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The combined associations of body weight and lifestyle

factors with all-cause and cause-specific mortality in men and women

Journal: BMJ

Manuscript ID BMJ.2016.034265

Article Type: Research

BMJ Journal: BMJ

Date Submitted by the Author: 30-Jun-2016

Complete List of Authors: Veronese, Nicola; University of Padova, Li, Yanping; HSPH Manson, JoAnn; Brigham and Women's Hospital, Dept. of Epidemiology Willett, Walter; Harvard School of Public Health, Nutrition Fontana, Luigi; Washington University in Saint Louis Hu, Frank; Harvard School of Public Health

Keywords: body weight, mortality, lifestyle

https://mc.manuscriptcentral.com/bmj

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The combined associations of body weight and lifestyle factors with all-cause and cause-1

specific mortality in men and women 2

3

Running title: BMI, lifestyle factors and mortality 4

5

Nicola Veronese1,2,*

, Yanping Li3,*

, JoAnn E. Manson4,5,6

, Walter C. Willett3,4,5

, Luigi Fontana1,7,8

, 6

Frank B. Hu3,4,5

7

1Division of Geriatrics and Nutritional Science, Washington University, St. Louis, MO, USA; 8

2Division of Geriatrics, Department of Medicine, University of Padova, Italy; 9

3Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA, USA; 10

4Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA; 11

5Channing Division of Network Medicine, Department of Medicine, Brigham and Women’s 12

Hospital, Harvard Medical School, Boston, MA, USA 13

6Division of Preventive Medicine, Department of Medicine, Brigham and Women’s Hospital, 14

Boston, Massachusetts 15

7Department of Clinical and Experimental Sciences, Brescia University Medical School, Brescia, 16

Italy; 17

8CEINGE Biotecnologie Avanzate, Napoli, Italy; 18

*Equally contributed to the paper. 19

20

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Correspondence to: 21

Frank B. Hu, Department of Nutrition, Harvard T.H. Chan School of Public Health, 655 Huntington 22

Avenue, Boston, MA 02115, USA Channing Division of Network Medicine, Brigham and 23

Women's Hospital and Harvard Medical School, Boston Department of Epidemiology, Harvard T.H. 24

Chan School of Public Health, Boston; Phone: 617.432.0113. Email: 25

[email protected] 26

27

Luigi Fontana, Division of Geriatrics and Nutritional Sciences and Center for Human Nutrition, 28

Washington University School of Medicine, St. Louis, MO 63110, USA; Department of Clinical 29

and Experimental Sciences, Brescia University, 25121 Brescia, Italy; CEINGE Biotecnologie 30

Avanzate, 80122 Napoli, Italy. Email: [email protected]. 31

32

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ABSTRACT 34

BACKGROUND: Some epidemiological data suggest that overweight and obese individuals have 35

lower mortality than normal-weight individuals. We aimed to evaluate the combined associations of 36

diet, physical activity, moderate alcohol consumption and smoking with body weight on risk of all-37

cause and cause-specific mortality. 38

METHOD AND FINDINGS: 74,582 women from the Nurses' Health Study (1980-2012) and 39

39,284 men from the Health Professionals Follow-up Study (1986-2012) free of cardiovascular 40

disease and cancer at baseline were followed in alongitudinal study with up to 32 years of follow-up. 41

Exposures included body mass index (BMI), Alternate Healthy Eating Index (AHEI) score, physical 42

activity level (PAL), smoking habits and alcohol drinking while outcome was mortality (all-cause, 43

cardiovascular, cancer). During up to 32 years of follow-up, 30,013 death cases were documented 44

(10,808 of cancer-mortality and 7,189 of CVD-mortality). In each of the 4 BMI categories studied 45

(18.5-22.4, 22.5-24.9, 25-29.9, ≥30 kg/m2), people with 1 or more healthy lifestyle factors had a 46

significantly lower risk of total, cardiovascular and cancer mortality than individuals with no low-47

risk lifestyle factors. A combination of at least 3 low-risk lifestyle factors and BMI between 18.5-48

22.4 kg/m2 was associated with the lowest risk of all-cause (HR: 0.39; 95%CI: 0.35-0.43), cancer 49

(HR: 0.40; 95%CI: 0.34-0.47) and cardiovascular (HR: 0.37; 95%CI: 0.29-0.46) mortality, 50

compared to those with BMI between 22.5-24.9 and none of the 4 low-risk lifestyle factors. 51

CONCLUSION: People in the 18.5-22.4 BMI range with high AHEI, PAL, moderate alcohol 52

drinking and non-smoking had substantially lower mortality rate. It is important to consider diet and 53

lifestyle factors when evaluating the relationship between BMI and mortality. 54

55

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INTRODUCTION 56

Data from experimental, epidemiological and clinical studies indicate that leanness is associated 57

with greater metabolic health and a lower risk of developing type 2 diabetes, cardiovascular disease 58

(CVD) and cancer.(1–3) However, data from some epidemiological studies are challenging this 59

concept and suggest that being overweight, and possibly even mildly obese, is associated with a 60

reduced mortality risk.(4,5) Normal weight, defined as a body mass index (BMI) between 18.5-61

24.9 kg/m2, is a broad reference group containing not only non-smoking individuals who are lean 62

because they are physically active and eating healthy diets, but also those who have fallen in the 63

normal BMI range for other reasons which accelerate the aging process (e.g. chronic inflammation, 64

chronic obstructive pulmonary disease, and neurodegenerative diseases), probably leading to an 65

artificially reduced mortality among the overweight and moderately obese groups.(6–10) Therefore, 66

when evaluating the relationship between BMI and mortality, it might be important to consider 67

lifestyle factors such as smoking, diet, moderate alcohol intake and physical activity levels. 68

In this large prospective cohort study, we examined the joint associations of BMI and lifestyle 69

factors with all-cause, cardiovascular and cancer mortality among 74,582 women from the Nurses' 70

Health Study (NHS 1980-2012) and 39,284 men from the Health Professionals Follow-up Study 71

