Dale McLerran

Association between Body-Mass Index and Risk of Death in More Than 1 Million Asians

BACKGROUND Most studies that have evaluated the association between the body-mass index (BMI) and the risks of death from any cause and from specific causes have been conducted in populations of European origin. METHODS We performed pooled analyses to evaluate the association between BMI and the risk of death among more than 1.1 million persons recruited in 19 cohorts in Asia. The analyses included approximately 120,700 deaths that occurred during a mean follow-up period of 9.2 years. Cox regression models were used to adjust for confounding factors. RESULTS In the cohorts of East Asians, including Chinese, Japanese, and Koreans, the lowest risk of death was seen among persons with a BMI (the weight in kilograms divided by the square of the height in meters) in the range of 22.6 to 27.5. The risk was elevated among persons with BMI levels either higher or lower than that range--by a factor of up to 1.5 among those with a BMI of more than 35.0 and by a factor of 2.8 among those with a BMI of 15.0 or less. A similar U-shaped association was seen between BMI and the risks of death from cancer, from cardiovascular diseases, and from other causes. In the cohorts comprising Indians and Bangladeshis, the risks of death from any cause and from causes other than cancer or cardiovascular disease were increased among persons with a BMI of 20.0 or less, as compared with those with a BMI of 22.6 to 25.0, whereas there was no excess risk of either death from any cause or cause-specific death associated with a high BMI. CONCLUSIONS Underweight was associated with a substantially increased risk of death in all Asian populations. The excess risk of death associated with a high BMI, however, was seen among East Asians but not among Indians and Bangladeshis.

Body-mass index and all-cause mortality: Individual-participant-data meta-analysis of 239 prospective studies in four continents.

Summary Background Overweight and obesity are increasing worldwide. To help assess their relevance to mortality in different populations we conducted individual-participant data meta-analyses of prospective studies of body-mass index (BMI), limiting confounding and reverse causality by restricting analyses to never-smokers and excluding pre-existing disease and the first 5 years of follow-up. Methods Of 10 625 411 participants in Asia, Australia and New Zealand, Europe, and North America from 239 prospective studies (median follow-up 13·7 years, IQR 11·4–14·7), 3 951 455 people in 189 studies were never-smokers without chronic diseases at recruitment who survived 5 years, of whom 385 879 died. The primary analyses are of these deaths, and study, age, and sex adjusted hazard ratios (HRs), relative to BMI 22·5–<25·0 kg/m2. Findings All-cause mortality was minimal at 20·0–25·0 kg/m2 (HR 1·00, 95% CI 0·98–1·02 for BMI 20·0–<22·5 kg/m2; 1·00, 0·99–1·01 for BMI 22·5–<25·0 kg/m2), and increased significantly both just below this range (1·13, 1·09–1·17 for BMI 18·5–<20·0 kg/m2; 1·51, 1·43–1·59 for BMI 15·0–<18·5) and throughout the overweight range (1·07, 1·07–1·08 for BMI 25·0–<27·5 kg/m2; 1·20, 1·18–1·22 for BMI 27·5–<30·0 kg/m2). The HR for obesity grade 1 (BMI 30·0–<35·0 kg/m2) was 1·45, 95% CI 1·41–1·48; the HR for obesity grade 2 (35·0–<40·0 kg/m2) was 1·94, 1·87–2·01; and the HR for obesity grade 3 (40·0–<60·0 kg/m2) was 2·76, 2·60–2·92. For BMI over 25·0 kg/m2, mortality increased approximately log-linearly with BMI; the HR per 5 kg/m2 units higher BMI was 1·39 (1·34–1·43) in Europe, 1·29 (1·26–1·32) in North America, 1·39 (1·34–1·44) in east Asia, and 1·31 (1·27–1·35) in Australia and New Zealand. This HR per 5 kg/m2 units higher BMI (for BMI over 25 kg/m2) was greater in younger than older people (1·52, 95% CI 1·47–1·56, for BMI measured at 35–49 years vs 1·21, 1·17–1·25, for BMI measured at 70–89 years; pheterogeneity<0·0001), greater in men than women (1·51, 1·46–1·56, vs 1·30, 1·26–1·33; pheterogeneity<0·0001), but similar in studies with self-reported and measured BMI. Interpretation The associations of both overweight and obesity with higher all-cause mortality were broadly consistent in four continents. This finding supports strategies to combat the entire spectrum of excess adiposity in many populations. Funding UK Medical Research Council, British Heart Foundation, National Institute for Health Research, US National Institutes of Health.

