Confidential: For Review OnlyWeight change across adulthood in relation to all cause and cause specific mortality: a prospective cohort study of U.S.
adults
Journal: BMJ
Manuscript ID BMJ-2019-050369
Article Type: Research
BMJ Journal: BMJ
Date Submitted by the Author: 23-Apr-2019
Complete List of Authors: Chen, Chen; Huazhong University of Science and Technology, School of Public HealthYe, Yi; Huazhong University of Science and Technology, School of Public HealthZhang, Yanbo; Huazhong University of Science and Technology, School of Public HealthPan, Xiong-Fei; Huazhong University of Science and Technology, School of Public HealthPan, An; Huazhong University of Science and Technology, School of Public Health
Keywords: Cohort study, Mortality, Obesity, Weight change
https://mc.manuscriptcentral.com/bmj
BMJ
Confidential: For Review Only
1
Weight change across adulthood in relation to all cause and cause specific
mortality: a prospective cohort study of U.S. adults
Chen Chen MBBS, Yi Ye MBBS, Yanbo Zhang MBBS, Xiong-Fei Pan Postdoc researcher, An Pan
Professor
Affiliations: Department of Epidemiology and Biostatistics, School of Public Health, Tongji Medical
College, Huazhong University of Science and Technology, Wuhan, 430030, China; Key Laboratory of
Environment and Health, Ministry of Education & Ministry of Environmental Protection, School of
Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan,
430030, China
Correspondence: An Pan, Department of Epidemiology and Biostatistics, School of Public Health,
Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China;
telephone and fax numbers: +86-27-83627309; email: [email protected].
Key words: Body weight changes, Young adult, Middle Aged, Aged, Mortality
Word count: 4731
3 main tables, 2 main figures
Supplemental materials: tables S1-S10 and figures S1-S3
Page 1 of 58
https://mc.manuscriptcentral.com/bmj
BMJ
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
Confidential: For Review Only
2
What is already known on this topic
High body mass index in adulthood is associated with higher risk of premature deaths.
Scientific evidence about weight change from young to late adulthood or from middle to late
adulthood in relation to risk of mortality was not entirely consistent.
Little is known about associations between weight change across adulthood especially from
young to middle adulthood and all cause and cause specific mortality.
What this study adds
Weight gain from young to middle adulthood was associated with increased risk of mortality from
all cause, cardiovascular disease and cancer in US adults. Weight loss over this period was not
significantly related to mortality. Individuals who remained obese had the highest risk of mortality.
Across adulthood, association between weight gain and mortality attenuated with increasing age
while the association with weight loss became stronger and significant in middle to late adulthood.
Our results highlight the importance of maintaining normal weight across adulthood, especially
preventing weight gain in early adulthood, for preventing premature deaths in later life.
Page 2 of 58
https://mc.manuscriptcentral.com/bmj
BMJ
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
Confidential: For Review Only
3
ABSTRACT (word count 399)
OBJECTIVE
To investigate the association between weight changes across adulthood and mortality.
DESIGN
Prospective cohort study.
SETTING
U.S. National Health and Nutrition Examination Survey (NHANES) 1988-1994 and NHANES 1999-
2014.
POPULATION
36 812 participants aged 40 years or over who recalled their weight at young adulthood (at age 25
years) and at middle adulthood (at ten years prior to NHANES survey, mean age of 47 years) and had
measured weight at late adulthood (at baseline NHANES survey, mean age of 57 years).
MAIN OUTCOME MEASURES
All cause and cause specific mortality from baseline until 31 December 2015.
RESULTS
During a mean follow-up of 10 years, 10 936 deaths occurred. Compared with participants remaining
normal body mass index (BMI), those who gained weight from non-obese BMI at young adulthood to
obese BMI at middle adulthood had a 33% (hazard ratio 1.33, 95% confidence interval 1.22 to 1.45),
52% (1.52, 1.28 to 1.81) and 26% (1.26, 1.02 to 1.56) higher risk of all cause mortality, cardiovascular
mortality and cancer mortality respectively; losing from obese to non-obese BMI over this period was
not significantly associated with mortality risk. Similar results were found for the relations of mortality
with weight change from young to late adulthood. Weight loss from middle to late adulthood was
Page 3 of 58
https://mc.manuscriptcentral.com/bmj
BMJ
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
Confidential: For Review Only
4
associated with increased risk of all cause mortality (1.44, 1.28 to 1.61) and cardiovascular mortality
(1.66, 1.32 to 2.09). Weight gain with BMI moving from non-obese to obese category over this period
was unrelated to mortality. Maintaining an obese BMI in all three intervals was consistently associated
with increased risk of mortality, while the associations were stronger when stable obesity occurred
from young to middle adulthood (1.93, 1.72 to 2.16) or to late adulthood (1.81, 1.59 to 2.05) compared
to that from middle to late adulthood (1.33, 1.22 to 1.45). Maximum overweight individuals had a very
modest or null association with mortality across adulthood. The association between weight change and
mortality across adulthood was more pronounced among participants who were less than 60 years old
at baseline and never smokers compared to their counterparts.