(1986-2012) who were free of cardiovascular disease (CVD) and cancer at baseline. We 72

hypothesized that nonsmoking individuals who were lean, and also exercised regularly and 73

followed a healthy diet with a moderate alcohol intake had the lowest mortality risk. 74

75

METHODS 76

Study Population 77

The Health Professions’ Follow-up Study (HPFS) was established in 1986, when 51,529 male US 78

health professionals (dentists, optometrists, osteopaths, podiatrists, pharmacists, and veterinarians) 79

aged 40–75 years completed a mailed questionnaire about their medical history and lifestyle.(11) 80

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The Nurses’ Health Study (NHS) began in 1976, when 121,701 female nurses 30 to 55 years of age 81

responded to a questionnaire regarding medical, lifestyle, and other health-related information.(11)

82

Both cohorts were designed with the similar questions on diet, exercise, smoking status and other 83

factors (the use of hormone replacement therapies and reproductive related questions were asked in 84

the NHS only). In both cohorts, questionnaires have been sent every two years to update this 85

information and identify newly diagnosed cases of various diseases. As shown in S1 Table, we 86

excluded subjects with previously diagnosed cancer and cardiovascular diseases at baseline. We 87

also excluded participants with baseline missing value of BMI, PAL, food frequency questionnaire 88

(FFQ) or smoking. After these exclusions, we included 74,582 women and 39,284 men. Excluded 89

participants and those included in this study were similar in terms of baseline age, BMI and 90

Alternate Healthy Eating Index (AHEI) (S2 Table). 91

The study was approved by the institutional review board of Brigham and Women’s Hospital in 92

Boston; completion of the self-administered questionnaire was considered to imply informed 93

consent. 94

95

Patient involvement 96

No patients were involved in setting the research question or the outcome measures, nor were they 97

involved in the design and implementation of the study. There are no plans to involve patients in 98

dissemination. 99

100

Assessment of exposure 101

Diet was assessed using a validated FFQ asking how often, on average, a participant had consumed 102

a particular amount of a specific type of food during the previous year.(12) The intake of nutrients

103

was computed by multiplying the frequency of consumption of each unit of food by its nutrient 104

content and accounting also for the consumption of alcoholic drinks. Diet quality was assessed 105

using the AHEI score that is strongly associated with the onset of metabolic and cardiovascular 106

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diseases in the general population.(13,14) Briefly, points were assigned for intake of each 107

component on a scale from 0 to 10, with 10 indicating adherence to the recommended levels of 108

servings per day and 0 the worst intake. Multivitamin use was scored as 2.5 points for 0 to 4 years 109

of use and 7.5 points for 5 or more years of use. We included 10 components of the index in our 110

diet score: higher intakes of vegetables, fruit, nuts, whole grains, polyunsaturated fatty acids, and 111

long chain omega 3 fatty acids and lower intakes of red and processed meats, sugar sweetened 112

beverages, trans fats, and sodium. In this analysis, AHEI was divided in quintiles, classifying the 113

two upper quintiles as healthier diets.(15–17) The information about diet was updated every 4 years. 114

Physical activity levels were investigated using a validated questionnaire and updated every 2 115

years.(18) We estimated the amount of hours per week spent in moderate-to-vigorous activities 116

(including brisk walking) requiring at least the expenditure of 3 MET or more per hour. The validity 117

and reproducibility of the questionnaire were evaluated and reported previously. Briefly, the 118

correlation between physical activity as reported in one week recalls and that reported on the 119

questionnaires was 0.79. The correlation between moderate to vigorous activity reported in diaries 120

and that reported on the questionnaires was 0.62.(19) 121

Smoking habits were categorized as never smoked, former smoker, or current smoker (including the 122

number of cigarettes smoked per day) and updated every two years. 123

Body mass index was calculated as self-reported weight (kg)/height (m)2. In our validation study, 124

the correlation between self-reported and technician-measured weight was 0.97.(20) 125

126

Definition of Low-risk Lifestyle Group 127

Low-risk lifestyle factors included never-smoking, physical activity levels ≥30 min/day at moderate 128

to vigorous intensity, moderate alcohol consumption defined as 5 to 15 g alcohol/d in women and 129

5–30 g alcohol/d in men (21), and the AHEI in upper two quintiles. Each factor was coded as 0 or 1, 130

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and the sum of these four scores together gave a final score of 0, 1, 2, 3 or 4 with higher scores 131

indicating a healthier lifestyle. 132

133

Assessment of Other Confounders 134

Information on potential confounders, such as age, ethnicity, use of multi-vitamin, regular use of 135

aspirin, postmenopausal hormone use (NHS only), family history of diabetes, cancer, or myocardial 136

infarction (in first-degree relatives) was collected via biennial questionnaires.

137

138

Ascertainment of deaths 139

Deaths were identified from state vital statistics records, the National Death Index, reported by the 140

families, and the postal system.(24) The follow-up for death in both cohorts was at least 98% 141

complete. Cause of death was identified from death certificates or review of medical records. In the 142

current analysis, we evaluated all-cause mortality, and also death from CVD (International 143

Classification of Diseases, eighth revision (ICD-8) codes 390 through 458) or cancer (ICD-8 codes 144

140 through 207). 145

146

Statistical Analysis 147

Participants contributed person time from the return of the baseline questionnaire (NHS, 1980; 148

HPFS, 1986) until the date of death, loss to follow-up, or the end of the follow-up period (30 June 149

2012 for NHS and 30 January 2012 for HPFS), whichever came first. 150

Proportional hazards assumption was evaluated with a likelihood-ratio test comparing the model 151

with and without an interaction term between time period and the joint categories of BMI and 152

lifestyles. The P value for the proportional hazards assumption was 0.44, indicating that the 153

proportional-hazards assumption was not violated in our analyses. We therefore used Cox 154

proportional hazard models to calculate the adjusted hazard ratios (HRs) of all-cause, cancer and 155

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cardiovascular mortality with their 95% confidence intervals (CIs) across BMI categories (kg/m2: 156

