyses, Relative risk estimation: It was not clear if potential confounders like smoking, income etc. been controlled for in the risk estimation. 7. It would be interesting to see how clustering of risk factors (e.g. two or more metabolic factors in combination) contributed to the risk. 8. Since previous studies (Ref 14 Singh et al) have reported risk of hemorrhagic stroke at lower levels of cholesterol, higher risk of mortality at lower levels of BMI and lower risk of mortality between FPG levels of 4.9-5.3 mmol/l suggest doing sensitivity analyses including a range of TMRED values instead of absolute values. # Reviewers' Comments to Author: VERSION 1 AUTHOR RESPONSE We sincerely appreciate the time spent in reviewing this manuscript and your advice to improve it. Please, see below our answers to your queries and comments. We also marked the corrected and revised parts of the text in red. We hope that you find them satisfactory. # Reviewer: 1 1. Overall: 1) If the authors are suggesting that Korea has culturally unique health behaviours to other populations, why have the authors used relative risk values taken from US, European and Asian population to use in their current estimation of attributable risk specific to the Korean population? Response) We used relative risks (RRs) from international pooling studies. The pooling studies with multiple populations have large numbers of participants and events that allow for more precise estimation of RR, controlling for confounders [1]. Large prospective cohort studies in U.S., European, and Asian populations have indicated that the relative risks are generalizable across different populations.[2-4] Furthermore, we confirmed that RRs from Korean population are similar to the RRs used in current study. For example, RR for 20 mm Hg higher usual systolic blood pressure (SBP) and ischemic stroke was 2.23 (2.17 to 2.30),[5] whereas estimation used in current study was 1.63 (1.57 1.69) for each 10 mmhg higher SBP. As the purpose of this analysis was to determine how the rapid transitions in Korean diet over the past decade has impacted burdens of disease in Korea, we have utilized population exposure data from the nationally-representative health and nutrition survey in Korea over a 13 year time period, reflecting changes in the Korean diet over time. Using RRs that have been found to be generalizable across populations, in conjunction with Korea-specific exposure data, strengthens the analysis and makes it possible to compare the burdens estimated for Korea with those from other countries. We added this point in Discussion section (Page 25) as follows: Seventh, we used generalised RRs from multiple ethnics including U.S., European, and Asian population, rather than use Korean-specific RRs. However, using RRs that have been found to be generalizable across populations strengthens the analysis and makes it possible to compare the burdens estimated for Korea with those from other countries. 1. Singh GM, Danaei G, Farzadfar F, et al. The age-specific quantitative effects of metabolic risk factors on cardiovascular diseases and diabetes: a pooled analysis. PloS one 2013;8:e65174.
2. Lawes CM, Rodgers A, Bennett DA, Parag V, Suh I, et al. Blood pressure and cardiovascular disease in the Asia Pacific region. J Hypertens 2003;21:707 16. 3. PSC. Collaborative overview ( meta-analysis ) of prospective observational studies of the associations of usual blood pressure and usual cholesterol levels with common causes of death: protocol for the second cycle of the Prospective Studies Collaboration. J Cardiovasc Risk 1999;6: 315 20. 4. Lutsey PL, Jacobs DR Jr, Kori S, Mayer-Davis E, Shea S, Steffen LM, et al. Whole grain intake and its cross-sectional association with obesity, insulin resistance, inflammation, diabetes and subclinical CVD: The MESA Study. Br J Nutr 2007;98:397-405. 5. Song YM, Sung J, Lawlor DA, Davey Smith G, Shin Y, Ebrahim S. Blood pressure, haemorrhagic stroke, and ischaemic stroke: the Korean national prospective occupational cohort study. BMJ 2004;328:324-5. 6. Essink-Bot ML1, Pereira J, Packer C, Schwarzinger M, Burstrom K. Cross-national comparability of burden of disease estimates: the European Disability Weights Project. Bull World Health Organ 2002;80:644-52. 2) Could the authors make clear early on in the manuscript the purpose using relative risk in their current analysis? It seems from reading further in the methods section that this relative risk was used to calculate the population attributable fraction and uncertainty level (UI), but this could be made clear early on so as the reader does not think that there are two parallel research questions being asked. Response) The relative risk was used to calculate the population attributable fraction and uncertainty of the attributable mortality. To clarify the purpose of using RR in the current analysis, we revised Method section (Page 10) as follows: To calculate population attributable fraction (PAF) and its uncertainty, we obtained the relative risk (RR) of cardiovascular disease, stroke, and diabetes mortality (or incidence) per unit of exposure from the most recent published systematic reviews, meta-analyses of randomized controlled trials, and observational studies, in conjunction with population exposure data from KNHANES, and TMRED values from the GBD study.