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Original Investigation |

Body Mass Index and Mortality Among Hospitalized Patients FREE

Francesco Landi, MD, PhD; Graziano Onder, MD; Giovanni Gambassi, MD; Claudio Pedone, MD; PierUgo Carbonin, MD; Roberto Bernabei, MD; for the Gruppo Italiano di Farmacovigilanza nell'Anziano (GIFA) Study Group
[+] Author Affiliations

From the Istituto di Medicina Interna e Geriatria, Universitá Cattolica del Sacro Cuore, Rome, Italy (Drs Landi, Onder, Gambassi, Pedone, Carbonin, and Bernabei); and the Center for Gerontology and Health Care Research, Brown University, Providence, RI (Dr Gambassi). A complete list of the Gruppo Italiano di Farmacovigilanza nell'Anziano (GIFA) investigators has been published previously (Eur J Epidemiol. 1999;15:893-901).


Arch Intern Med. 2000;160(17):2641-2644. doi:10.1001/archinte.160.17.2641.
Text Size: A A A
Published online

Background  Body mass index (weight in kilograms divided by the square of the height in meters [BMI]) is known to be associated with overall mortality. However, the effect of age on excess mortality from all causes associated with obesity is controversial. The aim of the present study is to determine the effect of age on the relationship between BMI and mortality.

Methods  We analyzed data from a large collaborative observational study group, the Italian Group of Pharmacoepidemiology in the Elderly (GIFA), that collected data on hospitalized patients. A total of 18,316 patients consecutively admitted to 79 clinical centers during 5 different surveys in 1998, 1991, 1993, 1995, and 1997 were enrolled in the present study. The main outcome measure was the relative hazard ratio of death for different levels of BMI.

Results  Mortality rate was lowest among men and women with BMIs from 25.0 through 27.4 kg/m2 (relative risk, 0.24; 95% confidence interval, 0.15-0.38). The graphed relationship between BMI and mortality in younger patients was hyperbolic, with increased death rates at the lowest and highest BMI rankings. On the contrary, the older patients showed an increased death rate at the lowest BMIs with only a slight elevation at the highest BMIs (>35 kg/m2).

Conclusions  Our results suggest that BMI, a simple anthropometric measure of nutritional status, is an important predictor of mortality among young and old hospitalized patients. Even when controlling for clinical and functional variables, a low BMI remained a significant and independent predictor of shortened survival. Furthermore, the finding of the high BMI associated with minimum hazard in elderly subjects supports some past findings and opposes others and, if confirmed, has important implications for geriatric clinical guidelines.

Figures in this Article

THE GRAPHED relationship of body weight to mortality throughout the range of body mass index (weight in kilograms divided by the square of the height in meters [BMI]) has been described as J-shaped, U-shaped, inverse, positive, and even absent.16 In most population studies, the association between BMI and mortality is described by a U-shaped curve, with augmented risk in the lowest and highest percentiles of the distribution, even when controlling for comorbid disease, age, and smoking.7 However, the association between body weight and mortality remains controversial.8 In particular, important questions remain about the impact of age on the relationship between overweight conditions and mortality.911 The third edition of the Dietary Guidelines for Americans12 has recommended a higher BMI with increasing age. On the contrary, the last edition of analogous weight guidelines13 did not include age-specific recommendations.

Recent studies supported the hypothesis that the relative risk of death associated with obesity is lower for older than for younger adults10,11,1417 and that optimal weight for longevity may be higher in older people.1820 To evaluate further the risk of death associated with weight and to investigate whether this risk varies according to age, we examined the relationship between BMI and death rates in a large cohort of hospitalized patients.

The present study uses data from a large collaborative observational study group, the Italian Group of Pharmacoepidemiology in the Elderly (Gruppo Italiano di Farmacoepidemiologia nell'Anziano [GIFA]). The methods of the GIFA have been described in detail elsewhere.21 We considered all patients consecutively admitted in the 79 participating clinical centers during 5 different surveys in 1988, 1991, 1993, 1995, and 1997 for 13 months overall (N = 20,456). Subsequently, we excluded 1938 patients admitted to the hospital with explicit diagnosis of terminal illness and 202 patients with obesity-related diseases (ie, hypothyroidism, Cushing syndrome, and acromegaly). Procedures were in accordance with guidelines provided by the Catholic University ethical committee; the study was also approved and monitored by the steering committee of the National Research Council of Italy.

