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. 2023 Jul 5;18(7):e0287218. doi: 10.1371/journal.pone.0287218

Body mass index and all-cause mortality in a 21st century U.S. population: A National Health Interview Survey analysis

Aayush Visaria 1,*, Soko Setoguchi 1,2
Editor: Samantha Frances Ehrlich3
PMCID: PMC10321632  PMID: 37405977

Abstract

Introduction

Much of the data on BMI-mortality associations stem from 20th century U.S. cohorts. The purpose of this study was to determine the association between BMI and mortality in a contemporary, nationally representative, 21st century, U.S. adult population.

Methods

This was a retrospective cohort study of U.S. adults from the 1999–2018 National Health Interview Study (NHIS), linked to the National Death Index (NDI) through December 31st, 2019. BMI was calculated using self-reported height & weight and categorized into 9 groups. We estimated risk of all-cause mortality using multivariable Cox proportional hazards regression, adjusting for covariates, accounting for the survey design, and performing subgroup analyses to reduce analytic bias.

Results

The study sample included 554,332 adults (mean age 46 years [SD 15], 50% female, 69% non-Hispanic White). Over a median follow-up of 9 years (IQR 5–14) and maximum follow-up of 20 years, there were 75,807 deaths. The risk of all-cause mortality was similar across a wide range of BMI categories: compared to BMI of 22.5–24.9 kg/m2, the adjusted HR was 0.95 [95% CI 0.92, 0.98] for BMI of 25.0–27.4 and 0.93 [0.90, 0.96] for BMI of 27.5–29.9. These results persisted after restriction to healthy never-smokers and exclusion of subjects who died within the first two years of follow-up. A 21–108% increased mortality risk was seen for BMI ≥30. Older adults showed no significant increase in mortality between BMI of 22.5 and 34.9, while in younger adults this lack of increase was limited to the BMI range of 22.5 to 27.4.

Conclusion

The risk of all-cause mortality was elevated by 21–108% among participants with BMI ≥30. BMI may not necessarily increase mortality independently of other risk factors in adults, especially older adults, with overweight BMI. Further studies incorporating weight history, body composition, and morbidity outcomes are needed to fully characterize BMI-mortality associations.

Introduction

The U.S. prevalence of overweight and obesity has risen dramatically over the last 25 years, with more than half of all adults in the U.S. now overweight or obese [1]. It is well-established that elevated BMI can contribute to several cardio-metabolic conditions, including diabetes, hypertension, and coronary artery disease, which are among the leading causes of premature death in the U.S. [2].

A number of studies have examined the association between BMI and mortality in the general U.S. population, including the landmark Cancer Prevention Study I and II cohorts [3] and other National Cancer Institute Cohort Consortium studies [4]. Furthermore, in the most comprehensive pooled analysis of U.S. data to date, the Global BMI Mortality Collaboration conducted a participant-level meta-analysis of data from 45 cohort studies from the U.S. [5]. Nevertheless, epidemiologic evidence regarding the association between BMI and all-cause mortality has been inconsistent, especially with regards to overweight and class I obese individuals, with some meta-analyses demonstrating similar or lower risk of all-cause mortality [6,7] and others finding significantly elevated mortality risk in individuals with BMI >25 [5,8,9]. In addition, most U.S. studies to date have used data from the 1960s through the 1990s and have included predominantly non-Hispanic White men and women. In contrast, the contemporary U.S. population: (1) has a substantially different BMI distribution, with mean BMI having risen by more than 2 kg/m2 in both men and women since the 1970s [1,10], and increasing skewness towards obese-range BMIs [10]; (2) has seen >10 year increases in life expectancy both overall and among obese individuals [11,12]; (3) is more racially and ethnically diverse, with the percentage of non-Hispanic Whites decreasing from 84% in 1990 to 58% in 2020 [13]; and (4) has seen improvements in efficacy and access to treatment strategies for obesity-related conditions [14]. All of these factors may alter the association between BMI and mortality. Of the few studies using more contemporary populations [1518], they were either restricted by small sample sizes [1517] limiting analysis in racial and gender subgroups, and/or only rudimentarily characterized the dose-response relationship between BMI and mortality [17]. Furthermore, studies inconsistently adjusted for methodologic bias including confounding by illness-related weight loss, collider bias (e.g. the concept that conditioning on obesity-related disease may distort associations between risk factors like BMI and diet and subsequently bias downstream associations), and the healthy person effect (e.g. selection bias that may be introduced when selecting participants of different BMI groups who may otherwise be healthy) [15,16].

To address this gap, we examined the association between BMI and all-cause mortality in the general U.S. population using nationally representative data from the 1999–2018 National Health Interview Survey (NHIS).

Methods

Data sources and study population

The NHIS is a nationally representative survey of the civilian, noninstitutionalized U.S. population, following a multi-stage, probability design from 1999–2018. Further information about the dataset and the sample design can be found in the supplement and elsewhere [19,20]. Because this dataset is publicly available, de-identified, and population-based, this study was considered non-Human Subjects research and exempt from Rutgers Institutional Review Board approval. During the study period, the National Center for Health Statistics (NCHS) maintained IRB approval from the NCHS Research Ethics Review Board (ERB).

We included non-pregnant adults ≥20 years old with recorded BMI. We excluded participants with missing data on covariates (see S1 Appendix, Supplementary Methods) and outlier BMI values (<10, ≥99).

BMI, mortality, and covariates

BMI was calculated using self-reported weight and height (weight in kg/[height in m]2). To allow for comparability with previous studies and examination of non-linear associations, BMI was classified into 9 categories, consistent with the large, pooled analysis of National Cancer Institute Cohort Consortium studies: <18.5, 18.5–19.9, 20.0–22.4, 22.5–24.9, 25–27.4, 27.5–29.9, 30.0–34.9, 35.0–39.9, ≥40 kg/m2 [4].

All-cause mortality was determined from the U.S. National Death Index (NDI). The 1999–2018 NHIS was linked by the National Center for Health Statistics to the NDI up to December 31st, 2019 via patient unique identifiers [21].

We selected covariates a priori based on clinical knowledge and previous studies of BMI and mortality. These included demographics (age, gender, race/ethnicity), socio-behavioral factors (education, marital status, physical activity, smoking status, alcohol consumption, insurance coverage, region of residence, citizenship status), comorbidities (self-reported history of cardiovascular disease, non-skin cancer or melanoma, COPD, current asthma, liver disease, kidney disease, diabetes, or functional limitations), and healthcare utilization factors (doctor’s visit in the past 12 months, mental health visit in the past 12 months). Covariate categorizations are provided in the supplement (Extended Supplementary Methods). Questionnaire protocols and quality control procedures for each covariate are described elsewhere [20].

Statistical analysis

NHIS baseline characteristics were compared across the 9 specified BMI categories. To determine the association between BMI and all-cause mortality, we used Cox proportional hazard models (proportionality assumption verified using Schoenfeld residual plots), adjusting for covariates selected a priori and using BMI of 22.5–24.9 as the reference category. As only the year and quarter were available for death date and interview date, we used the difference between the year and quarter of the death date or end-of-follow-up and survey interview year and quarter to calculate time-to-event. Participants who died or reached the end of follow-up were censored. Cox models were adjusted for age, gender, race/ethnicity, education, marital status, physical activity, alcohol consumption, insurance coverage, region of residence, and citizenship status. Consistent with prior studies, we did not adjust for comorbidities in the main analysis, as they could be on the causal pathway between BMI and mortality or potential colliders for BMI and unmeasured confounders [35] (S1 Fig in S2 Appendix). However, we performed a sensitivity analysis adjusting for metabolic syndrome criteria and additionally excluding participants with any reported chronic disease to explore the independent relationship between BMI and all-cause mortality.

To understand the association between BMI and mortality in specific populations, we conducted analyses in women aged <65, women ≥65, men <65, and men ≥65, as prior studies have suggested weaker BMI-mortality associations in women and older adults. We also performed analyses stratified by race/ethnicity (non-Hispanic White, non-Hispanic Black, non-Hispanic Asian, Hispanic), as different ethnic groups exhibit differences in BMI distributions and associations with morbidity. We further conducted analyses among subgroups of disease-free individuals, utilizing different definitions of disease: minor morbidity, defined as self-reported history of cardiovascular disease, non-skin cancer except melanoma, COPD, current asthma, liver disease, kidney disease, diabetes, or functional limitations; and major morbidity, defined via Berrington de Gonzalez et al. [4] as self-reported history of cardiovascular disease and non-skin cancer or melanoma.

We also conducted analyses restricted to healthy never-smokers (no self-reported cardiovascular disease or non-skin cancer or melanoma) to address confounding by major chronic disease and smoking [4]. To examine the potential impact of reverse causality (i.e. confounding by illness-related weight loss), we conducted analyses limited to participants who did not die within the first two years of follow-up. Although some prior meta-analyses [5] have excluded the first five years of follow-up, there has been concern that such exclusions would lead to significant selection bias as a sizeable proportion of the study population would be excluded, without significant benefit in reducing reverse causality [22]. Nevertheless, we conducted sensitivity analyses excluding the first five years of follow-up.