<18.5, 18.5-22.4, 22.5-24.9, 25.0-27.4, 27.5-29.9, 30.0-34.9, 35.0-39.9, and ≥40). (22) We defined 157

a BMI of 22.5-24.9 as the referent category, which has been used in previous studies.(23). In 158

addition, this was the range of BMI associated with the lowest mortality in our cohorts (S1 Figure). 159

We updated the information during follow-up by using the most recently available information of 160

BMI and lifestyle factors. To minimize potential reverse causality bias, we stopped updating body 161

weight once the participants were diagnosed with chronic diseases such as cancer, cardiovascular 162

diseases, or diabetes. 163

The covariates included in the multivariable model were: age, ethnicity, current multivitamin use, 164

current aspirin use, status with regard to a family history of diabetes mellitus, myocardial infarction, 165

or cancer; and, for women, menopausal status and hormone use. If data were missing at a given 166

time point, the last observation was carried forward for 1 cycle. 167

We calculated the HRs across joint classification of number of low-risk lifestyle factors (0, 1, 2, or 168

≥3) and BMI (kg/m2: 18.5-22.4, 22.5-24.9, 25.29.9, and ≥30) because of too few cases for cause-169

specific mortality in some groups as shown in S3 Table. A similar analysis was performed 170

considering only the effect of AHEI, moderate alcohol consumption, and physical activity levels for 171

each BMI category after excluding ever-smokers. 172

Several sensitivity analyses were run to test the robustness of our results. First, we kept all missing 173

values at baseline and during follow-up, and imputed missing values of BMI and lifestyle factors by 174

applying a multiple imputation approach. Second, we calculated an expanded low-risk lifestyle 175

score by assigning weights to each low-risk factor based on the beta-coefficients from the 176

multivariable-adjusted Cox model with all-cause mortality as the outcome. We then summed up the 177

products of each binary lifestyle score multiplied by its weight, divided it by the sum of all beta 178

coefficient values, and then multiplied by 4, to make the low-risk lifestyle score easier to interpret. 179

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In this way, the expanded low-risk lifestyle score ranged from 0 to 4, and each unit of low-risk 180

lifestyle score represented the change in one risk factor. Third, we conducted analyses that assessed 181

the effects of specific combination of lifestyle factors on mortality. Finally, we conducted additional 182

analyses by combining the two normal weight groups. 183

We used SAS version 9.3 to analyze the data. Statistical significance was set at a two tailed P<0.05. 184

185

RESULTS 186

The characteristics of the study population according to baseline BMI are shown in Table 1 for 187

women and men. As reported in S4 Table, those with ≥ 3 low risk factors were 8.9% in women and 188

19.6% in men. 189

During up to 32 years of follow-up, 30,013 death cases were documented (10,808 of cancer-190

mortality and 7,189 of CVD-mortality). As shown in Table 2, compared to those with BMI 191

between 22.5 and 24.9 kg/m2, most other BMI categories had an increased risk of all-cause 192

mortality after adjusting for potential confounders. Among participants without any low risk 193

lifestyle factor, the association between BMI and mortality was U-shaped (P for non-linear trend < 194

0.0001), while among participants with one or more low risk lifestyle factors, the association 195

between BMI and mortality was in a more linear shape (Ps for linear trend < 0.0001) (P for 196

interaction < 0.0001, Table 3). 197

The mortality risk significantly decreased with the increasing numbers of low-risk lifestyle factors. 198

A combination of at least 3 low-risk lifestyle factors and BMI between 18.5-22.4 kg/m2 was 199

associated with the lowest risk of total (HR: 0.39; 95%CI: 0.35-0.43), cancer (HR: 0.40; 95%CI: 200

0.34-0.47) and cardiovascular (HR: 0.37; 95%CI: 0.29-0.46) mortality, compared to those with 201

BMI between 22.5-24.9 and none of the 4 low-risk lifestyle factors (Figure 1). These findings were 202

confirmed in never-smokers (HR=0.45; 95%CI: 0.33-0.61 for all-cause mortality; HR=0.47; 95%CI: 203

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0.29-0.77 for cancer mortality; HR=0.41; 95%CI: 0.21-0.80 for CVD mortality) (Figure 2). 204

Participants with all four low-risk factors (high AHEI scores, regular physical activity, never 205

smoking, with a moderate alcohol consumption) combined with a BMI between 18.5 and 24.9 206

Kg/m2, as compared with all others in the study population, had a reduced risk for all-cause 207

(HR=0.39; 95%CI: 0.32-0.47), cancer (HR=0.40; 95%CI: 0.29-0.54) or CVD (HR=0.41; 95%CI: 208

0.28-0.59) mortality (Table 4). 209

The results of sensitivity analyses using multiple imputations (S2 Figure), applying expanded low-210

risk lifestyle scores (S3 Figure), specific combinations of lifestyle factors in the low-risk category 211

(S4 Figure) or combining the two normal weight categories (S5 Figure) were similar to those from 212

the main analysis. 213

214

DISCUSSION 215

In these large prospective cohorts, we found after taking into account the effect of high PAL and 216

AHEI scores, moderate alcohol drinking and never-smoking, men and women in the 18.5-217

22.4 BMI range experienced substantially lower CVD, cancer and total mortality risk. 218

Our findings are in agreement with a recent meta-analysis, including about 30 millions participants, 219

showing that overweight and obesity are associated with increased risk of all-cause mortality, with 220

the nadir of the curve observed at BMI 23-24 among never smokers, 22-23 among healthy never 221

smokers, and 20-22 in studies with a follow-up over 20 years. (25) Of note, in a recent study 222

conducted among three Danish cohorts, the BMI associated with the lowest all-cause mortality 223

increased by 3.3 unit from cohorts enrolled from 1976-1978 through 2003-2013. (26) However, the 224

average follow-up duration for the 2003-2013 cohort was only 4.6 years, and thus the shift to higher 225

BMI associated with the lowest mortality in this cohort is likely to be due to reserve causation bias 226

(i.e. individuals with pre-existing or preclinical diseases have increased mortality but lower BMI 227