For each patient a questionnaire was completed at admission and updated daily by a study physician who received specific training for the study. Data recorded included sociodemographic characteristics such as age, sex, household composition, smoking status, and alcohol intake history; medical variables such as main and coexisting diseases, prescribed medications, physical findings, electrocardiography results, chest radiography findings, and complete blood count; neuropsychological variables; and physical function variables. Comorbidity was measured using the Charlson comorbidity index.22 Cognitive status was assessed with the Hodkinson's Abbreviated Mental Test Examination.23 Physical function was measured with a 6-item scale of activities of daily living ranging from 0 (independent) to 6 (total dependence).24

Weight and height were measured during the first day of hospitalization according to guidelines by de Groot and van Staveren25 and each measure was repeated 3 times and averaged.26 The BMI was then computed. We categorized BMI as lower than 18.5 kg/m2, 18.5 to 21.7 kg/m2, 21.8 to 24.9 kg/m2, 25.0 to 27.4 kg/m2, 27.5 to 29.9 kg/m2, 30.0 to 34.9 kg/m2, and 35.0 kg/m2 or higher. Combinations of these 7 categories are in accordance with the cutoff points proposed by the World Health Organization: a BMI between 18.5 and 24.9 kg/m2 defines the normal range; between 25.0 and 29.9 kg/m2, mildly overweight; and 30.0 kg/m2 or higher, moderately to severely overweight.27

Data were first analyzed by descriptive statistics. Continuous variables are presented as mean values ± SD. Differences in categorical parameters according to age and sex were tested using the Fisher exact test. Differences between continuous variables were assessed by analysis of variance comparisons for normally distributed parameters, or the Kruskal-Wallis test was adopted.

To address whether the relationship between different levels of BMI and mortality were homogeneous in the study population, we used a sex-adjusted Cox proportional hazards regression model stratifying the cohort according to age. Adjustments were made for all possible confounders. Cox models were adjusted for potential risk factors reported at admission: index of comorbidity, physical disability, cognitive impairment, smoking status, and alcohol abuse. Statistical analyses were performed using SPSS software (version 8; 1998, Chicago, Ill).

Table 1 gives the main sociodemographic, medical, and functional characteristics of the patients, according to sex and different age groups. On average, the women were older than the men (71.2 ± 15.8 vs 66.9 ± 16.5 years, respectively). Apart from smoking history and consumption of wine, men and women did not differ in regard to the prevalence of comorbidity and functional and cognitive impairment. On the contrary, among the older patients (>75 years) there was a higher prevalence of comorbidy and a higher level of functional impairment relative to those in the younger groups. The average BMI data are consistent with good nutritional status, and no age or sex differences. However, the stratified distribution of BMI reveals that a severe status of malnutrition (BMI<18.5 kg/m2) occurred quite frequently, with higher prevalence among women than men (7.3% vs 3.8%, respectively).

Table Graphic Jump LocationTable 1. Descriptive Analysis of Baseline Sociodemographic, Functional, and Clinical Parameters According to Age and Sex*

The overall in-hospital mortality rates were 2.9% (n = 260) and 3.2% (n = 288) for men and women, respectively, and this was not statistically significant (P = .22). Table 2 gives both the crude and adjusted relative risks of death for each of the BMI levels considered in the study. The graphed relationship was hyperbolic, with very little elevation in the highest level of BMI (>35.0 kg/m2) for both men and women. Mortality was lowest among men and women with BMIs from 25.0 through 27.4 kg/m2. Multivariate adjustment for other risk factors strengthened the association between severe malnutrition and mortality but did not substantially modify the results.

Table Graphic Jump LocationTable 2. Crude and Adjusted Relative Risks (RRs) of Mortality According to Body Mass Index (BMI) Levels*

A comparison of the shapes of the curves for different classes of age is presented in Figure 1. For younger patients (<65 years), the relationship between BMI and mortality was U-shaped, with increased death rates among both the leanest and the heaviest persons. On the contrary, the middle-aged and older patients showed only a slight elevation of death rates in the highest level of BMI (>35.0 kg/m2).

