The importance of serum triglycerides as a risk factor for

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1 Preventive Cardiology Serum Triglycerides as a Risk Factor for Cardiovascular Diseases in the Asia-Pacific Region Asia Pacific Cohort Studies Collaboration* Background The importance of serum triglyceride levels as a risk factor for cardiovascular diseases is uncertain. Methods and Results We performed an individual participant data meta-analysis of prospective studies conducted in the Asia-Pacific region. Cox models were applied to the combined data from 26 studies to estimate the overall and region-, sex-, and age-specific hazard ratios for major cardiovascular diseases by fifths of triglyceride values. During person-years of follow-up among individuals, 670 and 667 deaths as a result of coronary heart disease (CHD) and stroke, respectively, were recorded. After adjustment for major cardiovascular risk factors, participants grouped in the highest fifth of triglyceride levels had a 70% (95% CI, 47 to 96) greater risk of CHD death, an 80% (95% CI, 49 to 119) higher risk of fatal or nonfatal CHD, and a 50% (95% CI, 29% to 76%) increased risk of fatal or nonfatal stroke compared with those belonging to the lowest fifth. The association between triglycerides and CHD death was similar across subgroups defined by ethnicity, age, and sex. Conclusions Serum triglycerides are an important and independent predictor of CHD and stroke risk in the Asia-Pacific region. These results may have clinical implications for cardiovascular risk prediction and the use of lipid-lowering therapy. (Circulation. 2004;110: ) Key Words: Asia cardiovascular diseases coronary disease stroke triglycerides The importance of serum triglycerides as a risk factor for cardiovascular diseases is controversial. Many epidemiological studies have demonstrated a univariate association between triglycerides and cardiovascular risk, particularly in relation to coronary heart disease (CHD) However, this relationship is attenuated and often becomes nonsignificant after adjustment for major cardiovascular risk factors, particularly HDL cholesterol levels. More recently, the results of a meta-analysis showing an independent association between triglycerides and cardiovascular risk support the suggestion that at least some triglyceride-rich lipoproteins are directly atherogenic. 13 While recognizing this possibility, the recent National Cholesterol Education Program Adult Treatment Panel III (NCEP-ATPIII) guidelines imply that the evidence is insufficient and primarily view elevated triglycerides as a marker for other risks rather than as an independent risk factor. 14 Previous analyses have been hindered by a number of methodological problems. 5,15 One key limitation has been the potential for regression dilution bias when estimates of associations are based on a single baseline measure of triglycerides. 16,17 Such analyses are likely to underestimate true associations, particularly because measures of serum triglycerides exhibit a relatively high degree of intraindividual variability. 18 To date, very few studies of sufficient size describing the relationship between triglycerides and cardiovascular risk have had the ability to account for regression dilution. 19 Considerable variation in population levels of serum triglycerides has been noted across the Asia-Pacific region. 9,20 24 Furthermore, the epidemiology of cardiovascular diseases in much of the region is characterized by a relatively low incidence of CHD and a high incidence of stroke Few studies have examined the association between triglycerides and cardiovascular risk in nonwhite populations 9,29 or have specifically addressed stroke as an outcome of interest The Asia Pacific Cohort Studies Collaboration (APCSC) is an individual participant data meta-analysis of prospective cohort studies conducted in a number of Asian countries, Australia, and New Zealand. 35 With several hundred events recorded and with the availability of repeated measures of risk factors, allowing correction for regression dilution, the collaboration is able to produce reliable evidence on the nature and size of the associations between risk factors and cardiovascular diseases. In this report, we describe the results relating to serum triglycerides. Methods Participating Studies The design of the APCSC has been reported elsewhere. 