CONCLUSIONS
Stable obesity across adulthood, weight gain from young to middle adulthood and weight loss from
middle to late adulthood were associated with increased risk of mortality. Our study implies that
maintaining normal weight across adulthood, especially preventing weight gain in early adulthood, is
important for preventing premature deaths in later life.
Page 4 of 58
https://mc.manuscriptcentral.com/bmj
BMJ
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
Confidential: For Review Only
5
Introduction
Obesity is a major global public health problem. The global prevalence of adult obesity has increased
from 3% in 1975 to 11% in 2016 among men and from 6% to 15% among women. In the United States,
the prevalence of adult obesity was 36% for men and 38% for women in 2016 compared with 11% for
men and 14% for women in 1975.1 The U-shape or J-shape relationship between body mass index (BMI)
and mortality has been well established.2 3 However, many previous cohort studies only included a single
time measurement of BMI, which ignored the dynamic feature of body weight over time. Thus more
studies are needed to assess the long-term consequence of weight change during certain life periods. A
recent meta-analysis of 26 prospective studies among participants aged 40 to 65 years old at baseline
reported that both weight loss and weight gain from middle adulthood to old age were related to elevated
mortality risk.4 Another meta-analysis of 17 prospective studies among adults aged 60 years or older also
reached similar conclusion.5 However, adults gain weight more rapidly from young adulthood to middle
adulthood and excess adiposity mostly accrues in this period compared with the period from middle to
late adulthood when weight begins to stabilize or decrease.6 In addition, the prevention of weight gain
from young to middle adulthood might be more important than promoting weight loss because achieving
long-term weight loss and maintenance is difficult once an individual becomes obese.7 Thus, it is
important to evaluate the long-term impact of weight change, particularly weight gain from young to
middle adulthood, on future health.
Although most previous cohort studies reported that weight gain from young adulthood to either
midlife or late adulthood was associated with increased mortality risk,8-11 the results were not entirely
consistent with some reporting no significant association.12 13 Some studies found that weight loss was
associated with increased mortality risk12 14 15 while others did not.10 11 In addition, some studies only had
Page 5 of 58
https://mc.manuscriptcentral.com/bmj
BMJ
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
Confidential: For Review Only
6
two measurements of weight (from young adulthood around 20 years old to baseline survey),9-11 14 or
used the trajectory analysis approach when there were more than two measures of weight,16 17 or were
conducted in specific groups rather than the general population.10 13 A previous study in the US National
Health and Nutrition Examination Survey (NHANES) 1988-2004 evaluated the relations of all cause
mortality with weight status at age 25, at ten years before baseline and at baseline survey among adults
with a baseline age of 50 to 74 years.18 However, this study focused on the statistical modeling of obesity
history and suggested that a duration model performed well in predicting mortality.
Using updated data from the NHANES 1988-2014, we aimed to examine the relations of weight
changes from young adulthood (age of 25 years) to midlife (mean age of 47 years) and to late adulthood
(mean age of 57 years) with all cause and cause specific mortality and explore how the impact of weight
history varies by age.
Subjects and Methods
Study Population
Details of the NHANES have been described elsewhere.19 Briefly, NHANES used a complex, multistage,
probability sampling method to collect nationally representative health-related data of US population. It
was conducted periodically before 1999 and on a continuous basis thereafter. Data were obtained by in-
person interview, mobile physical examination and laboratory tests.
In the current analysis, we only included participants aged 40 or over at baseline survey, i.e., 40 052
participants from the NHANES III (1988-1994) and continuous NHANES (1999-2014) datasets, given
that death mostly occurred in older adults. We excluded participants who received household interview
but did not participate in physical examination (n=3198). We further excluded individuals without
Page 6 of 58
https://mc.manuscriptcentral.com/bmj
BMJ
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
Confidential: For Review Only
7
mortality data (n=42). Therefore, a total of 36 812 participants remained in our analytic cohort
(supplementary figure 1).
Assessments of weight change and covariates
Data on weight at age 25 years and at ten years prior to baseline NHANES survey were recalled in
baseline surveys. Baseline weight, height and waist circumference were measured during mobile physical
examination. BMI at age 25 years (BMI25), at ten years before survey (BMI10prior, mean age of 47 years,
range 30 to 80, interquartile range 36 to56) and at survey (BMIbaseline, mean age of 57 years, range 40 to
90, interquartile range 46 to 66) were calculated as weight (kg) divided by the square of height (m2). We
categorized each of the three BMI variables into standard groups: underweight (<18.5 kg/m2), normal
weight (18.5-24.9 kg/m2), overweight (25.0-29.9 kg/m2) and obese (≥30.0 kg/m2).20 Waist circumference
was divided into quartiles. Information on covariates including age, sex, race/ethnicity, education level,
household income level, marital status, smoking status, drinking status, family history of chronic diseases
(only including family histories of diabetes and heart diseases which have been consistently collected in
various survey cycles) and self-reported baseline diseases of diabetes, hypertension, cardiovascular
disease (CVD), chronic obstructive pulmonary disease (COPD) and cancer was available through
questionnaires at survey.