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due to weight loss). It should be noted that these studies did not take into account diet and lifestyle 228

factors. 229

Many epidemiological studies have shown a U-shape relationship between BMI and mortality, with 230

some studies showing the lowest mortality around 22.5-25, and others around 25-29.9.(4,27) Our 231

data are confirming that there is a U-shape relationship between BMI and mortality, with an 232

increased mortality risk in the <22.4 and ≥30 BMI range, as recently reported in a large meta-233

analysis including 189 studies without smokers and almost 4 millions participants.(28) However, 234

our data showed for the first time that among never-smoking men and women eating healthier diets, 235

with moderate alcohol intake and exercising regularly ≥30 min/d at moderate intensity, there was a 236

linear relation between BMI and mortality risk with the nadir in the 18.5-22.4 BMI category. The 237

problem is that only a small fraction of the North American and European populations is both 238

normal weight and practicing a healthy lifestyle (i.e., not smoking, exercising regularly, moderate 239

alcohol consumption, and eating a healthy diet).(29) In this study of US health professionals, only 240

19.6% of men and 8.9% of women, respectively, were lean and had ≥3 low-risk lifestyle factors. 241

Our findings suggest that in a substantial proportion of the US population, leanness is driven by 242

other factors that may increase mortality risk, including existing or preclinical chronic diseases that 243

may cause weight loss and cigarette smoking, which is also associated with lower body weight. The 244

reverse causation problem (i.e. low BMI is a consequence of chronic diseases) may be particularly 245

pronounced among those who were sedentary and consuming unhealthy diets, conditions which are 246

important determinants of chronic disease morbidity and mortality. This may explain why an 247

increased mortality was observed in the low BMI range of 18.5-22.4 only among those who did not 248

follow a healthy lifestyle, but not among those with a relatively healthy lifestyle. Increasing basic 249

and translational research suggests that smoking, a sedentary lifestyle and unhealthy hyper-caloric 250

diets cause an overstimulation of multiple mitogenic, inflammatory and oxidative pathways. (30–32) 251

These factors may accelerate the accumulation of unrepaired cellular damage and senescent cells, 252

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stimulate the DNA damage response, inhibit stem cells regenerative function, and promote 253

involuntary weight loss, organ dysfunction and frailty.(7,10,33–35) 254

BMI is a crude, but practical and inexpensive tool to measure adiposity in large population 255

studies.(22,36) However, it does not measure the lean/fat ratio or the distribution of fat and, most 256

importantly, the relative contribution of lifestyle and other metabolic factors on the risk of 257

developing a chronic disease and dying prematurely. In this study, we showed that, in each of the 258

four BMI categories, men and women with healthy lifestyles were powerfully protected against 259

CVD, cancer and total mortality. Interestingly, even within the obese category, individuals who do 260

not smoke, eat healthier diets, drink a moderate quantity of alcohol and exercise regularly, have a 261

much lower risk of mortality than those who have unhealthy lifestyles. The mechanisms responsible 262

for the protective effects of healthy lifestyles in these individuals are not completely known, but 263

likely encompass a series of metabolic and molecular alterations induced by exercise training, 264

healthier diets rich in vitamins and phytochemicals, and avoidance of smoking. These conditions 265

probably inhibit insulin resistance, inflammation, and oxidative stress, and slow the accumulation of 266

cellular and organ damage.(3,32–34). These results suggest that the health benefit by engaging in 267

even one healthy lifestyle behavior was seen in all BMI categories, especially among those in the 268

unhealthy BMI categories. 269

Our study had several strengths. The analysis is based on a large sample size and a long follow-up 270

with a large number of incident cases, which provide high statistical power for the analysis. Another 271

important strength is the high follow-up rate. In each two or four year cycle of the survey in our 272

cohorts, follow-up rates have averaged 94%. Other strengths include the repeated measurements of 273

diet, physical activity, smoking and other factors. Our study addresses not only the relation between 274

BMI, major lifestyle factors and all-cause mortality, but also cause-specific mortality. 275

The current study has some potential limitations. Our cohorts included only health professionals, 276

mostly white men and women, which limits the generalizability of the findings. However, the 277

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relative homogeneity of the study population in educational attainment and socioeconomic status 278

enhances the internal validity. Also, measurement errors in self-reported lifestyle factors are 279

inevitable. However, because of the prospective design, these measurement errors are typically 280

unrelated to the outcomes of the study and thus are likely to have attenuated the observed 281

associations. For this analysis, we did not have necessary validation data to correct for measurement 282

errors with repeated assessments of dietary patterns and other lifestyles over time as our current 283

validation data and methodology allow us to correct for measurement errors in baseline 284

measurements only. However, we used time-varying repeated assessments of lifestyles, which 285

would have substantially reduced within-person variations in the assessment of long-term dietary 286

and lifestyle patterns. 287

In conclusion, people in the 18.5-22.4 BMI range with high PAL, AHEI, moderate alcohol 288

consumption and non-smoking had substantially lower mortality rate. We also found that one or 289

more low-risk lifestyle behaviors significantly reduced mortality risk also in overweight and obese 290

individuals. Our data suggest that the U-shaped relationship between BMI and mortality observed in 291

many epidemiological studies is driven by an overrepresentation in our societies of individuals who 292

are lean because of chronic metabolic and pathological conditions caused by exposure to smoke, a 293

sedentary lifestyle and/or unhealthy diets. Finally, our findings indicate that leanness induced by 294

healthy lifestyles is the optimal way to promote healthy longevity and to reduce the risk of death. 295

296

297

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What is already known on this topic 298

Leanness is associated with greater metabolic health and a lower risk of developing type 2 diabetes, 299

cardiovascular disease, cancer and all-cause mortality. 300

However, data from some epidemiological studies suggest that being overweight, and possibly even 301

mildly obese, is associated with a reduced mortality risk. 302

What this study adds 303

One or more low-risk lifestyle behaviors significantly reduced mortality risk also in overweight and 304

obese individuals. 305

The U-shaped relationship between BMI and mortality observed in many epidemiological studies is 306

driven by an overrepresentation in our societies of individuals who are lean because of chronic 307

metabolic and pathological conditions caused by exposure to smoke, a sedentary lifestyle and/or 308

unhealthy diets. 309

310

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Acknowledgement: We would like to thank the participants and staff of the Nurses’ Health Study 311

and the Health Professionals Study that contributed data for their valuable contributions as well as 312

the following state cancer registries for their help: AL, AZ, AR, CA, CO, CT, DE, FL, GA, ID, IL, 313