35 In summary, cohort studies were eligible for inclusion and were invited Received November 5, 2003; de novo received April 20, 2004; revision received June 17, 2004; accepted June 18, From the Asia Pacific Cohort Studies Collaboration. *See the Appendix for a list of contributors. Correspondence to Dr Anushka Patel, Asia-Pacific Cohort Studies Collaboration Secretariat, The George Institute for International Health, University of Sydney, PO Box M201, Missenden Rd, Camperdown, Sydney NSW 2050, Australia. apatel@thegeorgeinstitute.org 2004 American Heart Association, Inc. Circulation is available at DOI: /01.CIR

2 Asia Pacific Cohort Studies Collaboration Triglycerides and Cardiovascular Diseases 2679 to participate if (1) the study population was from Asia or the Pacific region; (2) date of birth, sex, and blood pressure for each individual were recorded at baseline; and (3) 5000 person-years of follow-up had been completed. For the present analyses, only those studies with baseline measures of triglycerides were included. Studies were classified as Asian if their participants were recruited from mainland China, Hong Kong, Japan, Singapore, Taiwan, or Thailand or as ANZ if their participants were recruited from Australia or New Zealand. Measurement of Baseline Variables Triglycerides were measured at baseline in 26 of the 43 studies included in the APCSC database in March In addition to age, sex, and blood pressure, serum total cholesterol, serum HDL cholesterol, smoking status, alcohol consumption, body mass index, diabetes status, and fasting glucose were also included in the pooled data set when available. Lipid measurements were determined from serum samples, which were obtained in 90% of participants while fasting. Information on the method of triglyceride assay was available from 24 of the 26 studies; 23 of these, contributing 91% of participants, determined triglyceride levels with enzymatic methods. Total cholesterol was measured by enzymatic methods in the same 23 studies. HDL cholesterol was assayed with a precipitation method in 12 studies, by enzymatic methods in 10, and by electrophoresis in 1; it was not measured in 3 studies. Outcomes Each study reported deaths by underlying cause; some studies also reported nonfatal cardiovascular events. Twenty-four studies provided detailed information on the method of follow-up. In 19 of these studies, deaths were ascertained only by registry and/or hospital record linkage without routine follow-up visits. Nonfatal events were detected by various combinations of hospital database linkage, medical record review, and scheduled follow-up visits. Outcomes were classified according to the ninth revision of the International Classification of Diseases (ICD-9). The fatal outcomes considered in this analysis were CHD (ICD-9, 410 to 414), total stroke (ICD-9, 430 to 438), hemorrhagic stroke (ICD-9, to 432.9), and ischemic stroke (ICD-9, to 434.9). Two composite outcomes were also examined: fatal or nonfatal CHD and fatal or nonfatal stroke (total and for each stroke subtype). Statistical Methods All analyses used individual participant data and were restricted to those 20 years of age at study entry. For grouped analyses, individuals were classified according to approximately equal fifths of TABLE 1. Major Characteristics of Studies Study Name Subjects, n Triglycerides, mean (SD), mmol/l Women, % Mean Age, y Median Follow-Up, y Aito Town (0.51) Akabane* (0.77) Anzhen 02* (0.87) Beijing Aging (0.81) Civil Service Workers* (1.05) CVDFACTS (0.82) EGAT* (1.31) Fangshan* (1.19) Guangzhou Occupational* (1.18) Hong Kong* (1.52) Huashan* (1.05) Kounan Town* (0.83) Miyama (0.80) Ohasama (1.02) Saitama* (1.03) Seven Cities* (1.00) Shigaraki (0.99) Shirakawa* (0.66) Singapore Heart* (0.92) Singapore (1.47) Tanno/Soubetsu* (0.95) Xi an (0.53) Subtotal Asia (1.04) Australian Longitudinal Study of Aging* (0.99) Australian National Heart Foundation* (1.17) Busselton (0.96) Perth (0.95) Subtotal ANZ (1.07) Total (1.05) *Triglycerides confirmed as measured in fasting state. 90% of participants confirmed fasting.