We created weight change patterns for three time intervals: BMI25 to BMI10prior, BMI25 to BMIbaseline,
and BMI10prior to BMIbaseline. Using BMI at two time points, we defined five weight change patterns for
each of the three time intervals: stable normal (<25.0 kg/m2 at both times), maximum overweight (25.0-
29.9 kg/m2 at either time but not ≥30.0 kg/m2 at the other time), weight loss (≥30.0 kg/m2 at younger age
while <30.0 kg/m2 later), weight gain (<30.0 kg/m2 at younger age while ≥30.0 kg/m2 later), and stable
Page 7 of 58
https://mc.manuscriptcentral.com/bmj
BMJ
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
Confidential: For Review Only
8
obesity (≥30.0 kg/m2 at both times). The method has been described in detail in a previous publication
using the NHANES data.21 Based on a recent study conducted by Zheng et al,11 we also classified
absolute weight change in each time interval into five groups as the following: weight loss ≥2.5 kg,
weight loss or weight gain <2.5 kg (reference group), 2.5 kg≤ weight gain <10.0 kg, 10.0 kg≤ weight
gain <20.0 kg, and weight gain ≥20.0 kg.
Ascertainment of deaths
Mortality status was identified by probabilistic matching to the National Death Index through 31
December 2015 using a unique study identifier. Further details of the matching methodology are
available at the National Center for Health Statistics.22
Causes of deaths were classified according to the codes of International Statistical Classification of
Diseases and Related Health Problems, 10th Revision (ICD-10). Primary outcomes for our study were
mortality from all cause, cardiovascular disease (CVD, including heart diseases and stroke, codes I00-
I09, I11, I13, I20-I51, I60-I69), cancer (codes C00-C97) and other causes (such as diabetes, Alzheimer
disease, influenza, and accidents).
Statistical Analysis
We accounted for complex survey design factors for the NHANES including sample weights, clustering
and stratification whenever feasible. We defined baseline as the time when participants had their physical
examinations. Person years were counted from baseline to the date of death, loss to follow-up or 31
December 2015, whichever came first. We used cox proportional hazards models with time in study as
the underlying time metric to calculate the hazard ratios (HRs) and corresponding 95% confidence
Page 8 of 58
https://mc.manuscriptcentral.com/bmj
BMJ
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
Confidential: For Review Only
9
intervals (95% CIs) for all cause and cause specific mortality in relation to weight change patterns, using
stable normal pattern as the reference. We examined proportional hazards assumption by creating a time-
dependent covariate defined by the cross product of follow-up time and weight change patterns.
Likelihood ratio tests comparing models with and without the variable were not significant, suggesting
no departure from the proportional hazards assumption.
For the main analyses, we examined associations between weight change patterns and mortality in the
three time intervals: BMI changes from age 25 years to ten years prior to baseline (BMI25 to BMI10prior),
to approximate weight change from young to middle adulthood; BMI changes from ten years before
baseline to baseline (BMI10prior to BMIbaseline), to approximate weight change from midlife to late
adulthood; BMI changes from age 25 years to baseline (BMI25 to BMIbaseline), to approximate weight
change during the whole adulthood period. We also investigated associations between absolute weight
change groups and mortality in the above three time intervals. In addition, we tested the possible
nonlinear relationship between absolute weight change and mortality risk by non-parametrically
restricted cubic splines,23 and tests for nonlinearity were conducted through the likelihood ratio test
comparing the models with and without the cubic spline terms. Participants with missing BMI data in
certain age point were excluded based on specific analysis.
We adjusted for baseline age (years, continuous), sex, and race/ethnicity (non-Hispanic White, non-
Hispanic Black, Mexican American, and others) in model 1. We further adjusted for education level (less
than high school, high school or equivalent, and college or above), household income level, marital status
(married, separated including widowed and divorced groups, and never married groups), smoking (never
smoker, ever smoker and current smoker) and drinking status (never drinker and ever drinker), and family
history of diabetes and heart diseases in model 2. In the absolute weight change analyses, we also
Page 9 of 58
https://mc.manuscriptcentral.com/bmj
BMJ
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
Confidential: For Review Only
10
included baseline height and weight at the beginning of the change period as potential confounders in
model 2. Finally, we additionally adjusted for baseline histories of diabetes, hypertension, CVD, cancer
and COPD, as those comorbidities could be mediators for the association between weight change and
mortality. Percentages of missing values of covariates were less than 7%, and we included them as
missing indicators accordingly. We conducted stratified analyses and potential effect modifications by
baseline age (<60 and ≥60 years), sex and smoking status (ever and never smokers). To evaluate the
impact on premature death, we also examined the relations with deaths occurred before 65 years old,
between age 66 and 75 years, between age 76 and 85 years and after 85 years old.