Stages of Change in Adopting Healthy Diets: Fat, Fiber, and Correlates of Nutrient Intake

The stages of change construct, which addresses the readiness to change, has only recently been applied to dietary behavior, such as fat consumption. This article describes the application of the stages of change construct to dietary fat and fiber consumption and examines the association of dietary stages to eating practices and related demographic and psychosocial factors in a large, geographically diverse population of workers. We present results from the baseline survey of 17,121 employees in the Working Well Trial. We assessed stage from an algorithm based on seven items and measured dietary intake with an 88-item food frequency questionnaire. Findings indicated that a greater proportion of the population has actively tried to reduce fat intake than to consume more fiber. Stage of change was associated with fat, fiber, and fruit and vegetable intake in a stepwise manner, as predicted. In multivariate analyses that controlled for demographic characteristics, stage of change predicted between 8 and 13% of the variance in dietary intake, and more than demographic variables. These findings have implications for the design of nutrition interventions and for the evaluation of intermediate outcomes.

Smoke exposure, histologic type and geography-related differences in the methylation profiles of non-small cell lung cancer.

Aberrant methylation of several known or putative tumor suppressor genes occurs frequently during the pathogenesis of lung cancers. There are major smoke exposure, histology, geography and gender‐related changes in non‐small cell lung cancer (NSCLC). We investigated smoking‐related, histologic, geographic and gender differences in the methylation profiles of resected NSCLCs. We examined 514 cases of NSCLC and 84 corresponding nonmalignant lung tissues from 4 countries (USA, Australia, Japan and Taiwan) for the methylation status of 7 genes known to be frequently methylated in lung cancers [p16, RASSF1A (RAS association domain family 1), APC, RARβ, CDH13, MGMT and GSTP1]. Multivariate analyses were used for data analysis. Adenocarcinoma was the major histologic type in women and never smokers; analyses that involved smoke exposure and gender were limited to this histology. Our major findings are a) methylation status of any single gene was largely independent of methylation status of other genes; b) the rates of methylation of p16 and APC and the mean Methylation Index (MI), a reflection of the overall methylation status, were significantly higher in ever smokers than in never smokers; c) the mean MI of tumors arising in former smokers was significantly lower than the mean of current smokers; d) the methylation rates of APC, CDH13 and RARβ were significantly higher in adenocarcinomas than in squamous cell carcinomas; e) methylation rates of MGMT and GSTP1 were significantly higher in the USA and Australian cases than in those from Japan and Taiwan; and (f) no significant gender‐related differences in methylation patterns were noted. Our findings demonstrate important smoke exposure, histologic type and geography‐related differences in the methylation profiles of NSCLC tumors.

Association between body mass index and cardiovascular disease mortality in east Asians and south Asians: pooled analysis of prospective data from the Asia Cohort Consortium

Objective To evaluate the association between body mass index and mortality from overall cardiovascular disease and specific subtypes of cardiovascular disease in east and south Asians. Design Pooled analyses of 20 prospective cohorts in Asia, including data from 835 082 east Asians and 289 815 south Asians. Cohorts were identified through a systematic search of the literature in early 2008, followed by a survey that was sent to each cohort to assess data availability. Setting General populations in east Asia (China, Taiwan, Singapore, Japan, and Korea) and south Asia (India and Bangladesh). Participants 1 124 897 men and women (mean age 53.4 years at baseline). Main outcome measures Risk of death from overall cardiovascular disease, coronary heart disease, stroke, and (in east Asians only) stroke subtypes. Results 49 184 cardiovascular deaths (40 791 in east Asians and 8393 in south Asians) were identified during a mean follow-up of 9.7 years. East Asians with a body mass index of 25 or above had a raised risk of death from overall cardiovascular disease, compared with the reference range of body mass index (values 22.5-24.9; hazard ratio 1.09 (95% confidence interval 1.03 to 1.15), 1.27 (1.20 to 1.35), 1.59 (1.43 to 1.76), 1.74 (1.47 to 2.06), and 1.97 (1.44 to 2.71) for body mass index ranges 25.0-27.4, 27.5-29.9, 30.0-32.4, 32.5-34.9, and 35.0-50.0, respectively). This association was similar for risk of death from coronary heart disease and ischaemic stroke; for haemorrhagic stroke, the risk of death was higher at body mass index values of 27.5 and above. Elevated risk of death from cardiovascular disease was also observed at lower categories of body mass index (hazard ratio 1.19 (95% confidence interval 1.02 to 1.39) and 2.16 (1.37 to 3.40) for body mass index ranges 15.0-17.4 and <15.0, respectively), compared with the reference range. In south Asians, the association between body mass index and mortality from cardiovascular disease was less pronounced than that in east Asians. South Asians had an increased risk of death observed for coronary heart disease only in individuals with a body mass index greater than 35 (hazard ratio 1.90, 95% confidence interval 1.15 to 3.12). Conclusions Body mass index shows a U shaped association with death from overall cardiovascular disease among east Asians: increased risk of death from cardiovascular disease is observed at lower and higher ranges of body mass index. A high body mass index is a risk factor for mortality from overall cardiovascular disease and for specific diseases, including coronary heart disease, ischaemic stroke, and haemorrhagic stroke in east Asians. Higher body mass index is a weak risk factor for mortality from cardiovascular disease in south Asians.