3 2680 Circulation October 26, 2004 TABLE 2. Distribution of Major Risk Factors by Baseline Triglycerides Fifth Adjusted by Age and Sex Fifth of Triglycerides Variables n* r 1 ( 0.7 mmol/l) 2 ( mmol/l) 3 ( mmol/l) 4 ( mmol/l) 5 ( 1.9 mmol/l) Mean (95% CI) Age, y ( ) 47.2 ( ) 49.2 ( ) 50.4 ( ) 50.7 ( ) Body mass index, kg/m ( ) 22.6 ( ) 23.3 ( ) 24.1 ( ) 25.2 ( ) Systolic blood pressure, mm Hg ( ) ( ) ( ) ( ) ( ) Serum total cholesterol, mmol/l ( ) 4.95 ( ) 5.16 ( ) 5.38 ( ) 5.67 ( ) Serum HDL cholesterol, mmol/l ( ) 1.45 ( ) 1.38 ( ) 1.30 ( ) 1.17 ( ) Serum total-to-hdl cholesterol ratio ( ) 3.67 ( ) 4.08 ( ) 4.54 ( ) 5.47 ( ) Fasting blood glucose, mmol/l ( ) 5.04 ( ) 5.14 ( ) 5.23 ( ) 5.50 ( ) Percentage (95% CI) Current smoking ( ) 31.3 ( ) 32.6 ( ) 33.5 ( ) 34.1 ( ) Current alcohol consumption ( ) 46.7 ( ) 45.5 ( ) 45.6 ( ) 45.4 ( ) History of diabetes ( ) 2.1 ( ) 2.7 ( ) 3.2 ( ) 5.2 ( ) P for trend, all *Number of participants with data available for each variable. Spearman s coefficient for correlation with triglycerides. baseline triglycerides for the entire study population ( 0.7, 0.8 to 1.0, 1.1 to 1.3, 1.4 to 1.8, and 1.9 mmol/l). Trends in mean values of other major continuous cardiovascular risk factors across these fifths were assessed through simple linear regression, with the groups coded in rank order. Trends in percentages for binary risk factors were assessed similarly with 2 tests for trend. 36 Cox proportional-hazards regression models were used to estimate hazard ratios (HRs) for usual triglyceride level, with corresponding 95% CIs calculated by use of the floating absolute risk method. 36,37 Loglinearity of triglyceride associations was explored both through fitting fifths of triglycerides as a continuous predictor and through the HR and 95% CI for a 1-SD increase in continuous usual log-transformed triglyceride level. Log-transformation of triglyceride values was performed to account for the extreme right skewness of the data. All Cox models included systolic blood pressure, smoking status, and time-dependent age plus stratification variables for study and sex. This method allows background risk to vary by sex and between studies but assumes that there are equal relative effects of triglycerides throughout. The base model was additionally adjusted for the total-to-hdl cholesterol ratio. Some risk factors were incompletely recorded for specific individuals within the studies in which triglycerides were routinely measured. Multiple imputation methods 38,39 were used to estimate these missing values (0.4%, 0.9%, and 26% values missing for smoking status, total cholesterol, and HDL cholesterol, respectively). Additional modeling with separate adjustment for total cholesterol and HDL cholesterol was performed, and further adjustment for diabetes, alcohol consumption, and body mass index was done. Sensitivity analyses restricted analyses to subgroups of participants with (1) no missing covariate values of smoking status, total cholesterol, and HDL cholesterol at baseline; (2) confirmed fasting blood samples; and (3) fasting glucose measurements available. To assess the association of usual triglyceride level with each outcome, baseline triglyceride measurements were adjusted to account for regression dilution bias. Repeated fasting triglyceride measurements were available in 6% of participants from 3 studies (2 in Asia and 1 in ANZ) between 2 and 20 years after the baseline measurement. These repeated measures were used to estimate a regression dilution coefficient (1.9) with the use of a linear mixed regression model that accounted for the heterogeneity of variance between studies, within-subject correlation, and the varying time intervals between measurements. 