Place holder to copy figure label and caption

Multivariate relative risk of death from all causes according to age and body mass index. The top figure includes subjects younger than 65 years (42 deaths); center, 65-74 years (90 deaths); and bottom, 75 years and older (413 deaths). The reference category was made up of patients with body mass indexes lower than 18.5 kg/m2. Analyses were adjusted for sex, index of comorbidity, physical disability, cognitive impairment, smoking, and alcohol abuse.

Graphic Jump Location

The results of this large observational study suggest that a very low BMI has an important prognostic implication for patients in an acute care setting, independent of age, sex, and other nonnutritional risk factors. On the contrary, the excess mortality associated with highest levels of BMI in younger patients declined considerably with age in all degrees of obesity (BMI >30.0 kg/m2). These data are consistent with previous studies in different settings6,911,16,19 that evaluated mortality rates among geriatric populations as a function of BMI. Even when controlling for multiple other potential risk factors, such as comorbidity, smoking, alcohol consumption, and functional and cognitive impairment, the mortality rate among elderly patients was greatest at the lowest BMI and not at the highest BMI rankings.

Our findings suggest that obesity does not qualify as a risk factor in hospitalized older patients, assuming that an obesity-related disease has been excluded. However, the findings of some epidemiological surveys that compared death rates according to BMI across age groups support the hypothesis of important prognostic implications of obesity even in older people.7,28,29 Recently, Calle and colleagues7 have demonstrated that the risk of death from all causes increases throughout the range of moderately and severely overweight conditions for both men and women in all age groups. Disagreement in specific findings may be ascribed to differences in populations studied, exclusion criteria, risk factors controlled for in the analysis, and cutoff points for categories of BMI.

Some limitations of the present study must be acknowledged. Overall, results from the present study should be considered cautiously, given the relatively low number of events in the younger group (42 deaths) and among those with the highest level of BMI (12 deaths). Second, malnutrition and obesity were quantified by a single measurement of BMI at only 1 time point. This cross-sectional approach to assess the relationship between BMI and mortality does not provide evidence for direct causality. In some patients, weight loss may be the result of an illness that is ultimately fatal, a circumstance that produces the appearance of higher mortality among those with lower BMIs. Furthermore, we had no direct measure of adiposity or of lean body mass, and we had no measure of central adiposity, such as the waist-to-hip ratio. The BMI cannot distinguish adequately between fat mass and lean tissue mass, and it may be a less useful indicator of adiposity among the older patients who have a greater amount of body fat at a given BMI than younger ones because of to age-related declines in muscle mass.30 Finally, a more critical consideration is that patients studied were only those hospitalized, indicating that an acute problem existed. For this reason we are not authorized to extend the results to community-dwelling elderly individuals.

Despite these methodological problems, a comparison of present and previous analyses suggests that treating overweight conditions should be avoided in hospitalized older patients. On the contrary, our findings support the well-established increase in the risk of death associated with malnutrition in all age groups.10,11,16,19,31 Indeed, overweight conditions and obesity are important determinants of mortality among younger and middle-aged patients but not in older patients. Our results complement previous studies indicating that the relative risk associated with greater body weight declines with age.9 Obesity increases morbidity, impairs quality of life, and is one of the most important causes of mortality.32,33 The evidence makes clear that obesity is a major public health problem in industrialized countries. However, the relationship between body weight and mortality remains controversial in the geriatric population. Our data and those of previous studies support the hypothesis that the optimal weight for longevity may be higher in older people.

Accepted for publication April 4, 2000.

This study was partially supported by grant 94000402 from the National Research Council and by Neopharmed Italia SpA, Rome, Italy.

Corresponding author: Francesco Landi, MD, PhD, Istituto di Medicina Interna e Geriatria, Centro Medicina dell'Invecchiamento, Universitá Cattolica del Sacro Cuore, Largo Agostino Gemelli 8, 00168 Rome, Italy (e-mail: francesco_landi@rm.unicatt.it).