Sensitivity analyses using NHANES

Limitations of the NHIS include use of self-reported data and lack of laboratory data and information on waist circumference, change in weight over time, and other potential confounding variables including additional comorbidities and dietary factors. To address these limitations, we estimated associations between BMI and all-cause mortality in the 1999–2018 National Health and Nutrition Examination Surveys (NHANES) stratified by waist circumference, weight change, and using alternate definitions to define healthy individuals. Further information about the NHANES study population can be found elsewhere [23] and in the supplement.

Both NHIS and NHANES analyses utilized weights to produce nationally representative estimates and to account for oversampling of certain groups including older adults and members of ethnic minorities. All analyses also accounted for the complex survey design with strata and cluster variables using a traditional Taylor linearization approach to obtain accurate variance estimates. Analyses were conducted using SAS version 9.4 (SAS Institute Inc., Cary, NC) with a two-sided significance level of 0.05.

Results

Sample characteristics

The study sample included 554,332 adults (mean age 46 years, 50% female, 69% non-Hispanic White, 12% non-Hispanic Black, 42% smoking at least 100 cigarettes in their life). The mean BMI was 27.5 (SD 6.1). Between the first four-year cycle (1999–2002) and the last cycle (2015–2018), mean BMI rose from 26.7 to 28.0 kg/m2 and prevalence of BMI of ≥30 increased from 22% to 31% (p<0.001 for trend; see S2 Fig in S2 Appendix for distribution of BMI). Nearly 21% had BMI of 25.0–27.4, and 14% had BMI of 27.5–29.9 (Table 1). Compared to participants with BMI of 22.5–24.9, those with BMI ≥40 were more likely to be female (63% vs. 52%), non-Hispanic Black (21% vs. 9.6%), and U.S. citizens (96% vs. 91%) (Table 1). Individuals with a BMI of 30–34.9 had more than double the proportion of diabetes (13% vs. 4.3%) and nearly double the proportion of MI (4.2% vs. 2.6%) and hypertension (39% vs. 20%) compared to a BMI of 22.5–24.9. Participants with BMI <18.5 also had a high comorbidity burden, including 7.8% (vs. 6.0%) with non-skin malignancy, 9.8% (vs. 4.6%) with COPD, and 11% (vs. 3.6%) with functional limitations.

Table 1. Baseline characteristics by BMI category among NHIS 1999–2018 participants.

NHIS 1999–2018 Body Mass Index (BMI) Category
Variables Overall <18.5 kg/m2 18.5–19.9 20.0–22.4 22.5–24.9 25.0–27.4 27.5–29.9 30.0–34.9 35.0–39.9 ≥40
Number of Subjects 554,332 10,316
(1.9%)
21,648
(4.0%)
74,485
(14%)
103,441
(19%)
115,601
(21%)
77,835
(14%)
93,002
(17%)
35,347
(6.3%)
22,657
(3.9%)
Demographics/Sociobehavioral Factors
Age, median (IQR) 44
(31–58)
36
(23–59)
35
(23–52)
39
(25–54)
43
(29–58)
46
(33–60)
47
(34–59)
47
(35–59)
46
(34–57)
45
(33–56)
> = 65 (%) 120,742 (18%) 2890 (21%) 4364 (15%) 15066 (16%) 23561 (19%) 26972 (19%) 17869 (19%) 20206 (18%) 6533 (15%) 3281 (11%)
Sex (% Female) 301790 (50%) 8020 (74%) 16761 (75%) 49461 (64%) 56949 (52%) 52421 (41%) 34284 (39%) 47796 (46%) 20684 (52%) 15414 (63%)
Race/Ethnicity
Non-Hispanic White 354870 (69%) 6905 (70%) 14811 (73%) 50559 (72%) 68210 (71%) 74363 (70%) 48788 (68%) 57127 (67%) 20990 (65%) 13117 (63%)
Non-Hispanic Black 77647 (12%) 1063 (9.1%) 2095 (8.5%) 7666 (8.8%) 11720 (9.6%) 14678 (10%) 11558 (12%) 15877 (14%) 7380 (17%) 5610 (21%)
Hispanic 90071 (14%) 1028 (8.5%) 2283 (8.5%) 9539 (10%) 16141 (13%) 20379 (15%) 14396 (16%) 17021 (16%) 5970 (15%) 3314 (13%)
Non-Hispanic Asian 25371 (4.6%) 1210 (11%) 2230 (9.5%) 6038 (7.8%) 6406 (6.3%) 5053 (4.5%) 2181 (2.9%) 1685 (1.9%) 389 (1.1%) 179 (0.7%)
Native American/Multiracial/Other 6373 (1.1%) 110 (0.9%) 229 (0.9%) 683 (0.8%) 964 (0.8%) 1128 (0.9%) 912 (1.0%) 1292 (1.3%) 618 (1.7%) 437 (1.9%)
Education
High School 316144 (54%) 6263 (58%) 11938 (53%) 40984 (52%) 57736 (53%) 66134 (54%) 45010 (54%) 54628 (56%) 20419 (56%) 13032 (56%)
Bachelor’s degree 197147 (38%) 3355 (34%) 7880 (38%) 26947 (39%) 36621 (38%) 40250 (37%) 27439 (38%) 32993 (38%) 13064 (38%) 8598 (40%)
Graduate Degree or Higher 41041 (7.9%) 698 (6.6%) 1830 (8.6%) 6554 (9.2%) 9084 (9.5%) 9217 (8.7%) 5386 (7.6%) 5381 (6.2%) 1864 (5.5%) 1027 (4.6%)
Citizenship Status
U.S. Citizen (%) 506092 (92%) 9195 (90%) 19546 (91%) 21648 (92%) 93494 (91%) 104285 (91%) 70796 (92%) 86005 (93%) 33516 (95%) 21776 (96%)
Region of Residence (N = 27965 missing from survey cycle 2004)
Northeast 88716 (18%) 1601 (18%) 3515 (18%) 12508 (19%) 17418 (19%) 19131 (18%) 12355 (18%) 14081 (17%) 5024 (16%) 3083 (15%)
Midwest 118320 (24%) 2054 (23%) 4457 (24%) 15243 (23%) 21261 (23%) 24174 (24%) 16727 (24%) 10841 (25%) 8072 (26%) 5491 (27%)
South 192678 (37%) 3653 (38%) 7264 (35%) 24511 (35%) 34537 (35%) 39331 (36%) 27224 (37%) 33675 (38%) 13596 (40%) 8887 (41%)
West 126653 (22%) 2477 (22%) 5276 (23%) 18271 (23%) 24712 (22%) 27038 (22%) 17614 (21%) 19936 (20%) 7103 (19%) 4226 (17%)
Smoking Status (Smoked>100 cigarettes?) 235349 (42%) 4592 (42%) 8590 (38%) 29950 (39%) 42874 (40%) 49625 (42%) 34093 (43%) 40818 (44%) 15348 (43%) 9459 (41%)
Marital Status
Never Married 124060 (21%) 3213 (36%) 6624 (32%) 21442 (28%) 24482 (22%) 22986 (18%) 14155 (16%) 17353 (16%) 7624 (19%) 6181 (24%)
Separated/Divorced/Widowed 156230 (18%) 3312 (21%) 5929 (18%) 19545 (17%) 28700 (18%) 32202 (18%) 21936 (18%) 26926 (19%) 10704 (20%) 6976 (22%)
Married 242740 (54%) 3222 (36%) 7726 (43%) 29034 (47%) 44347 (53%) 54104 (58%) 37452 (60%) 43491 (59%) 15055 (55%) 8309 (48%)
Other 31302 (6.8%) 569 (6.7%) 1369 (7.9%) 4464 (7.3%) 5912 (6.7%) 6309 (6.4%) 4292 (6.3%) 5232 (6.4%) 1964 (6.4%) 1191 (5.8%)
No alcohol consumption (%) 87271 (16%) 2307 (25%) 3960 (20%) 12312 (18%) 15799 (16%) 16803 (14%) 11347 (14%) 14648 (16%) 5901 (17%) 4194 (19%)
Physical Activity (Moderate-level activity minutes)
0 MEMs (Inactive) 210336 (36%) 5051 (46%) 8033 (37%) 25449 (32%) 35704 (32%) 41232 (35%) 29324 (37%) 38404 (41%) 15794 (44%) 11345 (48%)
0–150 MEMs (Insufficiently Active) 97534 (18%) 1710 (17%) 3634 (17%) 12122 (17%) 16959 (16%) 19472 (17%) 13901 (18%) 17686 (19%) 7239 (20%) 4811 (22%)
150–300 MEMs (Sufficiently Active) 81385 (15%) 1238 (12%) 3218 (15%) 11521 (16%) 15696 (16%) 17659 (16%) 11443 (15%) 13225 (14%) 4745 (14%) 2640 (12%)
>300 MEMs (Highly Active) 165077 (31%) 2317 (24%) 6763 (32%) 25393 (35%) 35082 (36%) 37238 (32%) 23167 (30%) 23687 (26%) 7569 (22%) 3861 (18%)
Strength Training
Yes (≥2 times/week) 91434 (17%) 1258 (13%) 3753 (18%) 14471 (20%) 20408 (21%) 20949 (19%) 12657 (17%) 12125 (14%) 3872 (12%) 1941 (8.9%)
Health Service Factors
Insurance Coverage (%) 469533 (85%) 8691 (84%) 18120 (84%) 62806 (85%) 87798 (86%) 98077 (86%) 65955 (86%) 78851 (85%) 30022 (85%) 19213 (85%)
Doctor’s Visit in Past Year (%) 426906 (77%) 7806 (75%) 16440 (76%) 55879 (75%) 77786 (76%) 87120 (76%) 59756 (77%) 73758 (80%) 29185 (83%) 19176 (85%)
Mental Health Visit in Past 12 Months 43076 (7.4%) 934 (8.5%) 1911 (8.5%) 5832 (7.7%) 7157 (6.6%) 7783 (6.4%) 5548 (6.8%) 7613 (7.8%) 3503 (9.4%) 2795 (12%)
Comorbidities
Cardiovascular Disease (%) 61849 (13%) 1362 (14%) 2067 (10%) 6752 (10%) 10421 (11%) 12400 (13%) 9112 (14%) 11539 (15%) 4785 (17%) 3411 (19%)
History of Stroke 13113 (2.6%) 389 (3.9%) 497 (2.2%) 1450 (2.0%) 2196 (2.3%) 2583 (2.4%) 1946 (2.8%) 2396 (2.9%) 978 (3.3%) 678 (3.5%)
History of Myocardial Infarction 16224 (3.4%) 326 (3.4%) 404 (1.9%) 1461 (2.1%) 2490 (2.6%) 3429 (3.4%) 2600 (3.9%) 3253 (4.2%) 1378 (5.0%) 883 (4.9%)
History of Coronary Heart Disease 20774 (4.3%) 358 (3.7%) 493 (2.4%) 1808 (2.5%) 3265 (3.6%) 4388 (4.5%) 3320 (5.1%) 4240 (5.5%) 1738 (6.1%) 1164 (6.6%)
History of Other Heart Disease 34828 (7.5%) 788 (8.5%) 1303 (6.7%) 4135 (6.5%) 5952 (6.8%) 6769 (7.0%) 4921 (7.6%) 6322 (8.2%) 2636 (9.4%) 2002 (12%)
Diabetes (%) 38621 (8.0%) 292 (2.9%) 455 (2.1%) 1992 (2.9%) 4134 (4.3%) 6345 (6.1%) 5924 (8.8%) 9898 (13%) 5279 (18%) 4302 (25%)
Hypertension (%) 131439 (28%) 1529 (15%) 2611 (12%) 10112 (14%) 18473 (20%) 25709 (26%) 20993 (32%) 29708 (39%) 13033 (47%) 9271 (53%)
Kidney Disease (%) 8662 (1.7%) 261 (2.8%) 340 (1.7%) 902 (1.3%) 1326 (1.3%) 1562 (1.5%) 1185 (1.6%) 1627 (2.0%) 802 (2.6%) 657 (3.5%)
Asthma (%) 28996 (6.5%) 519 (6.3%) 963 (5.5%) 3176 (5.3%) 4231 (5.1%) 4921 (5.3%) 3846 (6.2%) 5732 (7.7%) 2901 (10%) 2707 (15%)
Chronic Obstructive Pulmonary Disease (COPD) (%) 35729 (5.8%) 1129 (9.8%) 1343 (5.5%) 3921 (4.7%) 5250 (4.6%) 6068 (4.6%) 4689 (5.4%) 6933 (6.8%) 3452 (9.0%) 2944 (12%)
Liver condition (%) 6543 (1.3%) 136 (1.5%) 210 (1.0%) 713 (1.0%) 941 (1.0%) 1266 (1.2%) 905 (1.3%) 1348 (1.7%) 584 (2.1%) 440 (2.2%)
Non-Skin Cancer/Malignancy (%) 39065 (6.4%) 757 (7.8%) 1084 (5.2%) 3689 (5.5%) 5353 (6.0%) 6078 (6.2%) 4183 (6.3%) 5080 (6.6%) 1862 (6.6%) 1194 (6.5%)
Functional Limitations (%) 27665 (5.1%) 1049 (11%) 1007 (4.5%) 2770 (3.7%) 3738 (3.6%) 4234 (3.7%) 3266 (4.3%) 5416 (6.2%) 2983 (9.5%) 3202 (17%)
Depressive Symptoms (%) 15589 (3.1%) 491 (5.3%) 678 (3.3%) 1755 (2.6%) 2374 (2.5%) 2553 (2.5%) 1909 (2.7%) 2998 (3.6%) 1522 (5.1%) 1309 (7.1%)
Disease Status per Cancer Prevention Cohort Study II (%) 114155 (25%) 2528 (28%) 4001 (21%) 13288 (20%) 19235 (22%) 22214 (23%) 16208 (25%) 21092 (28%) 8972 (32%) 6617 (37%)
NHIS Disease* (%) 197353 (42%) 3281 (35%) 5526 (28%) 19558 (30%) 31026 (35%) 39003 (40%) 29755 (46%) 40248 (54%) 17009 (61%) 11947 (69%)