40 Repeated measures were also available from these 3 studies for total and HDL cholesterol and for systolic blood pressure. The same basic approach was used to estimate adjusted regression dilution coefficients with these covariates accounted for. Results Baseline Data The 26 studies in the APCSC with data on baseline triglycerides, which include a total of individuals with person-years of follow-up, are summarized in Table 1. Compared with participants in the ANZ studies, the Asian cohort tended to be older (49 versus 46 years; P 0.001) and included fewer women (47% versus 51%; P 0.001). The age- and sex-adjusted mean triglyceride values were 1.45 mmol/l (95% CI, 1.44 to 1.46) for Asian participants and 1.44 mmol/l (95% CI, 1.43 to 1.46) for ANZ participants. The age-adjusted mean triglyceride value was greater in men compared with women (1.58 mmol/l [95% CI, 1.57 to 1.58] versus 1.31 mmol/l [95% CI, 1.30 to 1.32]; P 0.001). The age- and sex-adjusted levels of major cardiovascular risk factors after stratification of the study population by fifths of baseline triglycerides are summarized in Table 2. Age, body mass index, systolic blood pressure, serum total cholesterol, serum total-to-hdl cholesterol ratio, fasting serum glucose, and prevalence of current smoking and diabetes all increased with increasing triglycerides (all P 0.001). Serum HDL cholesterol decreased with increasing triglycerides (P 0.001). Outcomes During follow-up, 5137 deaths occurred, of which 1932 (38%) were assigned an underlying cardiovascular cause (Table 3). Of these, 667 deaths were due to stroke (577 in Asia, 90 in ANZ), and 670 were due to CHD (349 in Asia, 321 in ANZ). In the Asian cohorts, stroke and CHD accounted for 41% and 25% of cardiovascular deaths, respectively; corresponding values in the ANZ cohorts were 17%

4 Asia Pacific Cohort Studies Collaboration Triglycerides and Cardiovascular Diseases 2681 TABLE 3. Cardiovascular Events No. of Deaths Fatal or Nonfatal Events* Study Name Subjects CVD Stroke Haem-S Isch-S U/K-S CHD Stroke Haem-S Isch-S U/K-S CHD Aito Town Akabane Anzhen Beijing Aging Civil Service Workers CVDFACTS EGAT Fangshan Guangzhou Occupational Hong Kong Huashan Kounan Town Miyama Ohasama Saitama Seven Cities Shigaraki Shirakawa Singapore Heart Singapore Tanno/Soubetsu Xi an Subtotal Asia Australian Longitudinal Study of Aging Australian National Heart Foundation Busselton Perth Subtotal ANZ Total CVD indicates cardiovascular disease; CHD, coronary heart disease; Haem-S, hemorrhagic stroke; Isch-S, ischemic stroke; U/K-S, stroke of unknown type or subarachnoid hemorrhage. *Only studies that reported both fatal and nonfatal outcomes contributed events to this combined end point. and 61%. Nonfatal events were recorded in 10 studies for stroke (456 events) and 8 studies for CHD (180 events). Triglycerides and Risk of CHD There was a continuous, positive association between usual triglyceride levels and the risk of CHD that persisted after adjustment for age, sex, blood pressure, smoking, and totalto-hdl cholesterol ratio (Figure 1). Compared with those individuals grouped in the lowest fifth of usual triglyceride values, the risk of fatal CHD was 70% (95% CI, 47 to 96) greater for participants with usual triglyceride levels in the highest fifth. For the composite outcome of fatal or nonfatal CHD, the corresponding value was 80% (95% CI, 19 to 119). Each 1-SD-higher level of log-triglycerides was associated with a significantly greater risk of death resulting from CHD (HR, 1.33; 95% CI, 1.09 to 1.62) and fatal or nonfatal CHD (HR, 1.56; 95% CI, 1.20 to 2.03). Triglycerides and Risk of Stroke Overall, no association between triglycerides and risk of fatal stroke was observed (Figure 1C). However, evidence of a positive log-linear association emerged when the combined outcome of fatal or nonfatal stroke was considered (Figure 1D). Compared with those in the lowest fifth of triglycerides, the risk of fatal or nonfatal stroke among individuals in the highest fifth was increased by 50% (HR, 1.50; 95% CI, 1.29 to 1.76). On examination of stroke subtypes (Figure 2), triglycerides appeared to be associated with the risk of ischemic stroke, although, with a substantially greater number of events recorded, a significant log-linear trend across the fifths was observed only for the combined fatal and nonfatal outcome. The HR for the risk of fatal or nonfatal ischemic stroke comparing the highest and lowest fifths of triglycerides was 1.97 (95% CI,1.52 to 2.55). For the same outcome, the HR associated with each 1-SD-higher level of