[16, 26] 3) Regarding the results section, it is not clear why the authors have not done any statistical analysis to compare the change in the distribution of the presented risk factors between time points. For example stating there was a 6% decrease in systolic blood pressure between 1998-2011, but with no analysis to test weather this difference is significant. Response) The statistical difference in distribution of risk factors between 1998 and 2011 was estimated by non-parametric trend test. Significance was defined where P value is below than 0.05. We added details of statistical analysis in the Statistical analyses section of manuscript (Page 12). 4) Also it is unclear from the current analysis what confounders specifically were controlled for. For example was physical activity controlled for in all the relative risk values used? Response) We collected the relative risk which had been adjusted for potential confounders such as age, sex, education, socioeconomic status, physical activity, smoking, and alcohol consumption. We added explanation for relative risk in Method (Page 11) and Discussion section (Page 24) as follows: For risk factors-disease pairs which no recent published papers, we conducted de novo metaanalysis following previous study.[16] The aetiological effect of risk factors had adjusted for potential confounders such as age, sex, education, socioeconomic status, physical activity, smoking, and alcohol use. The details were provided elsewhere.[12] We used RRs from meta-analyses of observational studies adjusted for potential confounders such as age, sex, education, socioeconomic status, physical activity, smoking, and alcohol use. 2. Language: The authors are encouraged to scrutinise the manuscript for grammatical errors, which appear frequently. The authors are encouraged to use the term risk factors throughout the manuscript in
place of risk or factors alone. For example metabolic risk factors in place of metabolic factors or metabolic risk Response) Current manuscript was edited by English native speaker. The mixed use of the term risk and factors was corrected throughout the manuscript. 3. Specific Comments: 1) Title I suggest the authors remove the s after changes and burdens to make the title read better. Response) Thank you for your suggestion. The title was revised as follows: Estimating change in cardiovascular disease and diabetes burdens due to dietary and metabolic transition in Korea 1998-2011: A comparative risk assessment analysis 2) Abstract Page 2, line 11: Suggest the authors use the term metabolic risk factors in place of metabolic risks. Response) Thank you for your suggestion. The term was revised. Page 2, line 11-16: The authors could be specific about what diseases are considered cardiometabolic diseases in this manuscript and clarify whether it is death by disease or disease incidence, or both, that are the outcomes of the study. Response) Thank you for your comment. The outcome was death by specific disease. The details of data sources for outcomes (CMD mortality) was provided in Method: Disease-specific deaths (Page 11). The relevant sentence in Abstract (Page 2) was revised as follows: This study aims to evaluate the contributions of dietary and metabolic risk factors to death from cardiometabolic diseases (CMDs). Page 2, line 20: The authors could be specific about exactly what risk factors are included. Having this information in the abstract will aid the reader. Response) Due to word count limit, we could not specify all risk factors that used in analyses. However, we revise relevant sentence (Page 2) as follows: We used data on the 6 dietary and 4 metabolic risk factors by sex, age, and year from the Korea National Health and Nutrition Examination Survey. Page 2, line 23: What is the total number of participants included in analysis, n=? Response) The exposure data for this study was based on data from the nationally representative Korean National Health and Nutrition Survey for years 1998-2011. Total sample sizes for each risk factor between 1998 and 2011 have been added as part of Supplemental Table 1. Page 2, line 23-24:9: It may help to clarify what the relative risk is being compared to, for example this measure is used to compare the risk between exposed and unexposed group. Are the authors using relative risk to compare a Korean population to another population? Response) The relative risks estimate age-specific dose-response relationships between the exposure of interest and the outcome of interest. For example, the relative risks for the relationship between blood pressure and ischemic heart disease estimate, for each age group of interest, the increase in risk of heart disease per 10 mmhg increase in blood pressure. To clarify this, we have added the units for each RR in Table 1. Page 2, line 25-32: Could the authors clarify whether the population attributable risk is being used to compare the optimal versus suboptimal risk exposure level within the Korean population? Response) The population attributable fraction (PAF) from each risk factor reflects the proportional reduction in deaths for each disease causally associated with the exposure that would occur if the actual exposure distribution in population had been reduced or increased to the optimal exposure distribution.[1] Since we used risk exposure distribution from Korean population, the PAF from current