*NHIS Disease definition: Presence of any one of the following: Self-reported asthma, COPD, emphysema, chronic bronchitis, non-skin cancer, current liver disease, cardiovascular disease (CAD, HF, stroke, MI), diabetes, hypertension, kidney disease, or functional limitation.

**Disease definition of the Cancer Prevention Cohort Study II includes presence of current asthma, cardiovascular disease, COPD, and non-skin cancer. Unintentional weight loss of at least 10 pounds, which was also included in the original disease definition, was not included in this study as there is no NHIS equivalent.

Association between BMI and mortality

We observed 75,807 deaths during a median follow-up of 9 (IQR, 5–14 years; range, 0–20) years. Crude 5-year mortality rates per 1,000 person-years ranged from 10.7 among those with BMI of 30–34.9 to 35.2 per 1,000 person-years in those with BMI <18.5 (S1 and S2 Tables in S2 Appendix). The unadjusted risks of all-cause mortality were similar across BMI from 20.0 to 29.9 kg/m2 (unadjusted HR [95% CI]; BMI 20.0–22.4: 0.96 [0.93, 0.99], BMI 22.5–24.9: 1.00 [Ref], BMI 25.0–27.4: 1.03 [1.00, 1.06], BMI 27.5–29.9: 1.01 [0.98, 1.04]) but were significantly elevated in participants with BMI of 30–34.9 (1.08 [1.04, 1.11]), BMI of 35–39.9 (1.12 [1.07, 1.16]), BMI ≥40 (1.31 [1.24, 1.37]), and BMI <18.5 (1.90 [1.79, 2.01]). These patterns became more apparent after adjustment for covariates (Fig 1A) and after further restricting the cohort to healthy (without non-skin cancer or melanoma or cardiovascular disease at baseline), never-smokers who did not die within the first two years of follow-up (Fig 1B). Upon additionally controlling for comorbidities including diabetes and hypertension (potential colliders), risk of mortality marginally decreased among overweight BMI categories (BMI 20.0–22.4: 1.10 [1.03,1.19], BMI 22.5–24.9: 1.00 [Ref], BMI 25.0–27.4: 0.95 [0.89,1.00], BMI 27.5–29.9: 0.96 [0.90, 1.02]).

Fig 1. Association between BMI and all-cause mortality in the overall NHIS cohort.

Fig 1

Fig 1 shows the hazard ratios for BMI categories, relative to a BMI of 22.5–24.9. Confidence bands represent 95% CI. (A) presents the hazard ratios for the overall cohort. The blue line represents the overall cohort. The red line depicts healthy, never-smoking individuals. Healthy defined as no self-reported history of cardiovascular disease or non-skin cancer except melanoma. (B) presents the hazard ratios for the overall cohort, excluding individuals who died within 2 years of follow-up. The blue line represents the overall sample. The red line depicts healthy, never-smoking individuals. Healthy defined as no self-reported history of cardiovascular disease or non-skin cancer or melanoma. Please note that hazard ratios for BMI groups for all subjects and healthy, never-smokers are relative to different reference groups and thus may not be comparable.

BMI and mortality in subgroups

Gender and age group

The BMI-mortality patterns observed in the overall population remained largely the same in men and women, even after adjustment for covariates and restriction to healthy never-smokers (Fig 2). However, men and women aged ≥65 years had attenuated BMI-mortality associations compared to men <65 after restriction to healthy never-smokers (Fig 3). When stratifying by age group (≥65, 20–64) alone, we found that the decreased mortality seen from BMI of 25.0 to 29.9 was more pronounced in older adults and that younger adults had increased mortality risk (S3 Fig in S2 Appendix). Older adults also had significantly lower unadjusted risk of mortality among BMI of 30–34.9 compared to younger adults (HR [95% CI], BMI of 30–34.9; older adults: 0.85 [0.82, 0.89]; younger adults: 1.60 [1.52, 1.69]). These age-related differences persisted and remained statistically significant, after adjustment for covariates and after excluding participants who died within the first two years of follow-up (S3 Fig in S2 Appendix).