A comparison of statistical methods for clustered data analysis with Gaussian error.

We investigate by simulation the properties of four different estimation procedures under a linear model for correlated data with Gaussian error: maximum likelihood based on the normal mixed linear model; generalized estimating equations; a four-stage method, and a bootstrap method that resamples clusters rather than individuals. We pay special attention to the group randomized trials where the number of independent clusters is small, cluster sizes are big, and the correlation within the cluster is weak. We show that for balanced and near balanced data when the number of independent clusters is small (< or = 10), the bootstrap is superior if analysts do not want to impose strong distribution and covariance structure assumptions. Otherwise, ML and four-stage methods are slightly better. All four methods perform well when the number of independent clusters reaches 50.

Body Mass Index and Diabetes in Asia: A Cross-Sectional Pooled Analysis of 900,000 Individuals in the Asia Cohort Consortium

Background The occurrence of diabetes has greatly increased in low- and middle-income countries, particularly in Asia, as has the prevalence of overweight and obesity; in European-derived populations, overweight and obesity are established causes of diabetes. The shape of the association of overweight and obesity with diabetes risk and its overall impact have not been adequately studied in Asia. Methods and Findings A pooled cross-sectional analysis was conducted to evaluate the association between baseline body mass index (BMI, measured as weight in kg divided by the square of height in m) and self-reported diabetes status in over 900,000 individuals recruited in 18 cohorts from Bangladesh, China, India, Japan, Korea, Singapore and Taiwan. Logistic regression models were fitted to calculate cohort-specific odds ratios (OR) of diabetes for categories of increasing BMI, after adjustment for potential confounding factors. OR were pooled across cohorts using a random-effects meta-analysis. The sex- and age-adjusted prevalence of diabetes was 4.3% in the overall population, ranging from 0.5% to 8.2% across participating cohorts. Using the category 22.5–24.9 Kg/m2 as reference, the OR for diabetes spanned from 0.58 (95% confidence interval [CI] 0.31, 0.76) for BMI lower than 15.0 kg/m2 to 2.23 (95% CI 1.86, 2.67) for BMI higher than 34.9 kg/m2. The positive association between BMI and diabetes prevalence was present in all cohorts and in all subgroups of the study population, although the association was stronger in individuals below age 50 at baseline (p-value of interaction<0.001), in cohorts from India and Bangladesh (p<0.001), in individuals with low education (p-value 0.02), and in smokers (p-value 0.03); no differences were observed by gender, urban residence, or alcohol drinking. Conclusions This study estimated the shape and the strength of the association between BMI and prevalence of diabetes in Asian populations and identified patterns of the association by age, country, and other risk factors for diabetes.

An Automated Peak Identification/Calibration Procedure for High-Dimensional Protein Measures From Mass Spectrometers

Discovery of “signature” protein profiles that distinguish disease states (eg, malignant, benign, and normal) is a key step towards translating recent advancements in proteomic technologies into clinical utilities. Protein data generated from mass spectrometers are, however, large in size and have complex features due to complexities in both biological specimens and interfering biochemical/physical processes of the measurement procedure. Making sense out of such high-dimensional complex data is challenging and necessitates the use of a systematic data analytic strategy. We propose here a data processing strategy for two major issues in the analysis of such mass-spectrometry-generated proteomic data: (1) separation of protein “signals” from background “noise” in protein intensity measurements and (2) calibration of protein mass/charge measurements across samples. We illustrate the two issues and the utility of the proposed strategy using data from a prostate cancer biomarker discovery project as an example.

Impact of the Working Well Trial on the Worksite Smoking and Nutrition Environment

This article reports the effect of a worksite cancer control intervention on aspects of the physical and social environment related to dietary and smoking behaviors of employees. Data are from 111 intervention and control worksites that participated in the Working Well Trial. Employee surveys and interviews with key organizational informants assessed environmental and normative changes relevant to nutrition and tobacco use. Results indicated significant effects of the intervention on all nutrition outcomes: access to healthy food, nutritional information at work, and social norms regarding dietary choice. Significant benefits were not found for smoking norms or smoking policies. However, changes occurred in both the control and intervention sites on these variables. This first large analysis of environmental and normative effects of a worksite intervention is consistent with the employee behavior change findings for the trial and serves as a model for future analyses of multilevel worksite health promotion programs.