analyses allows to compare the contribution of risk factors to CMD mortality at optimal level versus current exposure levels within the Korean population. 1. Micha R, Kalantarian S, Wirojratana P, Byers T, Danaei G, Elmadfa I, et al. Estimating the global and regional burden of suboptimal nutrition on chronic disease: methods and inputs to the analysis. Eur J Clin Nutr 2012;66:119-29. Page 2, line 34: It would aid the reader to include the definitions of high blood pressure, high intake of sodium, low intake of fruits and wholegrains in the abstract, i.e what are the thresholds that define these exposures? Response) Due to word count limit, we could provide threshold of each risk factor. Instead, we provide this information in Table 1. Page 2 line 34-43: It may help clarify results if the results are presented per multiple of the population Response) The current results were based on absolute number of disease-specific deaths attributed to a dietary and metabolic risk factors.. 3) Introduction Page 4, line 15: Could the authors provide a reference for this statement about CVD and DM killing 38 million? Response) The reference for statement was added (Page 3) as follows: Along with rapid socio-economic changes, cardiometabolic diseases (CMDs) including cardiovascular disease (CVD) and diabetes mellitus (DM) have been the leading cause of global death, killing 38 million people.[1] 1. World Health Organizaion. Global status report on noncommunicable diseases 2014, 2014. Page 4, line 26: I think the authors mean to say modifiable risk factors Response) The term was corrected. Page 4, line 44: I think the authors mean to say Chinese population Response) The expression was corrected. Page 4, line 36: The sentence reads clearer with the word that is removed Response) We supposed that the reviewer indicated line 46. The word that was removed from Page 4, line 46 as follows: The burden of disease study in China emphasized the necessity of nation-specific estimates for chronic diseases to reflect region specific changes in health and surveillance system. Page 4, line 52: This sentence should read based on the nations please add a the here. Response) The definite article was added. Page 5, line 6-11: A reference is needed for this statement about Korea s unique diet compared to western and other Asian diets. Response) The traditional Korean diet is traditionally high in rice, low in fat, and abundant in plant food, which is distinguishable from Western and other Asian diets.[1-3] The references were added. 1. Kim J, Jo I, Joung H. A rice-based traditional dietary pattern is associated with obesity in Korean adults. J Acad Nutr Diet 2012;112:246-53. 2. Song Y, Joung H. A traditional Korean dietary pattern and metabolic syndrome abnormalities. Nutr Metab Cardiovasc Dis 2012;22:456-62.
3. Lee MJ, Popkin BM, Kim S. The unique aspects of the nutrition transition in South Korea: the retention of healthful elements in their traditional diet. Public Health Nutr 2002;5:197-203. Page 5 line 17: I think this should read burden of disease not burden of risk Response) The sentence was revised as follows: Yet, with the absence of systematic and comparable methods to estimate the nationally representative burden of disease attributable to risk factors 4) Methods Page 5, line 56-57: Can the authors clarify whether this pertains to the theoretical minimum risk exposure level? Response) The hypothetical alternative distribution is equal to theoretical minimum risk exposure level. Page 6, line 21: Could the authors clarify why sugar and alcohol intake were not included as dietary risk factors? Response) Those risk factors were excluded from current analysis because the KNHANES did not investigate intake amount of alcohol and sugar. Also, previous study regarded alcohol use as a lifestyle (behavioural) risk factors rather than dietary risk factor. In terms of sugar intake, we found that intake frequency of soft drink was the only source of sugar from the KNHANES that makes hard to estimate actual amount of sugar intake in Koreans. Based on your comment, we revised limitation as follows (Page 25): The further study with behavioural risk factors including alcohol use and smoking is required in current population. Additionally, although high sugar intake has appeared to increase risk of CMDs, the risk of sugar intake was excluded current analysis since the KNHANES did not investigate consumption amount of sugar or sugar sweetened beverage in detail. Page 7, table 1: The authors are encouraged to provide evidence as rationale for the selection of the theoretical minimum risk exposure level of each dietary and metabolic risk factor? Response) The evidence for theoretical minimum risk exposure level of each dietary and metabolic risk factor was provided in Table 1 and Methods: Theoretical minimum-risk distributions (Page 11) as follows: TMRED were obtained from previous literature.[16, 32] Page 9, line 9: Can the authors clarify what population the Korean population is being compared to in the relative risk analysis? Response) The population attributable fraction compares the current exposure distribution in the Korean population with a theoretical optimal risk factor distribution that is associated with lowest disease risk. This comparison between actual and counterfactual exposure distributions, i.e. the current exposure distribution in a population, and the ideal exposure distribution that is associated with lowest risk, is a cornerstone of the comparative risk assessment methodology.[1] 1. Murray CJ, Ezzati M, Lopez AD, Rodgers A, Vander Hoorn S. Comparative quantification of health risks conceptual framework and methodological issues. Popul Health Metr 2003;1(1):1. Page 10, line 6: Can the authors clarify how many had no missing data? Response) As your comment, we added detailed information on sample size in Supplementary Table 1. Page 10, line 11: This should read whose intake Response) The expression was revised.