Fig 2. Association between BMI and all-cause mortality by gender.

Fig 2

Fig 2 shows the hazard ratios for BMI categories, relative to a BMI of 22.5–24.9, by gender. Confidence bands represent 95% CI. The blue line represents all subjects within subgroup. The red line depicts healthy, never-smoking subjects within subgroup. Healthy defined as no self-reported history of cardiovascular disease or non-skin cancer or melanoma. (A) presents the hazard ratios among males overall. (B) presents the hazard ratios for females overall. (C) presents the hazard ratios among males, excluding individuals who died within 2 years of follow-up. (D) presents the hazard ratios among females, excluding individuals who died within 2 years of follow-up. Please note that hazard ratios for BMI groups for all subjects and healthy, never-smokers are relative to different reference groups and thus may not be comparable.

Fig 3. Association between BMI and All-cause mortality by gender and age group.

Fig 3

Fig 3 shows the hazard ratios for BMI categories, relative to a BMI of 22.5–24.9, by gender and age group. All figures exclude first two years of follow-up. Confidence bands represent 95% CI. The blue line represents all individuals in subgroup. The red line depicts healthy, never-smoking individuals within subgroup. Healthy defined as no self-reported history of cardiovascular disease or non-skin cancer or melanoma. (A) presents the hazard ratios among females<65 years overall. (B) presents the hazard ratios for females greater than or equal to 65. (C) presents the hazard ratios among males<65. (D) presents the hazard ratios among males greater than or equal to 65. Please note that hazard ratios for BMI groups for all subjects and healthy, never-smokers are relative to different reference groups and thus may not be comparable.

Race/Ethnicity

Among non-Hispanic White, non-Hispanic Black, and Hispanic participants, 5-year mortality was highest in those with BMI <18.5 (White: 40 [95% CI, 38–43] per 1,000 person-years, Black: 43 [37–50], Hispanic: 20 [1625]). Five-year mortality was lowest at 11.7 (11.2–12.2) among those with BMI of 30.0–34.9 in White adults and 10.0 (8.8–11.3) at BMI of 35.0–39.9 in Black adults, and 7.1 [6.5–7.8] in Hispanic adults. The unadjusted risks of mortality were similar between non-Hispanic White, Black, and Asian adults but were significantly higher in Hispanic adults with BMIs from 25.0 to 29.9 (unadjusted HR [95% CI]. BMI of 25.0–27.4: White, 1.03 [0.99, 1.06]; Black, 1.06 [0.97, 1.15]; Asian, 1.07 [0.89, 1.28]; Hispanic, 1.14 [1.03, 1.25]; BMI of 27.5–29.9: White, 1.01 [0.98, 1.05]; Black, 0.98 [0.90, 1.06]; Asian, 0.95 [0.75, 1.20]; Hispanic, 1.15 [1.03, 1.29]). These patterns persisted, albeit insignificantly, after adjustment (Fig 4, P-interaction = 0.21).

Fig 4. Association between BMI and all-cause mortality by gender and age group.

Fig 4

Fig 4 shows the hazard ratios for BMI categories, relative to a BMI of 22.5–24.9, by race/ethnicity. Confidence bands represent 95% CI. The blue line represents all individuals. The red line depicts healthy, never-smoking individuals. Healthy defined as no self-reported history of cardiovascular disease or non-skin cancer or melanoma. (A) presents the hazard ratios among non-Hispanic Whites overall. (B) presents the hazard ratios for non-Hispanic Blacks. (C) presents the hazard ratios for Hispanics. (D) presents the hazard ratios among non-Hispanic Whites, excluding individuals who died within 2 years of follow-up. (E) presents the hazard ratios among non-Hispanic Blacks, excluding individuals who died within 2 years of follow-up. (F) presents the hazard ratios among Hispanics, excluding individuals who died within 2 years of follow-up. Please note that hazard ratios for BMI groups for all subjects and healthy, never-smokers are relative to different reference groups and thus may not be comparable.

Sensitivity analyses in NHANES population

The NHANES sample included 44,308 adults, with a mean age of 47 years, 51% female, and 69% non-Hispanic White (S3 Table in S2 Appendix). Mean BMI was approximately 1 kg/m2 higher in the NHANES cohort (using measured height and weight) compared to the NHIS cohort (using self-reported height and weight; S4 Table in S2 Appendix). In the overall NHANES population, the risk of all-cause mortality was similar across BMI groups from 22.5 to 29.9 (S5 Table in S2 Appendix). Unintentional weight loss significantly increased risk of mortality across all BMI categories (S7 Table in S2 Appendix). Adjusted HR [95% CI], BMI 25.0–27.4: 1.59 [1.25, 2.03], BMI of 27.5–29.9: 1.57 [1.19, 2.08], BMI of 30.0–34.9: 1.80 [1.42, 2.28]). Overweight and class I obese BMI participants with intentional weight loss or no weight change had similar or lower risk of mortality. The results were not sensitive to definition of ‘healthy’ population (S4 Fig in S2 Appendix, S8 Table in S2 Appendix), or inclusion of maximum lifetime BMI rather than baseline BMI in the model to account for weight history (S9 Table in S2 Appendix). Waist circumference (WC) modified risk of mortality, albeit insignificantly: those with overweight BMI (25.0–27.4 and 27.5–29.9) and elevated WC, but not normal WC, had higher risk of mortality, compared to participants with BMI of 22.5–24.9 with normal WC (S6 Table in S2 Appendix).

Discussion

Among 554,332 U.S. adults over a recent 20-year period, the risks of all-cause mortality were similar across a wide range of BMIs including conventionally overweight BMI ranges, namely 22.5 to 29.9 kg/m2. These findings persisted after adjustment for confounders, restriction to healthy never-smokers, and exclusion of participants who died within the first two years of follow-up [5]. Our findings were also replicated in the NHANES cohort with even better bias adjustment. Both BMI ≥30 and <18.5 were associated with significantly increased risk of mortality across all subgroups examined.

Our findings of similar all-cause mortality risks in a contemporary U.S. population over a wide range of BMI from 22.5–29.9 contrast with a pooled analysis of 19 cohort studies (15 U.S., 1976–2002) from the National Cancer Cohort Consortium [4], which found increased risk of mortality for BMI of 25.0–27.4 (HR for men: 1.06, women: 1.09) and 27.5–29.9 (men: 1.21, women: 1.19). Our results also contrast with the two largest landmark U.S. cohort studies, the NIH-AARP cohort [6,24] (data from 1995–2005) and the Cancer Prevention Study II (1982–1996) [3], both of which found 4–28% increased risk of mortality among BMI groups ≥25. Three large meta-analyses on BMI and all-cause mortality have been conducted in the past decade, utilizing studies from the 1960s through the 1990s [5,6,9]. North American results were largely driven by the aforementioned Cancer Prevention Study II and NIH-AARP cohorts. Our findings were similar to those from a meta-analysis by Flegal et al. [6] (data through 2012) and also to a representative NHANES study with data through the year 2000 [25], which both found similar or lower mortality risk for overweight BMI, although these studies used different reference BMI categories and confounding adjustments. As our statistical approach is similar to the landmark U.S. studies employing the bias adjustments recommended by the Global BMI Mortality Collaboration, the contrasting results are not likely to be explained by methodological differences.

In subgroup analyses, we found that older adults (≥65 years) demonstrated a wider range of minimally changed mortality risk than younger adults. In the NIH-AARP study, among 66–70-year-olds, mortality risk was similar for BMI of 25.0–26.4 compared to a reference of 23.5–24.9. However, they found increased risk of mortality for BMI ≥26.5 in both men and women [24]. In contrast, a recent 2014 meta-analysis by Winter et al. showed that among adults aged ≥65 worldwide, BMI through 30.0 was associated with 4–9% decreased mortality risk compared to a reference of 23.0–23.9 [7]. Although our findings were in the same direction, they were not statistically significant (as were those of Winter et al.), likely because we performed rigorous adjustments and included a broader reference of 22.5–24.9, which may have captured a healthier reference population. Nonetheless, these cohorts, other studies in older adults [26,27], and our findings have consistently shown no significantly different mortality risk for overweight-range BMI. Among younger adults, while BMI of 25–27.4 was not associated with increased mortality, there was nearly 20% higher mortality risk for young adults with a BMI of 27.5–29.9, which is consistent with effect measures from the pooled analysis of the National Cancer Cohort Consortium.