5 2682 Circulation October 26, 2004 Figure 1. Association between usual triglyceride level and death caused by CHD (A), fatal or nonfatal CHD (B), death resulting from stroke (C), and fatal or nonfatal stroke (D). Analyses are adjusted by time-dependent age, systolic blood pressure, smoking status, and total-to-hdl cholesterol ratio; study and sex are included as stratification variables. Bars show 95% CIs. Probability value for linear trend across fifths of triglycerides is shown. triglycerides was 1.35 (95% CI, 1.00 to 1.83). There was no evidence of a significant association between triglycerides and risk of hemorrhagic stroke. Subgroups of Participants Although there was an appearance of a stronger independent association between triglycerides and the risk of fatal CHD in the ANZ compared with the Asian population (Figure 3), the statistical test for heterogeneity was nonsignificant (HR for highest versus lowest fifth of triglycerides, 1.79 [95% CI, 1.50 to 2.14] versus 1.49 [95% CI, 1.20 to 1.84; P 0.09]). There was no evidence for an interaction between triglyceride level and age, sex, or diabetes status for fatal CHD. Sensitivity Analyses In addition to adjustment for study, sex, age, systolic blood pressure, and smoking status, separate adjustment for total cholesterol, HDL cholesterol, and total-to-hdl cholesterol ratio attenuated the association between triglycerides and fatal CHD by a similar extent ( 10% lower point estimate of the HR comparing the highest to the lowest fifth of usual triglyceride levels) (Figure 4A). Limiting the analysis to individuals with a triglyceride value 4.4 mmol/l and adding HDL cholesterol and calculated LDL cholesterol to the model with study, sex, age, systolic blood pressure, and smoking status also had little effect (HR associated with the highest versus lowest fifth of usual triglycerides for fatal CHD, 1.69 [95% CI, 1.44 to 1.99] versus 1.96 [95% CI, 1.71 to 2.56]). When analyses were restricted to the subset of participants with complete covariate data (therefore not requiring any imputations), there was little effect on the point estimates of association (HR associated with highest versus lowest fifth of usual triglyceride level for CHD death, 1.72; 95% CI, 1.46 to 2.02) (Figure 4B). Separate analyses for the subset of participants with confirmed fasting triglyceride values (Figure 4C) produced estimates of association similar to those observed for the overall fasting and nonfasting population. Further adjustment for diabetes status, alcohol consumption, and body mass index in the smaller number of studies with such data had little effect on the HRs for CHD death (data not shown). Although adjustment for fasting glucose attenuated the point estimate of the association between triglycerides and the risk of death as a result of CHD (Figure 4D), the number of events was small, resulting in wide CIs. Finally, there was no evidence of between-study heterogeneity in the association between triglycerides and any of the outcomes of CHD death (P 0.20), fatal or nonfatal CHD (P 0.32), hemorrhagic stroke (P 0.56), or ischemic stroke (P 0.85). Discussion To the best of our knowledge, this is the largest prospective analysis of the association between triglycerides and cardio-

6 Asia Pacific Cohort Studies Collaboration Triglycerides and Cardiovascular Diseases 2683 Figure 2. Association between usual triglyceride level and fatal ischemic stroke (A), fatal or nonfatal ischemic stroke (B), fatal hemorrhagic stroke (C), and fatal or nonfatal hemorrhagic stroke (D). Analyses and conventions as for Figure 1. vascular events published to date. The results indicate that serum triglyceride level is an independent determinant of cardiovascular risk across a broad population group within the Asia-Pacific region. The evidence is particularly strong for CHD; however, these data also indicate an independent association between triglycerides and risk of ischemic