Manson  JEWillett  WCStampfer  MJ  et al.  Body weight and mortality among women. N Engl J Med. 1995;333677- 685
Link to Article
Wannamethee  GShaper  AG Body weight and mortality in middle-aged British men: impact on smoking. BMJ. 1989;2991497- 1502
Link to Article
Lee  IMManson  JEHenneken  CH  et al.  Body weight and mortality: a 27-year follow-up of middle-aged men. JAMA. 1993;2702823- 2828
Link to Article
Stevens  JKeil  JERust  PF  et al.  Body mass index and body girth as predictors of mortality in black and white women. Arch Intern Med. 1992;1521257- 1262
Link to Article
Wilcosky  THyde  JAnderson  JJB  et al.  Obesity and mortality in the Lipid Research Clinics Program Follow-up Study. J Clin Epidemiol. 1990;43743- 752
Link to Article
Dorm  JMSchisterman  EFWinkelstein  WTrevisan  M Body mass index and mortality in a general population sample of men and women. Am J Epidemiol. 1997;146919- 931
Link to Article
Calle  EEThun  MJPetrelli  JMRodriguez  CHeath  CW Body-mass index and mortality in a prospective cohort of U.S. adults. N Engl J Med. 1999;3411097- 1105
Link to Article
Willet  WCDietz  WHColditz  GA Guidelines for healthy weight. N Engl J Med. 1999;341427- 434
Link to Article
Bender  RJockel  KHTrautner  CSpraul  MBerger  M Effect of age on excess mortality in obesity. JAMA. 1999;2811498- 1504
Link to Article
Antonelli Incalzi  RLandi  FCiprani  L  et al.  Nutritional assessment: a primary component of multidimensional geriatric assessment in the acute care setting. J Am Geriatr Soc. 1996;44166- 174
Landi  FZuccalà  GGambassi  G  et al.  Body mass index and mortality among older people living in the community. J Am Geriatr Soc. 1999;471072- 1076
Department of Agriculture,Department of Health and Human Services, Nutrition and Your Health: Dietary Guidelines For Americans. 3rd ed. Washington, DC Government Printing Office1990;
Department of Agriculture,Department of Health and Human Services, Nutrition and Your Health: Dietary Guidelines for Americans. 4th ed. Washington, DC Government Printing Office1995;
Singh  PNLindsted  KD Body mass and 26-year risk of mortality from specific diseases among women who never smoked. Epidemiology. 1998;9246- 254
Link to Article
Diehr  PBild  DEHarris  TBDuxbury  ASiscovick  DRossi  M Body mass index and mortality in nonsmoking older adults: the Cardiovascular Health Study. Am J Public Health. 1998;88623- 629
Link to Article
Lindsted  KDSingh  PN Body mass and 26-year risk of mortality among women who never smoked: findings from the Adventist Mortality Study. Am J Epidemiol. 1997;1461- 11
Link to Article
Stevens  JCai  JPamuk  EWilliamson  DFThun  MJWood  JL The effect of age on the association between body mass index and mortality. N Engl J Med. 1998;3381- 7
Link to Article
Cornoni-Huntley  JCHarris  TBEverett  DF  et al.  An overview of body weight of older persons, including the impact on mortality: the National Health and Nutritional Examination Survey I—Epidemiologic Follow-up Study. J Clin Epidemiol. 1991;44743- 753
Link to Article
Allison  DBGallagher  DHeo  MPi-Sunyer  FXHeymsfield  SB Body mass index and all cause mortality among people 70 and over: the Longitudinal Study of Aging. Int J Obes Relat Metab Disord. 1997;21424- 431
Link to Article
Losonczy  KGHarris  TBCornoni-Huntley  JC  et al.  Does weight loss from middle age to old age explain the inverse weight mortality relation in old age? Am J Epidemiol. 1995;141312- 321
Link to Article
Carbonin  PUPahor  MBernabei  RSgadari  A Is age an independent risk factor of adverse drug reactions in hospitalized medical patients? J Am Geriatr Soc. 1991;391093- 1099
Charlson  MEPompei  PAles  KLMackenzie  CR A new method of classifying prognostic comorbidity in longitudinal studies: development and validation. J Chronic Dis. 1987;40373- 383
Link to Article
Hodkinson  HM Evaluation of a mental test score for assessment of mental impairment in the elderly. Age Ageing. 1972;1233- 238
Link to Article
Katz  SFord  ABMoskowitz  RW  et al.  Studies of illness in the aged: the index of ADL—a standardized measure of biological and psychosocial function. JAMA. 1963;18594- 101
Link to Article
de Groot  CPGMvan Staveren  WA Nutrition and the elderly: a European collaborative study in cooperation with the World Health Organization, Special Program for Research on Aging (WHO-SPRA) and the International Union of Nutritional Sciences (IUNS), Committee on Geriatric Nutrition—Manual of Operations, Euronut Report 11.  Wageningen, the Netherlands WHO1988;
Vir  SCLove  AHG Anthropometric measurements in the elderly. Gerontology. 1980;261- 8
Link to Article
Not Available, Physical status: the use and interpretation of anthropometry: report of a WHO expert committee. WHO Tech Rep Ser. 1995;8541- 452
Waaler  HT Height, weight and mortality: the Norwegian experience. Acta Med Scand (Suppl). 1984;6791- 56
Harris  TCook  EFGarrison  R  et al.  Body mass index and mortality among nonsmoking older persons: The Framingham Heart Study. JAMA. 1988;2591520- 1524
Link to Article
Borkan  GAHults  DEGerzof  SGRobbins  AHSilbert  CK Age changes in body composition revealed by computed tomography. J Gerontol. 1983;38673- 677
Link to Article
Galanos  ANPieper  CFKussin  PS  et al.  Relationship of body mass index to subsequent mortality among seriously ill hospitalized patients. Crit Care Med. 1997;251962- 1968
Link to Article
Mokdad  AHSerdula  MKDietz  WHBowman  BAMarks  JSKoplan  JP The spread of the obesity epidemic in the United States, 1991-1998. JAMA. 1999;2821519- 1522
Link to Article
Allison  DBFontaine  KRManson  JEStevens  JVanItallie  TB Annual deaths attributable to obesity in the United States. JAMA. 1999;2821530- 1538
Link to Article