There are several plausible reasons why participants with higher BMI (25.0–34.9) may have all-cause mortality risk similar to those with conventionally normal BMI (18.5–24.9): (1) overweight individuals may have survival advantages in various adverse circumstances, such as critical illness, major morbidities, and severe infection [28,29] that are not offset by the increased risk of chronic metabolic diseases; (2) overweight individuals without disease may be metabolically healthy and have a more favorable body composition consisting of higher lean mass [30]. Further, BMI alone may be insufficient in classifying high-risk adiposity–both waist circumference [31,32] and weight change over time can modify BMI-mortality associations, as seen in our NHANES findings; (3) lean individuals who develop diseases such as hypertension or diabetes may have more aggressive or treatment-resistant disease, whereas overweight or obese individuals who develop such conditions may be able to manage or even reverse disease with weight loss strategies [33,34]; (4) finally, the U.S. population has become much more diverse, with greater representation of ethnic minorities and older adults in our cohort with potentially different body compositions [35] compared to previous cohorts. In fact, one limitation of prior U.S. studies is a lack of racial diversity and representativeness of the changing demographic landscape. Our study included >100,000 minority adults, who exhibited lower mortality risk at overweight and obese BMIs compared to non-Hispanic White adults. This finding is consistent with data from Calle et al. [7] and with subgroup analyses from other large U.S. cohort studies [36,37].

Our study had several limitations. First, all study data in the NHIS, including BMI, was self-reported, potentially leading to misclassification [38,39]. Nevertheless, the majority of prior landmark studies have used self-reported data and have also found high correlations between findings using measured vs. self-reported BMI [7]. Further, our NHANES results, which used measured BMI, were largely similar to those from the NHIS. Second, our study had shorter follow-up than some previous studies and thus may underestimate risk of mortality in higher-BMI groups due to residual effects of occult disease. Despite the shorter follow-up, we were able to exclude early deaths without greatly compromising sample size, and more than 40% of our study participants had at least ten years of follow-up. Third, in our NHIS analysis, we analyzed BMI from a single time point. While this practice is standard across prior landmark U.S. studies, weight trajectory over time may also be relevant to the association between BMI and mortality. Our NHANES analyses using maximum lifetime BMI showed minimal change in parameter estimates. Lastly, there is a possibility of residual confounding and lack of exclusion of occult disease, as NHIS data was self-reported and likely underestimate true disease burden. However, we found that findings were sensitive to more restrictive definitions of ‘healthy’ individuals using medication and laboratory data in the NHANES population, suggesting that the effect of underestimated disease burden is likely to be minimal.

In conclusion, our findings suggest that BMI in the overweight range is generally not associated with increased risk of all-cause mortality. Our study suggests that BMI may not necessarily increase mortality independently of other risk factors in those with BMI of 25.0–29.9 and in older adults with BMI of 25.0–34.9. Consequently, this highlights the potential limitations of BMI in capturing true adiposity and limitations of its clinical value independent of traditional metabolic syndrome criteria. Longitudinal studies incorporating weight history, complementary measures of body composition and body fat distribution (e.g. waist circumference, waist-to-hip ratio), undermeasured consequences of weight (e.g. psychological toll of obesity [40]), and morbidity outcomes are needed to fully characterize the relationship between BMI and mortality.

Supporting information

S1 Appendix. Extended supplementary methods.

(DOCX)

S2 Appendix. S1-S4 Figs and S1-S10 Tables.

(DOCX)

Data Availability

The datasets generated and analyzed during the current study are publicly available at the National Health Interview Survey (NHIS) official website: https://www.cdc.gov/nchs/nhis/nhis_2011_data_release.htm.

Funding Statement

The author(s) received no specific funding for this work.

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Decision Letter 0

Samantha Frances Ehrlich

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8 Nov 2022

PONE-D-22-25310

Body Mass Index and All-cause Mortality in a 21st Century U.S. Population: A National Health Interview Survey Analysis

PLOS ONE

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Reviewer #1: Thank you for the opportunity to review “Body Mass Index and All-cause Mortality in a 21st Century U.S. Population: A National Health Interview Survey Analysis”. I commend the authors on their study in using representative data to elucidate the associations between BMI and mortality. This study provides a much-needed update to the greater scientific communities understanding of BMI and mortality. Below are my comments, questions, and suggestions.

Overall

The proposed novelty of the study is the use of a more contemporary sample of the U.S. population compared to what has been previously seen in the literature. Authors state that “nearly all U.S. studies to date used data from the 1960s through the 1990s and have included predominantly non-Hispanic White men and women.” I think that this is generally true. However, there are some studies utilizing more contemporary national surveillance data sets that also examine hazard ratios specific to race-ethnic groups (see references below). I suggest reframing the introduction to account for these three studies while also simultaneously highlighting how you study accounts for limitations of them (e.g. Linked mortality data through 2019, subgroup analyses by gender and race-ethnicity, use of a more liberal categorization of BMI to examine a more precise dose-response relationship) In other words, I believe your study does a superb job of filling in some large gaps in the literature but does not highlight its strengths as much as it should.

Nguyen et al. Characterising the relationships between physiological indicators and all-cause mortality (NHANES): a population-based cohort study. Lancet Healthy Longev 2021; 2: e651–62. Study uses data from the 1999-2014 NHANES

Zheng et al. The Body Mass Index-Mortality Link across the Life Course: Two Selection Biases and Their Effects. Uses 1999-2010 NHANES

Howell et al. Maximum Lifetime Body Mass Index and Mortality in Mexican American Adults: the National Health and Nutrition Examination Survey III (1988–1994) and NHANES 1999–2010. Uses 199-2010 NHANES data

Suggest changing subjects to particpants

Abstract

No suggestions

Introduction

See “overall” comments. The addition of the three suggested studies to your references highlights that, yes there are some contemporary population-based studies that attempt to answer this question but still have limitations that your study circumvents. A couple of sentences discussing theses studies and their limitations would strengthen your rationale.

Methods

Were the STROBE guidelines followed for this study?

Suggest providing the references that detail the linking methodology for the NDI to the NHIS.

There are some studies that suggest the use of two years for mortality during follow-up exclusion may not be enough to control for residual confounding. Did you perform any sensitivity analysis with a larger follow-up time?

5 years exclusion criteria: Di Angelantonio E, Bhupathiraju SN, Wormser D, Gao P, Kaptoge S, De Gonzalez AB, Cairns BJ, Huxley R, Jackson CL, Joshy G, Lewington S. Body-mass index and all-cause mortality: individual-participant-data meta-analysis of 239 prospective studies in four continents. The Lancet. 2016 Aug 20;388(10046):776-86.

I’m wondering if having the NHANES analysis as a secondary, sensitivity analysis diminishes its potential impact. Why not include it in your abstract and primary methods? Other studies have done this. The results from your NHANES analysis are quite impactful. It is possible that it is a space issue. Nonetheless, the NHANES analysis provides good results.

I understand the rationale for not adjusting for comorbidities in the main analysis but why not conduct subgroup analysis by disease status (e.g. CVD, cancer, diabetes, hypertension) similar to Calle et al.? It seems you might have done this in your results for diabetes and hypertension (See first comment under results heading) but there is nothing written about it. It might be prudent to see if the dose-response seen in the overall sample holds when you restrict analysis to those with disease.

Calle EE, Thun MJ, Petrelli JM, Rodriguez C, Heath Jr CW. Body-mass index and mortality in a prospective cohort of US adults. New England Journal of Medicine. 1999 Oct 7;341(15):1097-105

Results

Page six, third paragraph seems to be missing results. “Upon additionally controlling for comorbidities including diabetes and hypertension,” there are no results listed after this.

Discussion

No suggestions

Reviewer #2: This manuscript examined the risk of all-cause mortality associated with body mass index using the 1999-2018 NHIS datasets linked to the NDI. BMI, classified into 9 categories, was found to only have increased risk at or above 30 BMI.

Overall Comments. I found this study to be nicely written and of sound methodology. The results and discussion, while brief, were well organized and most appropriate. My only comments, mentioned below, focus on adding a bit more detail.

Comments

** Page 5: Covariates. I understand the need for the supplement, but I recommend that a bit more detail be added on the covariates. Just mentioning them would be fine knowing that readers can seek out the supplement to learn about the details of specific categories.

88 Page 5: Statistical Procedures. Please provide more detail on the analyses and procedures that were used within SAS.

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Reviewer #2: No

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Attachment

Submitted filename: Plos One review.docx

PLoS One. 2023 Jul 5;18(7):e0287218. doi: 10.1371/journal.pone.0287218.r002

Author response to Decision Letter 0


2 Feb 2023

Please see response to reviewer file. Pasted below:

Responses to Reviewer #1

1. The proposed novelty of the study is the use of a more contemporary sample of the U.S. population compared to what has been previously seen in the literature. Authors state that “nearly all U.S. studies to date used data from the 1960s through the 1990s and have included predominantly non-Hispanic White men and women.” I think that this is generally true. However, there are some studies utilizing more contemporary national surveillance data sets that also examine hazard ratios specific to race-ethnic groups (see references below). I suggest reframing the introduction to account for these three studies while also simultaneously highlighting how you study accounts for limitations of them (e.g. Linked mortality data through 2019, subgroup analyses by gender and race-ethnicity, use of a more liberal categorization of BMI to examine a more precise dose-response relationship) In other words, I believe your study does a superb job of filling in some large gaps in the literature but does not highlight its strengths as much as it should.