stroke. The mixed results of previous studies are probably due to a number of factors. As previously discussed, bias resulting from regression dilution is an important limitation when associations are determined on the basis of a single baseline measurement of triglycerides. Although undesirable, decisions in clinical practice often rely on a single measurement of triglyceride level; thus, it could be argued that risk prediction tools using triglycerides should not adjust for regression dilution. However, it is appropriate to account for this potential bias when attempting to describe the true relationship between a risk factor and disease, as was the objective of the present analyses. Nevertheless, even without correction for regression dilution, triglycerides remain independently associated with CHD risk in the current study. The lack of consistency of previous data may also partly relate to different risk profiles for fasting and postprandial states. 9,41,42 However, it is likely that an important explanation for the variability of results of smaller studies relates to the marked heterogeneity in triglyceride-rich lipoproteins found in the circulation and the evidence directly implicating some but not all of these lipoproteins in atherogenesis. 43 In smaller studies, the effects of any such atherogenic particles are likely to be diluted and more difficult to detect. Apart from low statistical power, variability in the nature of triglyceride-rich lipoproteins may also explain the findings in other studies of a log-linear association with CHD risk at low levels of triglycerides, with a decline in this risk at higher levels. 10,44 Because of statistical correlation and complex metabolic interactions between triglyceride- and cholesterol-rich lipoproteins, most other studies have shown that the association between triglycerides and cardiovascular risk diminishes after adjustment for total cholesterol and, more importantly, HDL cholesterol. This was also observed in the present study, although the size of the attenuation was small, and the association between triglycerides and risk of cardiovascular disease remained statistically significant. It has been argued that adjustment for total cholesterol (as a surrogate for LDL cholesterol) is not appropriate because this procedure adjusts for the triglyceride-rich VLDL component of total cholesterol, which rises disproportionately as serum triglycerides increase. 5 Although our results may therefore reflect an overadjustment, this would imply that the association between triglycerides and cardiovascular risk may have been underestimated. Although LDL cholesterol was not directly measured in our studies, combined adjustment for HDL cholesterol and calculated LDL cholesterol did not change the conclusions. A more substantial reduction in the HR was

7 2684 Circulation October 26, 2004 Figure 3. HRs (and 95% CIs) comparing within subgroups risk of fatal CHD between individuals belonging to highest vs lowest fifth of usual triglyceride (TG) levels. Analyses are adjusted by study, sex, age at risk, systolic blood pressure, smoking, and total-to-hdl cholesterol ratio. *Diabetes subgroups compared in a smaller sample. noted after adjustment for baseline fasting glucose, an observation also made by others. 5,19 In the present analyses, the subset of participants for whom fasting glucose values were available at baseline was small, limiting our ability to draw reliable conclusions. There was, however, no evidence of a difference in the association between triglycerides and fatal CHD among individuals with and without diabetes. The data suggest that the association between triglycerides and stroke is not uniform. There is evidence of a significant positive log-linear association with ischemic stroke but not with hemorrhagic stroke. The lack of association with fatal stroke is consistent with a relatively high proportion of hemorrhagic events that have a higher case fatality. 