We conducted a series of sensitivity analyses to test the robustness of the results: performing separated
analysis in the NHANES 1988-1994 and 1999-2014 to examine the cohort effect; redefining the weight
change patterns by combinations of standard BMI categories in each two time points which generated a
16-category weight change group instead of using the five weight change patterns; excluding
underweight people to reduce the influence of underweight on the results; and excluding those who died
within the first three years of follow-up to minimize potential reverse causation caused by illness.
All analyses were performed using SAS 9.4 (SAS Institute, Inc., Cary, North Carolina). A two-tailed
P value of <0.05 was determined as statistically significant.
Patient involvement
No participants were involved in setting the research questions or outcome measures, or in the design
and implementation of the study.
Results
Page 10 of 58
https://mc.manuscriptcentral.com/bmj
BMJ
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
Confidential: For Review Only
11
Baseline characteristics and weight change pattern
Regarding weight change across adulthood, participants tended to gain more weight from age 25 years
to ten years prior to baseline survey (mean age of 47 years) than in the ten years period before baseline
(from mean age of 47 years to mean age of 57 years), and weight loss was more likely to occur over this
ten years period. Across adulthood, more than 15% participants gained weight with BMI moving from
non-obese to obese range, whereas less than 4.2% participants lost weight from obese to non-obese BMI
(supplementary table 1).
Table 1 presents baseline characteristics of study participants across weight change groups from age
25 years to baseline. Compared with individuals in the stable normal group, those losing from obese to
non-obese BMI were older, more likely to be men, less educated, current drinkers, to have lower
household income and to have comorbidities except for cancer, but were less likely to be non-Hispanic
Whites, married and never smokers. However, those who gained from non-obese BMI to obesity were
more likely to be non-Hispanic Black, never smokers, to have family history of chronic metabolic
diseases and to develop chronic diseases except cancer. The distributions of participants’ characteristics
were generally similar when classifying the participants with weight change in different time periods
(supplementary tables 2 and 3).
Relations of weight and weight change patterns with mortality
Among 36 812 participants, 10 936 deaths occurred during a mean follow-up of 10 years (363 811 person
years), including 3013 CVD deaths and 2373 cancer deaths. When evaluating the weight status at each
time point (supplementary table 4), we found that overweight and obesity at age 25 years were
significantly associated with increased risk of all cause mortality, while underweight showed null
Page 11 of 58
https://mc.manuscriptcentral.com/bmj
BMJ
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
Confidential: For Review Only
12
association. The BMI-mortality association changed to U-shape or reversed J-shape with increasing age
that underweight was associated with increased risk of mortality at ten years before baseline and at
baseline while the association with overweight disappeared or even reversed and the association with
obesity was substantially attenuated. Baseline waist circumference showed a U-shape association with
mortality, and significantly increased risks were observed for both low and high waist groups.
Separate analysis of the relations of weight change with mortality in the NHANES 1988-1994 and
1999-2014 showed no significant cohort effect (supplementary table 5), and thus we used the pooled
sample of the two periods in our final analysis. Table 2 shows the association between weight change
patterns in the three adulthood period in NHANES 1988-2014 and mortality risk using stable normal
BMI group as the reference. As expected, stable obese participants had increased risk of all cause
mortality across the adulthood, but the associations were stronger when the exposure was from age 25
years to ten years before baseline (HR 1.93, 95% CI 1.72 to 2.16) and from age 25 years to baseline
(1.81, 1.59 to 2.05) compared to that in the ten years period before baseline (1.33, 1.22 to 1.45). Gaining
weight with BMI moving from non-obese range at age 25 years to obese range in ten years prior to
baseline was associated with a 33% higher risk of all cause mortality (1.33, 1.22 to 1.45), while the
association was modest with weight gain from at age 25 years to baseline (1.11, 1.01 to 1.21) and not
significant in the ten years period before baseline (1.09, 0.95 to 1.25). Maximum overweight group
showed very modest or null association with all cause mortality in all three time intervals. Losing weight
from obesity to non-obese BMI in the ten years period before baseline was associated with a 44% higher
risk of all cause mortality (1.44, 1.28 to 1.61), but the association was not significant for the weight loss
pattern from age 25 years to ten years before baseline or to baseline.
We observed similar patterns of results for CVD mortality but with slightly stronger effect estimates.