Thank you for your thorough review of our manuscript. It was much appreciated by our research team. We have now reframed the introduction to better address newer studies that have utilized data from the 2000-2010s, including the ones you shared. As you mentioned, some strengths of our study beyond the more recent study period include 1) subgroup analyses with sufficient power given our large sample size. NHANES data, while rich in clinical information, is far smaller than the NHIS data used in our primary analysis, and 2) comprehensive adjustment for bias and confirmation of findings in both NHIS and NHANES datasets.

Revision:

“Of the few studies using more contemporary populations15-87, they were restricted by small sample sizes limiting analysis in racial and gender subgroups, had inadequate adjustment for methodologic bias including reverse causality, collider bias, effect modification, and the healthy person effect, and/or only rudimentarily characterized the dose-response relationship between BMI and mortality.” (Introduction, Paragraph 2, Page 3)

2. Suggest changing subjects to particpants

Thank you for this suggestion. We have now changed the term ‘subjects’ to ‘participants’ throughout the manuscript text.

3. Introduction: See “overall” comments. The addition of the three suggested studies to your references highlights that, yes there are some contemporary population-based studies that attempt to answer this question but still have limitations that your study circumvents. A couple of sentences discussing theses studies and their limitations would strengthen your rationale.

Thank you again for the suggestion. As noted above, we have changed the introduction to reflect the three studies suggested as well as one other study we found upon literature review.

4. Were the STROBE guidelines followed for this study?

Yes, we made sure to use the STROBE guidelines checklist while preparing the manuscript.

5. Suggest providing the references that detail the linking methodology for the NDI to the NHIS.

Thank you for this suggestion. We have now included the citation for the analytic file detailing the linking methodology for NDI to any National Center for Health Statistics (NCHS) survey.

Citation: National Center for Health Statistics. The Linkage of National Center for Health Statistics Survey Data to the National Death Index — 2019 Linked Mortality File (LMF): Linkage Methodology and Analytic Considerations, June 2022. Hyattsville, Maryland. Available at the following address: https://www.cdc.gov/nchs/data-linkage/mortality-methods.htm.

6. There are some studies that suggest the use of two years for mortality during follow-up exclusion may not be enough to control for residual confounding. Did you perform any sensitivity analysis with a larger follow-up time?

Thanks for this insightful comment. We did conduct several sensitivity analyses to account for reverse causality and residual confounding, including increasing the follow-up exclusion to 5 years as was done in the meta-analysis referenced. Exclusion of early deaths is a technique to try and account for subclinical/undiagnosed disease that may lead to weight loss and thus disproportionately contribute to lower BMI groups. However, we did not find any significant change in risk of mortality across any of the BMI categories. Several studies have noted similar findings – that increasing the exclusion follow-up time period may not significantly impact risks; however, it can lead to significant selection bias because a sizeable portion of the population can be excluded. We thus opted not to exclude 5 years of follow-up. To clarify this further, we explained this in more detail in the discussion and also included a supplementary table S10 that excludes the first 5 years of deaths.

Revisions:

“To examine the potential impact of reverse causality due to subclinical disease, we conducted analyses limited to participants who did not die within the first two years of follow-up. Although some prior meta-analyses have excluded the first five years of follow-up, there has been concern that such exclusions would lead to significant selection bias as a sizeable proportion of the study population would be excluded, without significant benefit in reducing reverse causality. Nevertheless, we conducted sensitivity analyses excluding the first five years of follow-up.” (Methods, Statistical Analysis, Paragraph 3, pg. 5)

See Supplementary Table S10.

7. I’m wondering if having the NHANES analysis as a secondary, sensitivity analysis diminishes its potential impact. Why not include it in your abstract and primary methods? Other studies have done this. The results from your NHANES analysis are quite impactful. It is possible that it is a space issue. Nonetheless, the NHANES analysis provides good results.

Thank you for this comment. We agree with your assessment that the NHANES results are quite impactful and provide further insight complementary to NHIS findings. However, due to word count/table limitations, we could not include it in the primary analysis and is instead in the supplement. We felt the NHIS, given its large sample size, provided much more robust estimates and allowed for subgroup analyses so it was used as the primary analysis.

8. I understand the rationale for not adjusting for comorbidities in the main analysis but why not conduct subgroup analysis by disease status (e.g. CVD, cancer, diabetes, hypertension) similar to Calle et al.? It seems you might have done this in your results for diabetes and hypertension (See first comment under results heading) but there is nothing written about it. It might be prudent to see if the dose-response seen in the overall sample holds when you restrict analysis to those with disease.

Thank you for this comment. We in fact did do subgroup analyses by disease status as determined by Calle et al., Berrington de Gonzalez et al., and our own more rigorous definition of disease. We acknowledge that this was likely not clear in the manuscript, so we have clarified this now in the revised manuscript. All figures in the main analysis have a subgroup of healthy, never-smokers who do not have CVD or cancer. In the supplementary file, Figure S2 shows the BMI-mortality associations by disease-free status. The red line depicts never-smoking individuals without minor morbidity, defined as self-reported history of cardiovascular disease, non-skin cancer except melanoma, COPD, current asthma, liver disease, kidney disease, diabetes, or functional limitations. The blue line depicts never-smoking participants without major morbidity, defined via Berrington de Gonzalez et al. as self-reported history of cardiovascular disease and non-skin cancer except melanoma. We did not show individuals with disease because of the aforementioned biases of reverse causality and confounding by pre-existing disease. Although we do not show the data, we did conduct the analysis which showed the BMI-mortality curve shifts downwards, suggesting more inverse associations with mortality at overweight BMI ranges. However, this is more likely to be due to confounding than a true inverse association.

Revision:

“We further conducted analyses among subgroups of disease-free individuals, utilizing different definitions of disease: minor morbidity, defined as self-reported history of cardiovascular disease, non-skin cancer except melanoma, COPD, current asthma, liver disease, kidney disease, diabetes, or functional limitations; and major morbidity, defined via Berrington de Gonzalez et al.4 as self-reported history of cardiovascular disease and non-skin cancer except melanoma.” (Methods, Statistical Analysis, Paragraph 2, Pg. 4)

9. Results: Page six, third paragraph seems to be missing results. “Upon additionally controlling for comorbidities including diabetes and hypertension,” there are no results listed after this.

Thank you for catching this typo. We had initially intended on deleting the sentence completely. However, we have now updated the text to complete the sentence to illustrate the concept of collider bias. This was meant to be more of a sensitivity analysis as adjustment for obesity-related comorbidities such as diabetes and hypertension would likely lead to collider bias, leading to the appearance that mortality risks are lower than they really are.

Revision:

“Upon additionally controlling for comorbidities including diabetes and hypertension (potential colliders), risk of mortality marginally decreased among overweight BMI categories (BMI 20.0-22.4: 1.10 [1.03,1.19], BMI 22.5-24.9: 1.00 [Ref], BMI 25.0-27.4: 0.95 [0.89,1.00], BMI 27.5-29.9: 0.96 [0.90, 1.02]).” (Results, Paragraph 2, Page 6)

Responses to Reviewer #2

10. Page 5: Covariates. I understand the need for the supplement, but I recommend that a bit more detail be added on the covariates. Just mentioning them would be fine knowing that readers can seek out the supplement to learn about the details of specific categories.

Thank you for this suggestion. We had included the list of covariates that we adjusted for in the Cox proportional hazards regression in the ‘Statistical Analysis’ section but realized that they were not explicitly mentioned in the Covariate subsection. We have now moved the text from the Statistical Analysis section to the Covariates subsection and provided more detail.

“Cox models were adjusted for age, gender, race/ethnicity, education, marital status, physical activity, alcohol consumption, insurance coverage, region of residence, and citizenship status.” (Methods, Statistical Analysis, Paragraph 1, pg. 4)

11. 88 Page 5: Statistical Procedures. Please provide more detail on the analyses and procedures that were used within SAS.

Thank you for this comment. We have now provided further information on the specific SAS analyses used.

Attachment

Submitted filename: BMI_mortality_PLOSOne_ResponsetoReviewer.docx

Decision Letter 1

Samantha Frances Ehrlich

16 Feb 2023

PONE-D-22-25310R1Body Mass Index and All-cause Mortality in a 21st Century U.S. Population: A National Health Interview Survey AnalysisPLOS ONE

Dear Dr. Visaria,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process. Please address my comments to revised manuscript (below).

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Journal Requirements:

Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript. If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice.

Additional Editor Comments (if provided):

Thank you for your careful consideration of the reviewers' comments.

Please add mention that the STRBE guidelines checklist was followed in preparing this manuscript.

In the Introduction, statements pertaining to racial diversity and racial subgroups (e.g., ‘more racially diverse’) should also include ‘ethnicity’ (e.g., ‘more racially and ethnically diverse’).

There is a statement in the Introduction, ‘inadequate adjustment for methodological bias including reverse causality, collider bias, effect modification, and health person effect’. Perhaps this needs to be split into several sentences in order to clarify the points being made. For one, effect modification is not a methodological bias (though an inadequate sample size to investigate effect modification would be a limitation to prior work).