IN, IA, KY, LA, ME, MD, MA, MI, NE, NH, NJ, NY, NC, ND, OH, OK, OR, PA, RI, SC, TN, 314

TX, VA, WA, WY. 315

Funding: The cohorts were supported by grants of UM1 CA186107, P01 CA87969, R01 316

HL088521, UM1 CA167552, and R01 HL35464 from the National Institutes of Health. L.F. and 317

N.V. were supported by grants from the Bakewell Foundation and the Longer Life Foundation (an 318

RGA/Washington University Partnership). The funders play no-role in the design of the study; the 319

collection, analysis, and interpretation of the data; and the decision to approve publication of the 320

finished manuscript. The authors assume full responsibility for analyses and interpretation of these 321

data. 322

Contributors: NV, YL, LF, and FBH were involved in the study conception and design. WCW, 323

FBH, and JEM obtained funding. WCW, FBH, and JEM provided study materials or patients and 324

collected and collated data. All authors were involved in analysis and interpretation of the data. NV 325

drafted the article; NV, YL, LF, JEM, WCWCand FBH revised it critically for important 326

intellectual content; all authors approved the final version. LF and FBH is the guarantors. 327

Competing interests: All authors have completed the ICMJE uniform disclosure form at 328

www.icmje.org/coi_disclosure.pdf (available on request from the corresponding author) and declare: 329

no support from any organization for the submitted work other than those detailed above; no 330

financial relationships with any organizations that might have an interest in the submitted work in 331

the previous three years; no other relationships or activities that could appear to have influenced the 332

submitted work. 333

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Ethical approval: The study protocol was approved by the institutional review boards of the 334

Brigham and Women’s Hospital and the Harvard School of Public Health. Completion of the self 335

administered questionnaire was considered to imply informed consent. 336

Transparency statement: The lead authors (the manuscript’s guarantors) affirm that the 337

manuscript is an honest, accurate, and transparent account of the study being reported; that no 338

important aspects of the study have been omitted; and that any discrepancies from the study as 339

planned (and, if relevant, registered) have been explained. 340

Data sharing: No additional data available. 341

342

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Figure legends 487

Figure 1. Hazard ratios* for all-cause and cause-specific mortality according to joint classification 488

of a low-risk lifestyle score**

and body mass index based on pooled results from NHS and HPFS 489

cohorts 490

*Adjusted for age; race; current multivitamin use, and current aspirin use; status with regard to a family history of 491

diabetes mellitus, myocardial infarction, or cancer; and, for women, menopausal status and hormone use. 492

**Low risk lifestyles include never-smoking, exercise ≥30 min/d at moderate or vigorous intensity, the Alternate 493

Healthy Eating Index score in the upper two fifth (quintiles), and moderate alcohol consumption (moderate: 5 to 15 g 494

alcohol/d in women, 5–30 g alcohol/d in men). Each factor was coded as 0 or 1 and sum four scores together, so the 495

healthy lifestyles scores were 0, 1, 2, 3 or 4 (healthiest). 496

497

Figure 2. Hazard ratios* for all-cause and cause-specific mortality according to joint classification 498

of a low-risk lifestyle score**

and body mass index among never smoking men and women 499

*Adjusted for age; race; current multivitamin use, and current aspirin use; status with regard to a family history of 500

diabetes mellitus, myocardial infarction, or cancer; and, for women, menopausal status and hormone use. 501

**Low risk lifestyles include exercise ≥30 min/d at moderate or vigorous intensity, the Alternate Healthy Eating Index 502

score in the upper two fifth (quintiles) and moderate alcohol consumption (moderate: 5 to 15 g alcohol/d in women, 5–503

30 g alcohol/d in men). Each factor was coded as 0 or 1 and sum three scores together, so the healthy lifestyles scores 504

were 0, 1, 2, or 3 (healthiest). 505

506

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Supporting information captions 507

S1 Table. Sample sizes before and after baseline exclusions in the NHS and HPFS cohorts 508

S2Table Comparison of baseline characteristics between included and excluded study participants 509

(Mean (SD) or %) 510

S3 Table: The number of deaths during the follow-up period according to joint classifications of 511

body mass index and healthy lifestyle scores 512

S4 Table: Distribution proportion of low-risk lifestyle factors (%) according to the BMI categories 513

S1 Figure. Hazard ratios for all-cause mortality according to BMI by each unit 514

S2 Figure. Hazard ratios for all-cause and cause-specific mortality according to joint classification 515

of low-risk lifestyle score and body mass index based on multiple imputations for missing value at 516

baseline and during follow-up period 517

S3 Figure. Hazard ratios for all-cause and cause-specific mortality according to joint classification 518

of body mass index and low-risk lifestyle score using an expanded low-risk lifestyle score 519

S4 Figure. Hazard ratios for all-cause mortality and cause-specific mortality by specific 520

combinations of lifestyle factors in the low-risk category 521

S5 Figure. Hazard ratios for all-cause and cause-specific mortality according to joint classifications 522

of low-risk lifestyle score and body mass index by combining the two normal weight groups 523

524

525

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Table 1: Age-adjusted baseline Characteristics in the Nurses’ Health Study (NHS, 1980) and 526

Health Professions’ Follow-up Study (HPFS, 1986) 527

528

BMI (kg/m2)