Figures

Place holder to copy figure label and caption

Multivariate relative risk of death from all causes according to age and body mass index. The top figure includes subjects younger than 65 years (42 deaths); center, 65-74 years (90 deaths); and bottom, 75 years and older (413 deaths). The reference category was made up of patients with body mass indexes lower than 18.5 kg/m2. Analyses were adjusted for sex, index of comorbidity, physical disability, cognitive impairment, smoking, and alcohol abuse.

Graphic Jump Location

Tables

Table Graphic Jump LocationTable 1. Descriptive Analysis of Baseline Sociodemographic, Functional, and Clinical Parameters According to Age and Sex*
Table Graphic Jump LocationTable 2. Crude and Adjusted Relative Risks (RRs) of Mortality According to Body Mass Index (BMI) Levels*

References

Manson  JEWillett  WCStampfer  MJ  et al.  Body weight and mortality among women. N Engl J Med. 1995;333677- 685
Link to Article
Wannamethee  GShaper  AG Body weight and mortality in middle-aged British men: impact on smoking. BMJ. 1989;2991497- 1502
Link to Article
Lee  IMManson  JEHenneken  CH  et al.  Body weight and mortality: a 27-year follow-up of middle-aged men. JAMA. 1993;2702823- 2828
Link to Article
Stevens  JKeil  JERust  PF  et al.  Body mass index and body girth as predictors of mortality in black and white women. Arch Intern Med. 1992;1521257- 1262
Link to Article
Wilcosky  THyde  JAnderson  JJB  et al.  Obesity and mortality in the Lipid Research Clinics Program Follow-up Study. J Clin Epidemiol. 1990;43743- 752
Link to Article
Dorm  JMSchisterman  EFWinkelstein  WTrevisan  M Body mass index and mortality in a general population sample of men and women. Am J Epidemiol. 1997;146919- 931
Link to Article
Calle  EEThun  MJPetrelli  JMRodriguez  CHeath  CW Body-mass index and mortality in a prospective cohort of U.S. adults. N Engl J Med. 1999;3411097- 1105
Link to Article
Willet  WCDietz  WHColditz  GA Guidelines for healthy weight. N Engl J Med. 1999;341427- 434
Link to Article
Bender  RJockel  KHTrautner  CSpraul  MBerger  M Effect of age on excess mortality in obesity. JAMA. 1999;2811498- 1504
Link to Article
Antonelli Incalzi  RLandi  FCiprani  L  et al.  Nutritional assessment: a primary component of multidimensional geriatric assessment in the acute care setting. J Am Geriatr Soc. 1996;44166- 174
Landi  FZuccalà  GGambassi  G  et al.  Body mass index and mortality among older people living in the community. J Am Geriatr Soc. 1999;471072- 1076
Department of Agriculture,Department of Health and Human Services, Nutrition and Your Health: Dietary Guidelines For Americans. 3rd ed. Washington, DC Government Printing Office1990;
Department of Agriculture,Department of Health and Human Services, Nutrition and Your Health: Dietary Guidelines for Americans. 4th ed. Washington, DC Government Printing Office1995;
Singh  PNLindsted  KD Body mass and 26-year risk of mortality from specific diseases among women who never smoked. Epidemiology. 1998;9246- 254
Link to Article
Diehr  PBild  DEHarris  TBDuxbury  ASiscovick  DRossi  M Body mass index and mortality in nonsmoking older adults: the Cardiovascular Health Study. Am J Public Health. 1998;88623- 629
Link to Article