For the covariates paragraph (i.e., just prior to the ‘Statistical Analysis’ section): I suggest rephrasing ‘non-skin cancer except melanoma’ for clarity (here and throughout the manuscript, I believe this adjustment includes cancers at various sites but only melanoma for skin cancer). I also suggest including clarification of the ‘healthcare utilization factor’ variable (in parenthesis, as is done for the other covariates). Please indicate the specific supplement section where the covariate categorization is provided (and throughout the manuscript, for all mentions of ‘provided in the supplement’, please state a specific supplement section).

In the Statistical Analysis section, ‘we did not adjust for comorbidities in the main analysis, as they could be on the causal pathway between BMI and mortality or potential colliders’: Without including a DAG and explanation of potential intermediate variables at play, it is difficult to follow the potential collider argument. BMI may be causally associated with a comorbidity, such as diabetes (i.e., an arrow from BMI leading to diabetes), and diabetes causally associated with mortality (i.e., an arrow from diabetes to mortality, the causal pathway argument). However, I find it hard to justify an arrow stemming from mortality to diabetes, indicating that mortality is ‘causing’ diabetes, which would be the case if diabetes were hypothesized to be a collider here. I suggest clarifying with a DAG or removing all reference to collider bias.

Also in the Statistical Analysis section: ‘To examine the potential impact of reverse causality due to subclinical disease…’, I suggest including mention/brief clarification of what is meant by the term ‘reverse causality’, as eloquently described by your reference, Banack et al. 2019:

‘in the context of obesity-mortality research, the term reverse causality is often used to refer to a situation in which disease status affects both exposure and outcome, because disease often causes weight loss and disease increases mortality risk. Despite being called reverse causality, this is actually a concept that fits the standard definition of confounding in epidemiology…. This is why, in the context of obesity-mortality studies, the phrase reverse causality is often used interchangeably with the terms “confounding by preexisting disease” or “confounding by illness-related weight loss”

The readership of PLOS One includes epidemiologists, obesity-mortality researchers, and others, and without clarification, the language may be confusing to some.

In the Results section, characteristics: ‘Between the first four-year cycle (1999-2002) and the last cycle (2015-2018), mean BMI rose from 26.7 to 28.0 kg/m2 and prevalence of BMI of ≥30 increased from 22% to 31% (p<0.001 for trend; Supplementary Figure S1). Nearly 21% had BMI of 25.0-27.4, and 14% had BMI of 27.5-29.9.’ Supplementary Table S1 displays Mortality Rates by Subgroups, and Supplementary Table S2 displays Mortality Rates by Survey Cycle Year. Neither of these tables presents prevalence estimates directly (though these can be calculated from the data included in Table 2) so I wonder if the Supplementary Figure S1 reference here was in error? Could you clarify whether, ‘Nearly 21% had BMI of 25.0-27.4, and 14% had BMI of 27.5-29.9’ encompasses prevalence estimates for all years combined?

In the Results section, Race/ethnicity: Supplementary Table S1 does not present five-year mortality rates and unadjusted risks by race/ethnicity, please add these data or indicate ‘data not show’ (though I prefer adding the data). Did the difference between Hispanic adults with BMIs from 25.0 to 29.9 vs. other groups attain statistical significance? Was this examined with a cross product?

Discussion section: As you suggest, time period effects (e.g., differences in the racial ethnic make-up of the U.S. population over time) may explain the contrasting results, therefore mention of the time period under study for all prior work would be help to include (i.e., the meta-analysis by Flegal et al. covered what time frame/period?).

Discussion section: ‘weight change over time can both confound associations with mortality’ is confusing as written, please clarify.

Discussion section: Second to last paragraph, ‘In summary, our study of a contemporary representative….’ includes recommendations and conclusions outside of the scope of the data presented here (e.g., ‘Clinicians patients may benefit from using complementary measures of adiposity…’ and ‘guidance on management of overweight and obesity’). I suggest removing this paragraph and including mention of the limitations of BMI as a measure in the previous paragraph (or elsewhere). The last paragraph does a lovely job of summarizing the main take away points from these data and analyses.

[Note: HTML markup is below. Please do not edit.]

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PLoS One. 2023 Jul 5;18(7):e0287218. doi: 10.1371/journal.pone.0287218.r004

Author response to Decision Letter 1


28 May 2023

Responses to Reviewer and Editor Comments:

1. Please add mention that the STRBE guidelines checklist was followed in preparing this manuscript.

Thank you for this suggestion. We have now included a sentence in the Methods section confirming we have used the STROBE guidelines checklist.

2. In the Introduction, statements pertaining to racial diversity and racial subgroups (e.g., ‘more racially diverse’) should also include ‘ethnicity’ (e.g., ‘more racially and ethnically diverse’).

Thank you for pointing out this oversight. We have now included ‘ethnicity’ in the mentioned sentence.

Revision: “In contrast, the contemporary U.S. population: (1) has a substantially different BMI distribution, with mean BMI having risen by more than 2 kg/m2 in both men and women since the 1970s, and increasing skewness towards obese-range BMIs; (2) has seen >10 year increases in life expectancy both overall and among obese individuals; (3) is more racially and ethnically diverse…” (Introduction, Page 3)

3. There is a statement in the Introduction, ‘inadequate adjustment for methodological bias including reverse causality, collider bias, effect modification, and health person effect’. Perhaps this needs to be split into several sentences in order to clarify the points being made. For one, effect modification is not a methodological bias (though an inadequate sample size to investigate effect modification would be a limitation to prior work).

Thank you for this comment. We have now changed the wording of the sentence and provided more descriptions of each of the sources of bias.

Revision: “Of the few studies using more contemporary populations, they were either restricted by small sample sizes limiting analysis in racial and gender subgroups, and/or only rudimentarily characterized the dose-response relationship between BMI and mortality. Furthermore, studies inconsistently adjusted for methodologic bias including confounding by illness-related weight loss, collider bias (e.g. the concept that conditioning on obesity-related disease may distort associations between risk factors like BMI and diet and subsequently bias downstream associations), and the healthy person effect (e.g. selection bias that may be introduced when selecting participants of different BMI groups who may otherwise be healthy).” (Introduction, Page 3)

4. For the covariates paragraph (i.e., just prior to the ‘Statistical Analysis’ section): I suggest rephrasing ‘non-skin cancer except melanoma’ for clarity (here and throughout the manuscript, I believe this adjustment includes cancers at various sites but only melanoma for skin cancer). I also suggest including clarification of the ‘healthcare utilization factor’ variable (in parenthesis, as is done for the other covariates). Please indicate the specific supplement section where the covariate categorization is provided (and throughout the manuscript, for all mentions of ‘provided in the supplement’, please state a specific supplement section).

Thank you for this comment. We have clarified the phrasing of the cancer comorbidity covariate to read as “non-skin cancer or melanoma”. We have also included a description of the healthcare utilization factors included in our analysis, and specified the specific supplement section to be referenced.

Revision: “…comorbidities (self-reported history of cardiovascular disease, non-skin cancer or melanoma, COPD, current asthma, liver disease, kidney disease, diabetes, or functional limitations), and healthcare utilization factors (doctor’s visit in the past 12 months, mental health visit in the past 12 months). Covariate categorizations are provided in the supplement (Extended Supplementary Methods)” (Methods, BMI, Mortality, and Covariates, Page 4)

5. In the Statistical Analysis section, ‘we did not adjust for comorbidities in the main analysis, as they could be on the causal pathway between BMI and mortality or potential colliders’: Without including a DAG and explanation of potential intermediate variables at play, it is difficult to follow the potential collider argument. BMI may be causally associated with a comorbidity, such as diabetes (i.e., an arrow from BMI leading to diabetes), and diabetes causally associated with mortality (i.e., an arrow from diabetes to mortality, the causal pathway argument). However, I find it hard to justify an arrow stemming from mortality to diabetes, indicating that mortality is ‘causing’ diabetes, which would be the case if diabetes were hypothesized to be a collider here. I suggest clarifying with a DAG or removing all reference to collider bias.

Thank you for this thoughtful comment. We have now included a DAG in the Supplement (Supplementary Figure S1) to illustrate the ways in which intermediary conditions such as diabetes and hypertension may be colliders. Briefly, we can posit that BMI is causally associated with diabetes and diabetes is causally associated with mortality. If there is an unmeasured confounder, such as poor nutrition, that is associated with BMI, and is causally associated with diabetes and mortality, diabetes becomes a collider (BMI and poor nutrition ‘collide’ on diabetes). Adjusting for diabetes but not for diet (as it is unmeasured) may create a spurious association between BMI and diet and affect the association between BMI and mortality through this pathway. Preston and Stokes explain this phenomenon in much greater detail and more eloquently in the following paper: Preston SH, Stokes A. Obesity paradox: conditioning on disease enhances biases in estimating the mortality risks of obesity. Epidemiology (Cambridge, Mass.). 2014 May;25(3):454.

Revision: “Consistent with prior studies, we did not adjust for comorbidities in the main analysis, as they could be on the causal pathway between BMI and mortality or potential colliders for BMI and unmeasured confounders3-5 (Supplementary Figure S1).”