Equal proportion of adult male and female homozygous for the 677C T mutation in the methylenetetrahydrofolate reductase polymorphism

Evidence suggests that a polymorphism of the autosomal gene encoding for 5,10 methylenetetrahydrofolate reductase (MTHFR) [Frosst et al., 1995] gives rise to a thermolabile form [Kang et al., 1988] of the enzyme that in the homozygous state is associated with increased levels of homocysteine under conditions of less than optimal folate nutrition [Jacques et al., 1996]. This polymorphism is due to a C!T substitution at nucleotide 677 which converts an alanine to valine in a conserved portion of themolecule [Frosst et al., 1995] and appears to be a risk factor for increased plasma levels of homocysteine and vascular diseases [Boushey et al., 1995; Jacques et al., 1996; Kluijtmans et al., 1997]. In a 1999 letter to the Editor of the American Journal of Medical Genetics, RimaRozen et al. presented data examining the frequencies of the three methylenetetrahydrofolate reductase (MTHFR) genotypes in newborn healthy infants ascertained by the California Birth Defects Monitoring Program [Rozen and Shaw, 1999]. It was suggested that homozygosity for the common 677 C!Tmutation inMTHFR genewasmore frequent among newbornmales than among newborn females. The apparent gender difference was observed among 915 newborn infants used as control populations in studies of an association between the MTHFR polymorphism and neural tubedefects.RozenandShaw [1999] stratified this groupof 915 newborn control healthy infants by MTHFR genotypes and found that among 150 infants who had the TT variant for MTHFR only 50 (33%) were female. This was significantly less (P< 0.01) than the expected 50% of female infants. Weexamined the frequencies of the threeMTHFRgenotypes in 559 healthy, Caucasian, male and female adult volunteers from Seattle, WA for a controlled intervention study of homocysteine response to folic acid supplementation with variable dosage. As shown in Table I, and similar to the findings of Rozen and Shaw [1999], we detected a significantly lower proportion of females than males to be homozygous for the 677C!Tmutation inMTHFR. Among the 173 males and 386 females analyzed, we found 13.9% of male volunteers were TT homozygotes in comparison to 7.8% of female volunteers (Chi square: P< 0.05). We also found that the T allele relative frequency is significantly different betweenmales and females (P1⁄4 0.02). These results suggest some variation in our data in the MTHFR genotypes due to gender. We hypothesized that theremay be two possible reasons for the observed reduction in frequency ofMTHFR TT homozygotes in females. The first is a possible prenatal selection against TT female homozygotes, and the second is a possible higher T allele frequency in males than females. To explore the observed reduction in frequency of MTHFR TT homozygotes in females, we conducted a literature search for studies specifying MTHFR genotypes and gender for healthy adult individuals, typically from population and case-control studies.Weassumed that a sex difference observed at birth would survive into adulthood since we know of no postnatal condition associated with the MTHFR polymorphism that would eliminate such differences during childhood. The keywords used to produce a primary list in the PubMed literature search were MTHFR, gender, and sex. Two articles were carefully reviewed for related articles [Slattery et al., 1999;Ulrich et al., 2000]. Fromthis search, the list of articles in Table II was generated and was considered representative of the literature on the subject [Adams et al., 1996; Brugada and Marian, 1997; Christensen et al., 1997; Galinsky et al., 1997; Heijmans et al., 1999; Slattery et al., 1999; Stegmann et al., 1999; Chango et al., 2000; Delvin et al., 2000; D’Angelo et al., 2000; Ho, 2000; Hustad et al., 2000; Ulrich et al., 2000; Dekou et al., 2001; Dierkes et al., 2001; Guillen et al., 2001; Kimura et al., 2001; Saw et al., 2001; Wu et al., 2001; Beresford, 2004 unpublished data]. Each article was examined for information onMTHFR genotypes and gender. Table II shows the numbers and percentages of males and females with TT homozygosity for the MTHFR 677 C!T polymorphism, the total number of males and females, age group, and geographic and ethnic origin for each study. We show race/ethnicity data because the incidence of this genetic polymorphism varies among populations.Weshowgeographic originbecause theallele frequencies of theMTHFR 677C!Tpolymorphism also vary significantly between populations from different geographic areas. For example, the T allele frequency varies from 22 to 45% between populations from northern and southern European countries, respectively [Andreassi et al., 2003]. Based on data from these studies, we show no consistent gender difference in homozygosity for the common 677 C!T mutation in MTHFR gene. If the studies are combined, as indicated at the bottom of Table II, the TT genotype frequency is almost the same in males and females (11.6 and 11.5%, respectively). Assessing only studies with a total of over 100 males and 100 females from Table II, similar results were obtained (data not shown). We also calculated the predicted distributions of the genotypes for each gender using the relative frequencies of the C and T allele and the Hardy– Weinberg equation. We found that the predicted distributions are in complete accord with the observed distributions shown in Table I. The principles of the Hardy–Weinberg equation apply in these data suggesting there is no prenatal selection Cheryl A.M. Anderson and Arne Lund Jorgensen completed the work while at the University of Washington, School of Public Health and Community Medicine (CA) and Division of Medical Genetics (ALJ).