<

18.5

18.5-

22.4

22.5-

24.9

25.0-

27.4

27.5-

29.9

30.0-

34.9

35.0-

39.9

>=

40

NHS, 1980

n 1492 29125 19105 11563 5362 5552 1724 659

Age, years* 44.1 44.6 46.4 47.3 47.4 47.1 46.3 46.7

BMI, kg/m2 17.7 20.9 23.7 26.2 28.8 32.0 37.0 43.6

Alternate Healthy Eating Index 30.6 31.3 31.2 30.9 30.6 30.2 29.8 29.5

Physical activity, hours/week 3.8 4.2 3.9 3.7 3.5 3.3 2.9 2.7

Current smoking, % 45.6 32.1 28.5 26.9 25.2 21.9 21.2 18.2

Alcohol consumption, gram/day 7.6 7.6 6.7 5.7 4.8 3.8 2.8 2.6

Caucasian, % 97.9 98.0 97.6 97.3 96.8 96.9 97.4 96.0

Post-menopausal, % 46.2 42.3 42.8 43.2 43.2 43.3 42.1 40.7

Aspirin use, % 57.9 55.0 53.1 51.5 51.3 49.3 48.1 44.4

Multivitamin use, % 61.4 63.5 66.1 67.8 69.1 70.5 73.4 71.8

Family history of diabetes, % 21.2 24.1 28.1 30.6 33.5 38.1 40.2 39.8

Family history of MI, % 22.8 22.9 24.7 25.5 27.0 27.2 27.1 27.9

Family history of cancer, % 14.2 13.8 13.8 13.5 13.2 13.6 13.0 14.2

HPFS, 1986

n 139 5639 13092 12585 4805 2564 339 121

Age, years* 55.3 52.2 52.6 53.2 53.3 53.0 51.6 52.5

BMI, kg/m2 17.4 21.5 23.8 26.1 28.6 31.7 36.7 47.5

Alternate Healthy Eating Index 45.1 47.9 47.5 46.2 45.5 45.1 43.4 47.1

Physical activity, hours/week 2.2 3.3 3.2 2.7 2.2 1.7 1.2 2.1

Current smoking, % 24.1 11.2 8.9 9.9 10.4 9.8 8.9 9.7

Alcohol consumption, gram/day 12.5 10.6 11.6 11.6 11.8 10.4 9.6 10.9

Caucasian, % 89.3 92.8 94.2 94.5 94.5 94.6 96.0 93.8

Aspirin use, % 76.7 75.3 73.5 71.4 70.5 70.2 71.3 72.2

Multivitamin use, % 34.4 33.6 36.7 39.8 42.1 43.8 45.5 37.2

Family history of diabetes, % 12.6 18.2 19.6 21.7 22.7 26.6 28.9 23.4

Family history of MI, % 31.1 31.9 31.3 32.2 32.5 33.6 33.3 43.5

Family history of cancer, % 31.3 34.4 34.8 34.3 33.8 34.2 28.9 23.6

BMI: Body Mass Index; MI: Myocardial Infarction 529

530

531

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Confidential: For Review Only27

Table 2: Hazard ratios of all-cause mortality according to body mass index in the Nurses’ Health Study (NHS, 1980-2012) and Health

Professions’ Follow-up Study (HPFS, 1986-2012)

BMI (kg/m2)

<18.5 18.5-22.4 22.5-

24.9 25.0-27.4 27.5-29.9 30.0-34.9 35.0-39.9 >=40

NHS, 1980-2012

Person years 32722 653018 572034 416990 213264 217770 67570 25594

# deaths 528 4789 4246 3450 1909 2103 816 387 Crude incidence (105PY) 1614 733 742 827 895 966 1208 1512

Age-adjusted HR (95%CI) 2.22 (2.03-2.43) 1.13 (1.08-1.17) 1.0 1.06 (1.02-1.11) 1.14 (1.08-1.21) 1.32 (1.25-1.39) 1.86 (1.73-2.01) 2.52 (2.27-2.79)

Multivariate-adjusted 1* 2.11 (1.93-2.31) 1.13 (1.08-1.17) 1.0 1.04 (0.99-1.09) 1.09 (1.04-1.16) 1.23 (1.17-1.30) 1.71 (1.58-1.84) 2.21 (1.99-2.46)

Multivariate-adjusted 2** 1.92 (1.75-2.10) 1.13 (1.08-1.18) 1.0 1.01 (0.97-1.06) 1.04 (0.99-1.10) 1.15 (1.09-1.21) 1.54 (1.43-1.66) 1.94 (1.74-2.15)

HPFS, 1986-2012

Person years 2781 113480 282946 290160 125288 67988 9756 2843

# deaths 87 1594 3457 3689 1700 1021 172 65

Crude incidence (105PY) 3128 1405 1222 1271 1357 1502 1763 2287

Age-adjusted 1.69 (1.36-2.09) 1.07 (1.01-1.13) 1.0 1.06 (1.01-1.11) 1.26 (1.18-1.33) 1.52 (1.42-1.63) 2.12 (1.82-2.47) 2.77 (2.17-3.54) Multivariate-adjusted 1* 1.56 (1.26-1.93) 1.06 (1.00-1.13) 1.0 1.03 (0.99-1.08) 1.22 (1.15-1.30) 1.45 (1.35-1.55) 2.00 (1.72-2.34) 2.10 (1.64-2.69)


Pooled results Age-adjusted 2.13 (1.96-2.32) 1.12 (1.08-1.15) 1.0 1.06 (1.02-1.09) 1.19 (1.15-1.24) 1.38 (1.32-1.44) 1.91 (1.79-2.04) 2.56 (2.33-2.82)


Multivariate-adjusted 2**

1.85 (1.70-2.01) 1.12 (1.08-1.16) 1.0 0.99 (0.96-1.03) 1.06 (1.02-1.11) 1.17 (1.12-1.22) 1.55 (1.45-1.66) 1.92 (1.74-2.11)

Pooled results among never smokers

Age-adjusted 1.63 (1.37-1.94) 0.97 (0.91-1.03) 1.0 1.09 (1.03-1.15) 1.26 (1.17-1.35) 1.54 (1.43-1.65) 2.27 (2.04-2.52) 2.96 (2.54-3.45)



HR: hazard ratio; CI: confident interval;

* Adjusted for age; race; current multivitamin use, and current aspirin use; family history of diabetes mellitus, myocardial infarction, or cancer; and,

for women, menopausal status and hormone use. **

Further adjusted for smoking status (never smoker, former smoker, current smoker: 1-14, 15-24 or ≥ 25 cigarettes/d), exercise (hours/week: 0, 0.01-

1.0, 1.0-3.5, 3.5-6.0, ≥6), alternate healthy eating index (quintile) and alcohol drinking (g/d: 0, 0.1-4.9, 5.0-14.9, 15.0-19.9, 20.0-29.9, and ≥30).