Page 12 of 58
https://mc.manuscriptcentral.com/bmj
BMJ
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
Confidential: For Review Only
13
For example, the HR (95% CI) was 2.52 (1.97 to 3.23) for stable obesity from age 25 years to ten years
before baseline, 2.24 (1.71 to 2.94) from age 25 years to baseline and 1.45 (1.22 to 1.73) in the ten years
period before baseline. Likewise, those who had been non-obese at age 25 years but became obese at ten
years before baseline had an HR of 1.52 for CVD mortality (1.52, 1.28 to 1.81). We found no significant
associations between BMI change and cancer mortality except for those gained weight from non-obese
BMI at 25 years to obese BMI at ten years before baseline and the stable obesity group in the ten years
period before baseline. As for deaths from other causes, the results were generally comparable to all
cause mortality, except that losing from obesity to non-obese BMI was associated with increased risks
in all three time intervals (table 2). Further adjustment of baseline comorbidities attenuated the
associations, but stable obesity at all three time intervals remained significantly associated with higher
mortality risk while the association with weight gain was only significant for the period from age 25
years to ten years before baseline (supplementary table 6). When classifying the participants into the 16-
catergory weight change groups, the conclusion was generally consistent with the main results
(supplementary figure 2).
In the stratified analyses, we found significant interactions with baseline age and smoking status but
not sex (Figure 1), and the associations were stronger among participants who were less than 60 years
old at baseline and never smokers compared to their counterparts. When stratified by age at death, the
magnitude of associations was larger among participants who died before 65 years old than those who
died later (supplementary table 7). The relations of weight change patterns with all cause mortality were
materially unchanged after excluding underweight participants (supplementary table 8) or when
participants died within three years of follow-up were not included (supplementary table 9).
When evaluating the absolute weight changes, we identified a J-shape or U-shape association for all
Page 13 of 58
https://mc.manuscriptcentral.com/bmj
BMJ
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
Confidential: For Review Only
14
cause mortality with weight change across the three time intervals (Figure 2). When classified into
categories (table 3), extreme weight gain (weight gain ≥20 kg) was consistently associated with increased
risk of all cause mortality in all three time intervals, compared with stable weight group (weight change
within 2.5 kg). Moderate to large weight gain (10 kg ≤ weight gain <20 kg) was related to a modestly
increased risk of all cause mortality in the ten years period before baseline (1.12, 1.02 to 1.23), while
small to moderate weight gain (2.5 kg ≤ weight gain <10 kg) was not associated with all cause mortality
in any of the three time intervals. Those losing weight of more than 2.5 kg from age 25 years to baseline
had an HR of 1.21 (1.06 to 1.38) for all cause mortality and that of 1.30 (1.17 to 1.44) in the ten years
period before baseline. Significantly increased risk of CVD mortality was observed in extreme weight
gain from age 25 years to ten years before baseline and in the ten years period before baseline. Cancer
mortality risk was significantly higher in participants losing weight of more than 2.5 kg from age 25
years to baseline (1.48, 1.17 to 1.86) and in the ten year period before baseline (1.29, 1.09 to 1.53). The
relation of weight change with mortality of other causes was comparable to that of all cause mortality
(table 3). With the exception of the linear association of CVD mortality with weight change from age 25
years to ten years before baseline, the J-shape or reversed J-shape association between absolute weight
change across adulthood and cause specific mortality appeared in the restricted cubic spline analyses
(supplementary figure 3). Further adjustment of baseline comorbidities weakened the relations, with only
weight loss and extreme weight gain in the ten years period before baseline remained significant for all
cause mortality (supplementary table 10).
Discussion
In this large prospective study of national representative US adults, the lowest risk of mortality was
Page 14 of 58
https://mc.manuscriptcentral.com/bmj
BMJ
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
Confidential: For Review Only
15
observed in stable normal BMI participants, while stable obesity and weight gain across adulthood,
particularly weight gain from young to middle adulthood, were associated with increased risk of
mortality; in addition, weight loss from middle to late adulthood was significantly related to increased
mortality risk. Therefore, the findings underscore the importance of maintaining a normal weight across
adulthood, especially the prevention of weight gain in early adulthood, for reducing mortality risk in later
life.
Comparison with other studies
The association between BMI and mortality has been extensively studied in many prospective cohort
studies and in general a U-shape association was reported.24 However, many studies only measured BMI
once and thus could not capture the dynamic change feature of body weight. A number of studies with
repeated measures of BMI reported that both weight loss and weight gain in middle-aged to elderly adults
were associated with increased mortality risk.4 Similar findings were also observed in our recent analysis
in the Singapore Chinese population.25 In our current study, stable obesity and weight loss with BMI
moving from obese to non-obese range from middle to late adulthood had significantly higher mortality
risk (33% and 44% higher risks, respectively), but weight gain from non-obese BMI to obesity was not
significant (9% higher risk). In the previous meta-analysis, weight loss compared with stable weight was
associated with about 45% higher risk of all cause mortality, while weight gain was related to only 7%
higher risk (although statistically significant).4 Therefore, our results are largely consistent with previous
cohort studies on the relations of weight change from middle to late adulthood and mortality risk.