45 However, when the combined fatal and nonfatal stroke outcome is considered, ischemic events predominate, and evidence of a positive log-linear association with triglycerides emerges. These data are consistent with a role of elevated triglycerides in the atherothrombotic process but not in terms of hemorrhagic stroke risk. The association between triglycerides and cardiovascular disease appears consistent across participant subgroups. There was a trend suggesting a stronger association between triglycerides and fatal CHD in the ANZ compared with the Asian cohorts, although this result was not statistically significant and is likely to represent a chance finding. Unlike other studies, including the previous meta-analysis, 13,46 we were unable to demonstrate any differences in the associations between triglycerides and cardiovascular risk between men and women or between different age groups. In addition to providing unique pooled data on Asian populations and having repeated triglyceride measurements, allowing control of regression dilution bias, the present meta-analysis has a number of important advantages. The combination of data from many cohorts results in a large number of events that allow precise estimation of the association between triglycerides and cardiovascular risk both overall and within subgroups. The use of individual participant data allows accurate adjustment for covariates and provides an opportunity to reduce bias resulting from nonresponse through imputation of missing values. There are limitations, however, including differences in the method of triglyceride measurement, missing data on covariates, and incomplete information on nonfatal outcomes. Furthermore, given the limited data set available for adjustment for fasting blood glucose, the presence of some residual confounding remains a possibility. An emphasis on fatal outcomes, inclusion of only those studies that reported both fatal and nonfatal events when the composite outcomes were considered, and the various sensitivity analyses provide some reassurance that these factors are unlikely to have introduced substantial bias. In summary, these analyses provide robust evidence that serum triglyceride levels are associated with the risk of developing cardiovascular diseases independently of other major measured risk factors, including HDL cholesterol. Whether this translates to important improvements in the ability to predict individual risk of cardiovascular disease when triglyceride measurements are incorporated into risk algorithms is unknown, as is the specific role of therapy aimed at lowering serum triglyceride levels. The clinical implications of these findings warrant further investigation. Appendix Writing Committee A. Patel, F. Barzi, K. Jamrozik, T.H. Lam, H. Ueshima, G. Whitlock, M. Woodward. Executive Committee D. Gu, T.H. Lam, S. MacMahon, W. Pan, I. Suh, H. Ueshima, C. Lawes, A. Rodgers, M. Woodward. Statistical Analyses F. Barzi, V. Parag, M. Woodward. Principal APCSC Investigators S. Ameratunga, G. Andrews, N. Aoki, R. Broadhurst, L.Q. Chen, Z.M. Chen, S.K. Chew, S.R. Choudhury, H. Christensen, A. Dobson, X.H. Fang, J.L. Fuh, M. Fujishima, X.F. Duan, G. Giles, D.F. Gu, T. Hashimoto, Y. He, D. Heng, S.C. Ho, M. Hobbs, Z. Hong, H. Horibe, A. Hozawa, M.S. Huang, K. Hughes, Y. Imai, H. Iwamoto, R. Jackson, K. Jamrozik, S.H. Jee, C.Q. Jiang, M. Kagaya, I.S. Kim, Y. Kita, Y. Kiyohara, M.W. Knuiman, N. Kubo, T.H. Lam, J. Lee, S.C. Li, Y.H. Li, Z.Z. Li, L.S. Liu, S. MacMahon, H. Maegawa, Y. Matsutani, K. Nakachi, M. Nakamura, R. Norton, A. Nozaki, T. Ohkubo, A. Okayama, W.H. Pan, S. Saitoh, K. Sakata, G.L. Shan, K. Shimamoto, P. Sritara, I. Suh, A. Tamakoshi, H. Tanaka, Z. Tang, H. Ueshima, T.A. Welborn, G. Whitlock, J. Woo, X.G. Wu, Z.L. Wu, Z.S. Wu, J.X. Xie, T. Yamada, Q.D. Yang, C.H. Yao, S.X. Yao, X.H. Yu, H.Y. Zhang, B. Zhou, B.F. Zhou, J. Zhou. Acknowledgments This project has received grants from the National Health and Medical Research Council of Australia, the Health Research Council of New Zealand, and the US National Institutes of Health and an unrestricted educational grant from Pfizer Inc.

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