Lindsted  KDSingh  PN Body mass and 26-year risk of mortality among women who never smoked: findings from the Adventist Mortality Study. Am J Epidemiol. 1997;1461- 11
Link to Article
Stevens  JCai  JPamuk  EWilliamson  DFThun  MJWood  JL The effect of age on the association between body mass index and mortality. N Engl J Med. 1998;3381- 7
Link to Article
Cornoni-Huntley  JCHarris  TBEverett  DF  et al.  An overview of body weight of older persons, including the impact on mortality: the National Health and Nutritional Examination Survey I—Epidemiologic Follow-up Study. J Clin Epidemiol. 1991;44743- 753
Link to Article
Allison  DBGallagher  DHeo  MPi-Sunyer  FXHeymsfield  SB Body mass index and all cause mortality among people 70 and over: the Longitudinal Study of Aging. Int J Obes Relat Metab Disord. 1997;21424- 431
Link to Article
Losonczy  KGHarris  TBCornoni-Huntley  JC  et al.  Does weight loss from middle age to old age explain the inverse weight mortality relation in old age? Am J Epidemiol. 1995;141312- 321
Link to Article
Carbonin  PUPahor  MBernabei  RSgadari  A Is age an independent risk factor of adverse drug reactions in hospitalized medical patients? J Am Geriatr Soc. 1991;391093- 1099
Charlson  MEPompei  PAles  KLMackenzie  CR A new method of classifying prognostic comorbidity in longitudinal studies: development and validation. J Chronic Dis. 1987;40373- 383
Link to Article
Hodkinson  HM Evaluation of a mental test score for assessment of mental impairment in the elderly. Age Ageing. 1972;1233- 238
Link to Article
Katz  SFord  ABMoskowitz  RW  et al.  Studies of illness in the aged: the index of ADL—a standardized measure of biological and psychosocial function. JAMA. 1963;18594- 101
Link to Article
de Groot  CPGMvan Staveren  WA Nutrition and the elderly: a European collaborative study in cooperation with the World Health Organization, Special Program for Research on Aging (WHO-SPRA) and the International Union of Nutritional Sciences (IUNS), Committee on Geriatric Nutrition—Manual of Operations, Euronut Report 11.  Wageningen, the Netherlands WHO1988;
Vir  SCLove  AHG Anthropometric measurements in the elderly. Gerontology. 1980;261- 8
Link to Article
Not Available, Physical status: the use and interpretation of anthropometry: report of a WHO expert committee. WHO Tech Rep Ser. 1995;8541- 452
Waaler  HT Height, weight and mortality: the Norwegian experience. Acta Med Scand (Suppl). 1984;6791- 56
Harris  TCook  EFGarrison  R  et al.  Body mass index and mortality among nonsmoking older persons: The Framingham Heart Study. JAMA. 1988;2591520- 1524
Link to Article
Borkan  GAHults  DEGerzof  SGRobbins  AHSilbert  CK Age changes in body composition revealed by computed tomography. J Gerontol. 1983;38673- 677
Link to Article
Galanos  ANPieper  CFKussin  PS  et al.  Relationship of body mass index to subsequent mortality among seriously ill hospitalized patients. Crit Care Med. 1997;251962- 1968
Link to Article
Mokdad  AHSerdula  MKDietz  WHBowman  BAMarks  JSKoplan  JP The spread of the obesity epidemic in the United States, 1991-1998. JAMA. 1999;2821519- 1522
Link to Article
Allison  DBFontaine  KRManson  JEStevens  JVanItallie  TB Annual deaths attributable to obesity in the United States. JAMA. 1999;2821530- 1538
Link to Article

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