Adult weight gain mostly occurs from young to middle adulthood while studies on this critical period
are still lacking.26 In addition, we identified a J-shape association for all cause mortality and a linear
Page 15 of 58
https://mc.manuscriptcentral.com/bmj
BMJ
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
Confidential: For Review Only
16
association for CVD mortality, while very few studies reported the dose-response relationship between
weight change over this period and mortality. Using data from the National Institutes of Health-AARP
cohort with 109 947 never smokers aged 50 to 71 years at entry, Adams et al10 found that weight gain
was positively related to mortality, with stronger associations for gain between ages 18 and 35 years and
ages 35 and 50 years than between ages 50 and 69 years. The findings were consistent with ours that the
relations of stable obesity and weight gaining from non-obese to obese BMI with mortality were
generally stronger from young to middle or late adulthood than from middle to late adulthood. The
National Institutes of Health-AARP study also found that weight loss in late adulthood, but not in early
adulthood, was significantly associated with increased mortality risk, which again was consistent with
our results. A study in 1657 Finnish men with average age of 47 years at baseline reported that mortality
risk was significantly increased in the highest quartile of weight gain (≥15.0 kg) compared with the
lowest quartile.13 In the Southern Community Cohort study with 56 868 US participants aged 40 to 65 at
baseline, Hirko et al15 reported that maintaining an obese BMI and losing from obese to non-obese BMI
from age 21 years to approximately 52 years were associated with elevated mortality risk, while gaining
weight from non-obese to obese BMI was associated with a 8% lower risk of mortality. Reasons for the
inconsistent results between this study and ours might be that our study used stable normal BMI as the
reference group while this study used stable non-obesity as the reference group (thus people with
overweight at either time were included in the reference); this study also included more than two thirds
of black Americans and they previously reported that obesity in mid-to-late adulthood among blacks was
not associated with the same excess mortality risk seen among whites.27 Taken together, our results
indicate that avoiding obesity at young age and preventing weight gain from young to middle adulthood
could be an important strategy to reduce future mortality risk.
Page 16 of 58
https://mc.manuscriptcentral.com/bmj
BMJ
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
Confidential: For Review Only
17
A number of studies have also investigated the relations of weight change from young to late adulthood
and mortality risk, but the results were not entirely consistent. Similar to our results, most studies showed
gaining weight over this period was associated with increased risk of all cause mortality.9-11 18 In contrast,
a few studies reported that weight loss, but not weight gain, was related to increased mortality risk.12 28
The controversy might be due to the differences in sample size and statistical power and definitions of
weight change across studies, which made direct comparisons difficult. In addition, the baseline age
varied in different studies and previous studies showed that the obesity-mortality association tends to
decline with increasing age.29 30 As also shown in our study, the association between weight gain and
mortality attenuated with age while the association with weight loss became stronger and significant in
middle to late adulthood.
In the present study, the strongest association between weight gain and CVD mortality was observed
in participants who changed from non-obese BMI in young adulthood to obese BMI in middle adulthood.
Association between weight loss and CVD mortality was more pronounced in participants who moved
from obese to non-obese BMI from middle to late adulthood. In previous studies, similar results were
found.11 31 While it is logical that weight gain from young to middle adulthood may be a risk factor for
CVD death because obesity is a well-established risk factor for CVD mortality, it is unexpected that
weight loss in middle to late adulthood was also a risk factor for CVD mortality. One possible reason for
the positive association between weight loss and CVD mortality may be that a large decrease of BMI
from middle to late adulthood may indicate sarcopenia or muscle loss that can cause frailty and increase
risk of death.32 Another possibility is confounding by smoking and reverse causation due to underlying
severe chronic diseases. However, in our attempts to minimize such confounding by restricting analysis
in never smokers or excluding participants died within three years of follow-up, our results remained
Page 17 of 58
https://mc.manuscriptcentral.com/bmj
BMJ
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
Confidential: For Review Only
18
unchanged.
In our study, maximum overweight pattern was generally not significantly related to mortality risk
except for all cause and CVD mortality over the period of age 25 years to ten years before baseline.
Findings for this pattern were in accordance with most prior studies reporting null or modest association
between mild weight change and mortality.9 25 31 33
Strengths and limitations of our study
This study had several strengths including its large and nationally representative sample, high follow-up
rate and detailed analysis of weight change from young adulthood through midlife to late adulthood. The
importance of categorizing weight change throughout the entire adulthood into two special periods lies
in that natural tendency of weight gain from young to middle adulthood and weight loss from middle
adulthood to late adulthood could be differentiated and accounted. Furthermore, weight gain from young
to middle adulthood mostly reflects accumulation of fat mass while weight loss from middle to late
adulthood is usually accompanied with a decrease of lean mass and an increase in fat mass,7 30 therefore
there might be different underlying mechanisms of the harmful effect of weight change in certain life
period.
Several limitations also existed in the present study. First, our approximation of middle adulthood (age
range of 30 to 80, IQR 36 to 56) and late adulthood (age range 40 to 90, IQR 46 to 66) was overlapped.