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Table 3: Association between body mass index and all-cause mortality stratified by the number of low-risk lifestyle factors*,§

Numbers of BMI (kg/m2) P for

Low-risk factors <18.5 18.5-22.4 22.5-24.9

25.0-27.4 27.5-29.9 30.0-34.9 35.0-39.9 >=40 Trendǂǂǂǂ

None # deaths 266 2163 2257 2169 1133 1058 342 161

HR (95% CI)**

2.37 (2.08-2.69) 1.24 (1.17-1.32) 1.0 1.00 (0.94-1.06) 1.03 (0.96-1.10) 1.11 (1.03-1.19) 1.50 (1.34-1.68) 1.80 (1.53-2.11) 0.81

One

# deaths 237 2485 3091 3028 1604 1423 459 207

HR (95% CI)** 1.89 (1.65-2.16) 1.11 (1.06-1.17) 1.0 1.00 (0.95-1.05) 1.11 (1.05-1.18) 1.22 (1.15-1.30) 1.59 (1.44-1.75) 2.13 (1.84-2.45) <0.0001

Two

# deaths 92 1307 1746 1535 682 556 164 71

HR (95% CI)** 1.57 (1.27-1.94) 1.05 (0.97-1.13) 1.0 1.03 (0.96-1.10) 1.13 (1.03-1.23) 1.35 (1.22-1.48) 2.09 (1.78-2.46) 2.40 (1.89-3.05) <0.0001

Three or Four

# deaths 20 428 609 407 190 87 23 13

HR (95% CI)**

1.21 (0.77-1.91) 0.98 (0.86-1.11) 1.0 0.96 (0.84-1.09) 1.26 (1.07-1.48) 1.40 (1.11-1.76) 2.32 (1.52-3.54) 3.50 (2.00-6.13) <0.0001

P for interaction ƫ <0.0001

HR: hazard ratio; CI: confident interval;

* Low-risk lifestyle factors include never-smoking, exercise ≥30 min/d at moderate or vigorous intensity, the Alternate Healthy Eating Index score

in the upper two fifth (quintiles), and moderate alcohol consumption (moderate: 5 to 15 g alcohol/d in women, 5–30 g alcohol/d in men). Each

factor was coded as 0 or 1 and sum three scores together, so the healthy lifestyles scores were 0, 1, 2, 3 or 4 (healthiest). **

Adjusted for age; race; current multivitamin use, and current aspirin use; family history of diabetes mellitus, myocardial infarction, or cancer;

and, for women, menopausal status and hormone use. ǂ P for linear trend tested by treating BMI as a continuous variable.

§Significant non-linear relation of BMI with risk of all-cause mortality was only significant among people with none low-risk lifestyle factor (P for

non-linear trend <0.0001),which was tested using likelihood ratio method by comparing model with linear term only with model with both linear

and cubic spline terms stratified by numbers of low-risk lifestyle factors. ƫWe tested the multiplicative interaction between BMI (8 categories) and numbers of low-risk factors by comparing the −2 log likelihood of the

multivariate adjusted models with and without the cross product interaction term.

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Table 4 Multivariate-adjusted hazard ratios (95%CI) of all-cause and cause-specific mortality by specific combinations of lifestyle

factors in the low-risk category

Participants All-cause mortality Cancer mortality CVD mortality

Factors in low-risk category % #

deaths

HR (95% CI) #

deaths

HR (95% CI) #

deaths

HR (95% CI)

All other categories 38.7 9906 1.0 (reference) 3785 1.0 (reference) 2423 1.0 (reference)

Diet in top 2 quintiles 61.3 20107 0.85 (0.83-0.87) 7023 0.91 (0.87-0.94) 4766 0.89 (0.84-0.93)


Plus regular physical activity 87.5 28114 0.62 (0.59-0.65) 9973 0.70 (0.65-0.75) 6758 0.61 (0.55-0.67)


Plus never-smoking 94.4 29333 0.47 (0.44-0.51) 10525 0.51 (0.45-0.57) 7042 0.44 (0.37-0.52)


Plus moderate alcohol consumption 98.3 29839 0.43 (0.37-0.50) 10744 0.41 (0.32-0.52) 7143 0.46 (0.35-0.62)


Plus body mass index 18.5-24.9 kg/m2 98.9 29908 0.39 (0.32-0.47) 10767 0.40 (0.29-0.54) 7161 0.41 (0.28-0.59)

HR: hazard ratio; CI: confident interval; *

Adjusted for age; race; current multivitamin use, and current aspirin use; family history of diabetes mellitus, myocardial infarction, or cancer;

and for women, menopausal status and hormone use, and each lifestyle risk factors not already included in the model.

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Figure 1

59x79mm (300 x 300 DPI)

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Figure 2

59x78mm (300 x 300 DPI)

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Supporting information

S1 Table. Sample sizes before and after baseline exclusions in the NHS and HPFS cohorts

NHS HPFS

Year of baseline 1980 1976

Baseline sample 98,712 51,529

Baseline exclusion

Cancer 3972 2160

Cardiovascular diseases 2308 3996

Missing BMI 591 1032

Missing physical activity 12307 2237

Missing smoking 142 1664

Missing FFQ (AHEI and alcohol) 4810 1156

Sample size for study population 74,582 39,284

The Nurses’ Health Study (NHS) began in 1976, when 121,701 female nurses responded. In 1980,

98,712 nurses response the long questionnaire including questions with detail food items (FFQ)

and physical activities, which was treated as the baseline for NHS in the current study.