Figure caption: The following figure is a crude representation of our proposed DAG for the association between BMI and all-cause mortality. We can assume BMI is causally associated with diabetes and diabetes is causally associated with mortality. If there is an unmeasured confounder, such as poor nutrition, that is associated with BMI, and is causally associated with diabetes and mortality, diabetes becomes a collider (BMI and poor nutrition ‘collide’ on diabetes). Adjusting for diabetes but not for diet (as it is unmeasured) may create a spurious association between BMI and diet and affect the association between BMI and mortality through this pathway. Preston and Stokes explain this phenomenon in much greater detail and more eloquently in the following paper: Preston SH, Stokes A. Obesity paradox: conditioning on disease enhances biases in estimating the mortality risks of obesity. Epidemiology (Cambridge, Mass.). 2014 May;25(3):454.

6. Also in the Statistical Analysis section: ‘To examine the potential impact of reverse causality due to subclinical disease…’, I suggest including mention/brief clarification of what is meant by the term ‘reverse causality’, as eloquently described by your reference, Banack et al. 2019:

‘in the context of obesity-mortality research, the term reverse causality is often used to refer to a situation in which disease status affects both exposure and outcome, because disease often causes weight loss and disease increases mortality risk. Despite being called reverse causality, this is actually a concept that fits the standard definition of confounding in epidemiology…. This is why, in the context of obesity-mortality studies, the phrase reverse causality is often used interchangeably with the terms “confounding by preexisting disease” or “confounding by illness-related weight loss”

The readership of PLOS One includes epidemiologists, obesity-mortality researchers, and others, and without clarification, the language may be confusing to some.

Thank you for this clarification. We have now changed or supplemented all reference to ‘reverse causality’ with ‘confounding by illness-related weight loss’ which we feel is definitely more intuitive to understand and can be appreciated by all readers.

Revision: “To examine the potential impact of reverse causality (i.e. confounding by illness-related weight loss), we conducted analyses limited to participants who did not die within the first two years of follow-up.” (Methods, Statistical Analysis, Page 5)

Revision: “Furthermore, studies inconsistently adjusted for methodologic bias including confounding by illness-related weight loss, collider bias…” (Introduction, Page 3)

7. In the Results section, characteristics: ‘Between the first four-year cycle (1999-2002) and the last cycle (2015-2018), mean BMI rose from 26.7 to 28.0 kg/m2 and prevalence of BMI of ≥30 increased from 22% to 31% (p<0.001 for trend; Supplementary Figure S1). Nearly 21% had BMI of 25.0-27.4, and 14% had BMI of 27.5-29.9.’ Supplementary Table S1 displays Mortality Rates by Subgroups, and Supplementary Table S2 displays Mortality Rates by Survey Cycle Year. Neither of these tables presents prevalence estimates directly (though these can be calculated from the data included in Table 2) so I wonder if the Supplementary Figure S1 reference here was in error? Could you clarify whether, ‘Nearly 21% had BMI of 25.0-27.4, and 14% had BMI of 27.5-29.9’ encompasses prevalence estimates for all years combined?

Thank you for pointing this out. Supplementary Figure S1 (now Supplementary Figure S2) Panel C shows the distribution of BMI from the first four-year cycle to the last. We realize that it is not possible to calculate the mean BMI or the percent increase in BMI>=30 visually from that so we have now removed reference to Figure S1. The statement, “Nearly 21% had BMI of 25.0-27.4, and 14% had BMI of 27.5-29.9’ encompasses prevalence estimates for all years combined” refers to the prevalence for all years combined and is from Table 1.

Revision: “Between the first four-year cycle (1999-2002) and the last cycle (2015-2018), mean BMI rose from 26.7 to 28.0 kg/m2 and prevalence of BMI of ≥30 increased from 22% to 31% (p<0.001 for trend; see Supplementary Figure S2 for distribution of BMI). Nearly 21% had BMI of 25.0-27.4, and 14% had BMI of 27.5-29.9 (Table 1).” (Results, Sample Characteristics, Page 5)

In the Results section, Race/ethnicity: Supplementary Table S1 does not present five-year mortality rates and unadjusted risks by race/ethnicity, please add these data or indicate ‘data not show’ (though I prefer adding the data). Did the difference between Hispanic adults with BMIs from 25.0 to 29.9 vs. other groups attain statistical significance? Was this examined with a cross product?

Thanks for pointing out this oversight. We had included some data in the supplementary text underneath Supplementary Table S1 that we have now included in the main text: “Among non-Hispanic White, non-Hispanic Black, and Hispanic participants, 5-year mortality was highest in those with BMI <18.5 (White: 40 [95% CI, 38-43] per 1,000 person-years, Black: 43 [37-50], Hispanic: 20 [16-25]). Five-year mortality was lowest at 11.7 (11.2-12.2) among those with BMI of 30.0-34.9 in White adults and 10.0 (8.8-11.3) at BMI of 35.0-39.9 in Black adults, and 7.1 [6.5-7.8] in Hispanic adults.”

The multiplicative interaction (cross-product) between race/ethnicity and BMI on all-cause mortality did not reach significance after adjustment for covariates. However, we felt it was still important to include racial/ethnic subgroups because of the well-studied racial/ethnic differences in various components of body composition and CV risk factors. We have now more explicitly stated that in the text.

Revision: “These patterns persisted, albeit insignificantly, after adjustment (Figure 4, P-interaction = 0.21).” (Results, Race/ethnicity, Page 6)

8. Discussion section: As you suggest, time period effects (e.g., differences in the racial ethnic make-up of the U.S. population over time) may explain the contrasting results, therefore mention of the time period under study for all prior work would be help to include (i.e., the meta-analysis by Flegal et al. covered what time frame/period?).

Thank you for this comment. We have now included the time periods for all the referenced studies in the discussion section.

9. Discussion section: ‘weight change over time can both confound associations with mortality’ is confusing as written, please clarify.

Apologies for the confusing wording. We have now changed the wording slightly to have it read better.

Revision: “Further, BMI alone may be insufficient in classifying high-risk adiposity – both waist circumference31,32 and weight change over time can modify associations BMI-mortality associations, as seen in our NHANES findings” (Discussion, Page 8)

10. Discussion section: Second to last paragraph, ‘In summary, our study of a contemporary representative….’ includes recommendations and conclusions outside of the scope of the data presented here (e.g., ‘Clinicians patients may benefit from using complementary measures of adiposity…’ and ‘guidance on management of overweight and obesity’). I suggest removing this paragraph and including mention of the limitations of BMI as a measure in the previous paragraph (or elsewhere). The last paragraph does a lovely job of summarizing the main take away points from these data and analyses.

Thank you for this comment. We have adjusted the final two paragraphs of the discussion to exclude any out-of-scope implications and combined them into one paragraph.

Revision: “In conclusion, our findings suggest that BMI in the overweight range is generally not associated with increased risk of all-cause mortality. Our study suggests that BMI may not necessarily increase mortality independently of other risk factors in those with BMI of 25.0-29.9 and in older adults with BMI of 25.0-34.9. Consequently, this highlights the potential limitations of BMI in capturing true adiposity and limitations of its clinical value independent of traditional metabolic syndrome criteria. Longitudinal studies incorporating weight history, complementary measures of body composition and body fat distribution (e.g. waist circumference, waist-to-hip ratio), undermeasured consequences of weight (e.g. psychological toll of obesity), and morbidity outcomes are needed to fully characterize the relationship between BMI and mortality.” (Discussion, Page 8-9).

Attachment

Submitted filename: BMI_mortality_PLOSOne_ResponsetoReviewer_5.28.docx

Decision Letter 2

Samantha Frances Ehrlich

2 Jun 2023

Body Mass Index and All-cause Mortality in a 21st Century U.S. Population: A National Health Interview Survey Analysis

PONE-D-22-25310R2

Dear Dr. Visaria,

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Additional Editor Comments (optional):

Thank you for carefully addressing our comments.

Reviewers' comments:

Acceptance letter

Samantha Frances Ehrlich

9 Jun 2023

PONE-D-22-25310R2

Body Mass Index and All-cause Mortality in a 21st Century U.S. Population: A National Health Interview Survey Analysis

Dear Dr. Visaria:

I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department.

If your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information please contact onepress@plos.org.

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Kind regards,

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on behalf of

Dr. Samantha Frances Ehrlich

Academic Editor

PLOS ONE

Associated Data

    This section collects any data citations, data availability statements, or supplementary materials included in this article.

    Supplementary Materials

    S1 Appendix. Extended supplementary methods.

    (DOCX)

    S2 Appendix. S1-S4 Figs and S1-S10 Tables.

    (DOCX)

    Attachment

    Submitted filename: Plos One review.docx

    Attachment

    Submitted filename: BMI_mortality_PLOSOne_ResponsetoReviewer.docx

    Attachment

    Submitted filename: BMI_mortality_PLOSOne_ResponsetoReviewer_5.28.docx

    Data Availability Statement

    The datasets generated and analyzed during the current study are publicly available at the National Health Interview Survey (NHIS) official website: https://www.cdc.gov/nchs/nhis/nhis_2011_data_release.htm.


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