Therefore, we conducted a stratified analysis by baseline age, and results in participants less than 60
years old at baseline (which means participants were in their 30s to 50s ten years before baseline, thus
considered as middle adulthood) and more than 60 years old at baseline (which means participants were
in their 60s to 90s ten years before baseline, thus considered as late adulthood) further confirmed that
Page 18 of 58
https://mc.manuscriptcentral.com/bmj
BMJ
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
Confidential: For Review Only
19
weight gain in younger ages was associated with much higher mortality risk. Second, we used recalled
and self-reported weight data at age of 25 years and ten years prior to the baseline NHANES survey.
Because of the probable inaccuracy of recalled weight compared with actual weight and the fact that
people tend to underreport their weight, misclassification bias may be introduced. However, several
validation studies showed that self-reported weight is highly correlated with measured weight.34-36 Third,
some possible confounders such as diet and physical activity were not adjusted for because of lack of
consistent data in different cycles of NHANES surveys. Nevertheless, previous studies reported that
adiposity, diet and physical activity may act independently in relation to mortality.37 38 Fourth, we could
not differentiate intentional from unintentional weight change and supplementary information regarding
reasons of weight change in future studies may help better interpret the results and offer appropriate
intervention strategies accordingly. Lastly, we did not evaluate the relations of changes in other
adiposity-related markers such as waist circumference and fat mass with mortality due to lack of data.
Further studies with repeated data on those markers may provide more comprehensive picture of the
changes in obesity status and mortality risk.
Conclusions and public health implications
Our study showed that weight gain across adulthood was associated with increased risks of all cause,
CVD and cancer mortality with weight gain from young to middle adulthood showing the strongest
association, while weight loss in middle to late adulthood conferred elevated risks of all cause and CVD
mortality. Future studies are required to unravel the mechanisms underlying the association of weight
change in whole adulthood and mortality, particularly the relations of changes in body composition on
mortality. In addition, since weight loss is less achievable (less than 4.2% of study participants changed
Page 19 of 58
https://mc.manuscriptcentral.com/bmj
BMJ
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
Confidential: For Review Only
20
from obese to non-obese category across adulthood), our results suggest that the prevention of weight
gain might be more important. Taken together, our findings indicate that maintaining a normal weight
throughout the adulthood, especially the prevention of weight gain in early adulthood, should be
encouraged to reduce mortality risk, however, further studies are still needed to consider other health-
related and obesity-related factors, and clinical trials of weight loss on long-term health consequences
are also warranted.
Page 20 of 58
https://mc.manuscriptcentral.com/bmj
BMJ
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
Confidential: For Review Only
21
Contributors: CC, XF and AP conceived the study design. CC and YY did the statistical analysis. CC
and AP wrote the manuscript. All authors provided critical revisions on the draft and approved the
submitted draft. AP funded this study. AP is the guarantor and attests that all listed authors meet
authorship criteria and that no others meeting the criteria have been omitted.
Funding: The work was supported by the National Key Research and Development Program of China
to Dr. An Pan (2017YFC0907504). The funders had no role in design and conduct of the study; collection,
management, analysis, and interpretation of the data; preparation, review, and approval of the manuscript;
or the decision to submit the manuscript for publication.
Competing interests: All authors have completed the ICMJE uniform disclosure form at
http://www.icmje.org/coi_disclosure.pdf and declare: no support from any organization for the submitted
work other than those described above; no financial relationships with any organizations that might have
an interest in the submitted work in the previous three years; no other relationships or activities that could
appear to have influenced the submitted work.
Ethical approval: Approval of the study from the National Center of Health and Statistics Research
ethics review board was waived because the research was relied on publicly used, de-identified secondary
data.
Transparency declaration: The manuscript’s guarantor affirms that the manuscript is an honest,
accurate, and transparent account of the study being reported; that no important aspects of the study have
been omitted; and that any discrepancies from the study have been explained.
Data sharing: No additional data available.
Page 21 of 58
https://mc.manuscriptcentral.com/bmj
BMJ
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
Confidential: For Review Only
22
References
1. Abarca-Gómez L, Abdeen ZA, Hamid ZA, et al. Worldwide trends in body-mass index,
underweight, overweight, and obesity from 1975 to 2016: a pooled analysis of 2416
population-based measurement studies in 128· 9 million children, adolescents, and
adults. Lancet 2017;390:2627-42. doi: 10.1016/S0140-6736(17)32129-3.
2. Di Angelantonio E, Bhupathiraju SN, Wormser D, et al. Body-mass index and all cause
mortality: individual-participant-data meta-analysis of 239 prospective studies in four
continents. Lancet 2016;388:776-86. doi: 10.1016/S0140-6736(16)30175-1.
3. Bhaskaran K, dos-Santos-Silva I, Leon DA, Douglas IJ, Smeeth L. Association of BMI with
overall and cause specific mortality: a population-based cohort study of 3· 6 million
adults in the UK. Lancet Diabetes Endocrinol 2018;6:944-53. doi: 10.1016/S2213-
8587(18)30288-2.