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S2 Table. Comparison of baseline characteristics between included and excluded study

participants (Mean (SDDDD) or %)

Excluded Included

NHS, 1980

N 24,130 74,582

Age, years 48.4(7.0) 45.9(7.2)

BMI, kg/m2 24.7(4.7) 24.3(4.5)

Alternate Healthy Eating Index 31.7(6.4) 31.0(6.2)

Physical activity, hours/week 3.5(2.9) 3.9(2.9)

Alcohol consumption, gram/day 6.3(10.5) 6.4(10.6)

Current smoking, % 30.7 28.8

High blood pressure, % 21.1 15.5

Hypercholesterolemia, % 8.4 5.1

Diabetes, % 3.8 2.1

HPFS, 1986

N 12,245 39,284

Age, years 59.1(9.7) 52.9(9.5)

BMI, kg/m2 25.8(3.6) 25.5(3.3)

Alternate Healthy Eating Index 48.3(10.9) 46.7(10.8)

Physical activity, hours/week 2.8(4.7) 2.8(4.2)

Alcohol consumption, gram/day 11.2(15.8) 11.4(15.4)

Current smoking, % 25.5 9.8

High blood pressure, % 31.9 19.7

Hypercholesterolemia, % 20.4 10.5

Diabetes, % 5.9 2.4

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S3 Table: The number of deaths during the follow-up period according to joint classifications of

body mass index and healthy lifestyle scores*

BMI (kg/m2)

Cases, HR (95% CI) <18.5 18.5-22.4 22.5-24.9 25.0-29.9 >=30

All-cause mortality

None healthy lifestyle 266 2163 2257 3302 1561

One healthy lifestyle 237 2485 3091 4632 2089

Two healthy lifestyles 92 1307 1746 2217 791

Three healthy lifestyles 19 385 547 536 116

Four healthy lifestyles 1 43 62 61 7

Cancer mortality






CVD mortality






Low risk lifestyles include never-smoking, exercise ≥30 min/d at moderate or vigorous intensity,

the Alternate Healthy Eating Index score in the upper two fifth (quintiles), and moderate alcohol

consumption (moderate: 5 to 15 g alcohol/d in women, 5–30 g alcohol/d in men). Each factor was

coded as 0 or 1 and sum three scores together, so the healthy lifestyles scores were 0, 1, 2, 3 or 4

(healthiest).

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S4 Table: Distribution proportion of low-risk lifestyle factors (%) according to the BMI

categories

BMI Number of low-risk factors (PYs, %)

(kg/m2) None One Two Three Four

NHS

<18.5 26.0 38.2 25.6 9.0 1.1

18.5-22.4 20.3 38.7 29.2 10.5 1.3

22.5-24.9 21.2 40.7 28.2 8.9 1.1

25.0-27.4 22.6 43.3 26.3 7.2 0.7

27.5-29.9 24.1 44.9 25.0 5.6 0.5

30.0-34.9 25.5 46.8 23.2 4.3 0.2

35.0-39.9 27.0 49.3 20.6 3.0 0.1

>=40 30.5 47.4 19.3 2.7 0.1

Total 22.2 41.9 26.9 8.0 0.9

HPFS

<18.5 21.5 36.7 28.3 10.7 2.8

18.5-22.4 11.9 28.8 32.5 21.2 5.6

22.5-24.9 11.9 31.2 33.2 19.1 4.6

25.0-27.4 15.3 35.2 31.5 15.0 3.0

27.5-29.9 18.2 37.8 30.1 12.0 2.0

30.0-34.9 22.8 40.1 27.1 8.8 1.2

35.0-39.9 25.8 43.0 23.8 6.7 0.7

>=40 25.6 34.3 27.0 11.8 1.3

Total 14.9 33.9 31.6 16.1 3.5

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S1 Figure. Hazard ratios for all-cause mortality according to BMI by each unit

Adjusted for age; race; current multivitamin use, and current aspirin use; family history of diabetes mellitus, myocardial

infarction, or cancer; and, for women, menopausal status and hormone use, smoking status (never smoker, former

smoker, current smoker: 1-14, 15-24 or ≥ 25 cigarettes/d), exercise (hours/week: 0, 0.01-1.0, 1.0-3.5, 3.5-6.0, ≥6),

alternate healthy eating index (quintile) and alcohol drinking (g/d: 0, 0.1-4.9, 5.0-14.9, 15.0-19.9, 20.0-29.9, and ≥30).

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S2 Figure. Hazard ratios for all-cause and cause-specific mortality according to joint

classification of low-risk lifestyle score and body mass index based on multiple imputations

for missing value at baseline and during follow-up period

Low risk lifestyles include never-smoking, exercise ≥30 min/d at moderate or vigorous intensity, the Alternate Healthy

Eating Index score in the upper two fifth (quintiles), and moderate alcohol consumption (moderate: 5 to 15 g alcohol/d

in women, 5–30 g alcohol/d in men). Each factor was coded as 0 or 1 and sum three scores together, so the healthy

lifestyles scores were 0, 1, 2, 3 or 4 (healthiest).


infarction, or cancer; and, for women, menopausal status and hormone use.

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classification of body mass index and low-risk lifestyle score using an expanded low-risk

lifestyle score





To calculate the expanded low-riskscore, we assigned weights to each binary low-risk factor based on the beta-

coefficients from the multivariable-adjusted Cox model with all-cause mortality as the outcome. We then summed up

the products of each binary lifestyle score multiplied by its weight, divided it by the sum of all beta coefficient values,

and then multiplied by 4, to make the low-risk lifestyle score easier to interpret. In this way, the expanded low-risk

lifestyle score ranged from 0 to 4, and each unit of low-risk lifestyle score represented the change in one risk factor



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S4 Figure. Hazard ratios for all-cause mortality and cause-specific mortality by specific

combinations of lifestyle factors in the low-risk category

Not listed factors in each combination were 0, such as participants in “A: Diet in top 2 quintiles” group did not had any

other low risk factors, only “AHEI score in score in the upper two fifth”; “B: A + regular physical activity” group had

“AHEI score in the upper two fifth” and “exercise ≥30 min/d at moderate or vigorous intensity”, without any other

factors.

Not all potential combinations of lifestyle factors were presented.



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classifications of low-risk lifestyle score and body mass index by combining the two normal

weight groups







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