Page 10, line 11-13: Are the authors suggesting that reporting eating rice less than once per day is incorrect? This threshold may be too similar to what is normal for the goal of eliminating erroneous data. Response) The Korean diet typically consists of rice, as a staple food.[2, 3] Korea consumed a larger amount of rice than other Asian countries consuming rice as their staple food, accounting for 66 % of daily energy intake in the Korean population.[4, 5] Based on previous evidence,[1, 2] we regarded subjects who consumed rice less than 1 time per day across the year as those with implausible FFQ data. Then, we excluded those subjects to reflect common dietary habit of Korean. As your comment, evidences for exclusion criteria were provided as follows: Based on previous evidences, subjects who intake rice less than 1 time per day across the year were excluded to reflect dietary habit of Korean.[28, 29] 1. Chung HK, Park JY, Cho Y, Shin MJ. Contribution of dietary patterns to blood heavy metal concentrations in Korean adults: findings from the Fifth Korea National Health and Nutrition Examination Survey 2010. Food Chem Toxicol 2013;62:645-52. 2. Kim S, Moon S, Popkin BM. The nutrition transition in South Korea. Am J Clin Nutr. 2000;71:44-53. 3. Song Y, Joung H. A traditional Korean dietary pattern and metabolic syndrome abnormalities. Nutr Metab Cardiovasc Dis 2012;22:456-62. 4. Cha HM, Han G, Chung HJ. A study on the trend analysis regarding the rice consumption of Korean adults using Korean National Health and Nutrition Examination Survey data from 1998, 2001 and 2005. Nutr Res Pract 2012;6(3):254-62. 5. Song S, Young Paik H, Song WO, Song Y. Metabolic syndrome risk factors are associated with white rice intake in Korean adolescent girls and boys. Br J Nutr 2015;113:479-87. Page 10, line 15: Can the authors provide the exact sample size? Response) As your comment, we added detailed information on sample size in Method section (Page 10) as follows: After exclusion, the total sample size in KNHANES 1998-2011 ranged from 41,810 for fruit intake to 42,524 for whole grain intake (Supplementary Table 1). To obtain distribution of each risk factor, we used about 45,000 of subject (ranged from 44387 for glucose and 46,297 for BMI) who met the described criteria (Supplementary Table S1). Page 10, line 22: Can the authors provide the reference for this standardised protocol? Response) The reference was provided (Page 10). Page 10, line 25: Was blood pressure taken as a single measurement, or the average of three serial measurements? Response) For blood pressure, average of three serial measurements was used. We revised sentence in Method section (Page 10) as follows: The systolic blood pressure (SBP) was measured 3 times with a mercury sphyngmomanometer (Baumanometer, New York, NY, USA) applied to the right arm in the sitting position. The average of SBP was calculated using three measurements. Page 10, line 43: The authors are encouraged to provide the references for the evidence mentioned here. Response) The references were provided (Page 10). Page 11, line 6: The authors are encouraged to provide evidence to support the defined theoretical minimum risk exposure levels. Response) The evidence was provided (Page 11) as follows: TMRED were obtained from previous literature.[16, 32]
Page 12, line 44: Can the authors test the normality of the exposure distributions? Response) The distribution of variable values was investigated to test whether exposure distribution was satisfied assumption for normality. 5) Results Page 13, line 13-44: The authors could clarify for each risk factor what time period the change results pertain to? Response) To clarity the time period, the sentence (Page 13) was revised as follows: Across the time period of analysis (1998-2011), all dietary risk factors in Korea showed non-optimal levels. 6) Discussion The discussion could be enhanced by focusing more on the change in risk factors between 1998 and 2011 and also the change in death attributable to each risk factor between 1998 and 2011. Response) As your suggestion, Discussion section was revised focusing on the change in risk factors and death attributable to each risk factor (Page 20-26). 7) Figure Figure 1: The authors are encouraged to provide details of the non-parametric tests used to test the change across time? Response) Following your suggestion, the details of the non-parametric tests were added as follows: Estimation of temporal difference across year To see any overall temporal pattern of each risk factor and PAF across 1998-2011, a non-parametric trend test was conducted at a significance level of 0.05. A conventional parametric approach to a trend test is one based on a linear regression model. However, as results of an exploratory data analysis, it was observed that empirical distributions of a given risk factor dramatically vary across years, so that it was likely that the assumptions underlying a linear regression model did not hold. The non-parametric trend test of Cuzick [33] was considered as an alternative approach, which is an extended version of the Wilcoxon rank-sum test to compare mean values among groups of interest. All analyses were conducted using Stata 12.0 and R v.3.2.2. Also the graphs appear small and blurry, the authors are encouraged to submit higher quality images. Perhaps the authors could exclude graphs of the dietary and metabolic risk factors that did not differ across time, but mention in the text which risk factors did not change, leaving room for larger graphs of the risk factors that did show significant change across time. Response) we apologize for the low quality images. The low quality of graphs was due to upload size limitation. We would like to thank for your kind suggestion, however, the authors determined that it would be better to show the trends of all risk factors for clear understanding of readers. We will ask editor to provide images with higher resolution. Figure 2: This figure could be condensed into one graph showing the change in death attributable to each risk factor between 1998 and 2011 with analysis done to test whether this change is significantly different. Response) Thank you for your considerable suggestion. This is first study on burden of disease using CRA method in Korea. Therefore, the authors agreed that presenting all results to provide more precise information. # Reviewer: 2 1. Authors have estimated death due to CVD and diabetes and not the diseases per se. The title
should reflect the outcome, i.e. death due to CVD and not just CVD and diabetes. Response) The aim of the current study was to evaluate the contributions of dietary and metabolic risk factors to mortality of cardiovascular disease, and diabetes in Korea. Therefore, the title was revised as follows: Estimating change in cardiovascular disease and diabetes burdens due to dietary and metabolic transition in Korea 1998-2011: A comparative risk assessment analysis 2. Why was not CVD and diabetes considered? Was this information not available in KHANES? Response) Cardiometabolic includes cardiovascular disease and type 2 diabetes mellitus. Therefore, the outcome of current study was defined as individual mortality caused by diabetes, stroke, and cardiovascular diseases including ischemic heart disease, aortic aneurysm and dissection, hypertensive heart disease, and rheumatic heart disease. Outcomes were obtained from annual mortality statistics from KOSIS. 3. Disease-specific deaths: Authors have included deaths due to specific CVDs such as stroke, hypertensive, ischemic heart disease etc. How about deaths due to heart diseases that do not fall under specific heart condition? Response) To estimate burden of each risk factor to cadiometabolic disease mortality, we used risk factor-disease pairs with convincing evidence from well-established observational study or/and randomization control trial study. Therefore, the other/unspecified cardiovascular disease did not include in current analysis. However, we estimated a various range of cardiovascular disease burden attributable risk factors, including ischemic, hypertensive heart disease, but also aortic aneurysm and dissection and rheumatic heart disease. 4. How complete is the death register? Were the outcomes based on principal cause of death? Response) The outcome deaths due to cardiometabolic disease. The cause specific death number was obtained from KOSIS, the national statistical office in Korea. The KOSIS provides the number of deaths, the crude death rate, the ranking of causes of death, and trends in the death rate from the major causes of death. Causes specific mortality from KOSIS were classified according to the International Statistical Classification of Diseases and Related Health Problems, 10th revision.[1] 1. Shin HY, Lee JY, Song J, Lee S, Lee J, et al., Cause-of-death statistics in the Republic of Korea, 2014. J Korean Med Assoc. 2016;59:221-232. 5. How were those with underweight dealt with? Response) For metabolic risk including BMI, we used TMREDs based on the level corresponding to the lowest mortality rate in epidemiological studies. The PSC and APCSC studies suggested that the lowest risk of all-cause mortality was at BMIs of 20-23 kg/m2. [1, 2] Based on those evidence, we set the TMRED for BMI at levels of 21 kg/m2. Also, previous study reported that the observed increase in mortality by disease at lower BMI levels may be due to reverse causality. For many chronic disease (e.g. cardiovascular disease), weight loss may precede death by a decade or more. This phenomenon implicated that there is consistent dose-response relationship between BMI and disease outcome.[3] We tried to control effect from outlier value (in this case, severe underweight) by excluding participants with implausible data for BMI measurement and an upper or lower 3SD to the mean BMI value. Furthermore, we conduct sensitivity analysis for BMI as your suggestion and have presented as Supplementary Figure 6. 1. Ni Mhurchu C, Rodgers A, Pan WH, Gu DF, Woodward M. Body mass index and cardiovascular disease in the Asia-Pacific Region: an overview of 33 cohorts involving 310 000 participants. Int J Epidemiol 2004;33:751 758. 2. PSC. Body-mass index and cause-specific mortality in 900 000 adults: collaborative analyses of 57 prospective studies. Lancet 2009;373:1083 1096.
3. Singh GM, Danaei G, Farzadfar F, et al. The age-specific quantitative effects of metabolic risk factors on cardiovascular diseases and diabetes: a pooled analysis. PloS one 2013;8:e65174. 6. Statistical analyses, Relative risk estimation: It was not clear if potential confounders like smoking, income etc. been controlled for in the risk estimation. Response) We collected the relative risk which had been adjusted for potential confounders such as age, sex, education, socioeconomic status, physical activity, smoking, and alcohol consumption. We added explanation for relative risk in Method (Page 11) and Discussion section (Page 24) as follows: For risk factors-disease pairs which no recent published papers, we conducted de novo metaanalysis following previous study.[16] The aetiological effect of risk factors had adjusted for potential confounders such as age, sex, education, socioeconomic status, physical activity, smoking, and alcohol use. The details were provided elsewhere.[12] We used RRs from meta-analyses of observational studies adjusted for potential confounders such as age, sex, education, socioeconomic status, physical activity, smoking, and alcohol use 7. It would be interesting to see how clustering of risk factors (e.g. two or more metabolic factors in combination) contributed to the risk. Response) We would like to appreciate for raising this concern. The aim of the current study was to evaluate the individual contributions of dietary and metabolic risk factors to cardiometabolic disease and to inform national priorities for risk factor management in Korea. Therefore, we decided to focus effect of individual risk factors at current stage. A study on the effect clustering of risk factor on mortality of cardiometabolic diseases will be conducted as a further study. 8. Since previous studies (Ref 14 Singh et al) have reported risk of hemorrhagic stroke at lower levels of cholesterol, higher risk of mortality at lower levels of BMI and lower risk of mortality between FPG levels of 4.9-5.3 mmol/l suggest doing sensitivity analyses including a range of TMRED values instead of absolute values. Response) As your comment, results from sensitivity analyses including a range of TMRED values instead of absolute values have been added as part of Supplemental Table 2. Also, the description for sensitivity analysis were added in manuscript (Page 13, 20) and as follows: Sensitivity analysis was performed to the choice of the optimal level of each risk factor. Sensitivity analysis The results of the sensitivity analyses in Supplementary Figure S6. The results showed that change of optimal levels for SBP (from 115 to 110 mm Hg), fasting plasma glucose (from 5.3 to 4.9 mmol/l) and total cholesterol (from 4.0 to 3.8 mmol/l) increased the mortality attributable to each risk factor by 20-40% in 2010 and 2011. The change of optimal levels for BMI from 23 to 21 kg/m2 results more than two times increase of attributable mortality in both years. VERSION 2 REVIEW REVIEWER REVIEW RETURNED Michael Wheeler Baker IDI Heart and Diabetes Institute, Melbourne, Australia 10-Oct-2016 GENERAL COMMENTS I thank the authors for addressing the concerns raised and I know feel the manuscript is ready for publication. REVIEWER REVIEW RETURNED Charumathi Sabanayagam Duke-NUS Medical School, Singapore 11-Oct-2016
GENERAL COMMENTS I do not have any further comments. The manuscript may require some language corrections.