4. Karahalios A, English DR, Simpson JA. Change in body size and mortality: a systematic
review and meta-analysis. Int J Epidemiol 2017;46:526-46. doi: 10.1093/ije/dyw246.
5. Cheng FW, Gao X, Jensen GL. Weight Change and All cause Mortality in Older Adults: A
Meta-Analysis. J Nutr Gerontol Geriatr 2015;34:343-68. doi:
10.1080/21551197.2015.1090362.
6. Sheehan TJ, DuBrava S, DeChello LM, Fang Z. Rates of weight change for black and white
Americans over a twenty year period. Int J Obes Relat Metab Disord 2003;27:498-504.
doi: 10.1038/sj.ijo.0802263.
7. Fontana L, Hu FB. Optimal body weight for health and longevity: bridging basic, clinical, and
population research. Aging Cell 2014;13:391-400. doi: 10.1111/acel.12207.
Page 22 of 58
https://mc.manuscriptcentral.com/bmj
BMJ
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
Confidential: For Review Only
23
8. Strandberg TE, Strandberg A, Salomaa VV, Pitkala K, Miettinen TA. Impact of midlife weight
change on mortality and quality of life in old age. Prospective cohort study. Int J Obes
Relat Metab Disord 2003;27:950-4. doi: 10.1038/sj.ijo.0802313.
9. Shimazu T, Kuriyama S, Ohmori-Matsuda K, Kikuchi N, Nakaya N, Tsuji I. Increase in body
mass index category since age 20 years and all cause mortality: a prospective cohort
study (the Ohsaki Study). Int J Obes (Lond) 2009;33:490-6. doi: 10.1038/ijo.2009.29.
10. Adams KF, Leitzmann MF, Ballard-Barbash R, et al. Body mass and weight change in
adults in relation to mortality risk. Am J Epidemiol 2014;179:135-44. doi:
10.1093/aje/kwt254.
11. Zheng Y, Manson JE, Yuan C, et al. Associations of Weight Gain From Early to Middle
Adulthood With Major Health Outcomes Later in Life. JAMA 2017;318:255-69. doi:
10.1001/jama.2017.7092.
12. Yarnell JW, Patterson CC, Thomas HF, Sweetnam PM. Comparison of weight in middle
age, weight at 18 years, and weight change between, in predicting subsequent 14 year
mortality and coronary events: Caerphilly Prospective Study. J Epidemiol Community
Health 2000;54:344-8.
13. Jeffreys M, McCarron P, Gunnell D, McEwen J, Smith GD. Body mass index in early and
mid-adulthood, and subsequent mortality: a historical cohort study. Int J Obes Relat
Metab Disord 2003;27:1391.
14. Corrada MM, Kawas CH, Mozaffar F, Paganini-Hill A. Association of body mass index and
weight change with all cause mortality in the elderly. Am J Epidemiol 2006;163:938-49.
doi: 10.1093/aje/kwj114.
Page 23 of 58
https://mc.manuscriptcentral.com/bmj
BMJ
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
Confidential: For Review Only
24
15. Hirko KA, Kantor ED, Cohen SS, Blot WJ, Stampfer MJ, Signorello LB. Body mass index in
young adulthood, obesity trajectory, and premature mortality. Am J Epidemiol
2015;182:441-50. doi: 10.1093/aje/kwv084.
16. Mehta NK, Stenholm S, Elo IT, Aromaa A, Heliovaara M, Koskinen S. Weight histories and
mortality among finnish adults: the role of duration and peak body mass index.
Epidemiology 2014;25:707-10. doi: 10.1097/ede.0000000000000147.
17. Song M, Hu FB, Wu K, et al. Trajectory of body shape in early and middle life and all cause
and cause specific mortality: results from two prospective US cohort studies. BMJ
2016;353:i2195. doi: 10.1136/bmj.i2195.
18. Preston SH, Mehta NK, Stokes A. Modeling obesity histories in cohort analyses of health
and mortality. Epidemiology 2013;24:158-66. doi: 10.1097/EDE.0b013e3182770217.
19. Centers for Disease Control and Prevention (CDC). National Center for Health Statistics
(NCHS). National Health and Nutrition Examination Survey. Available from
https://www.cdc.gov/nchs/nhanes/about_nhanes.htm. Accessed 1 February 2019.
20. Health NIo. NHLBI obesity education initiative expert panel on the identification, evaluation,
and treatment of overweight and obesity in adults. The Evidence Report NIH 1998.
21. Stokes A, Collins JM, Grant BF, et al. Obesity Progression Between Young Adulthood and
Midlife and Incident Diabetes: A Retrospective Cohort Study of U.S. Adults. Diabetes
Care 2018;41:1025-31. doi: 10.2337/dc17-2336.
22. National Center for Health Statistics. Available from https://www.cdc.gov/nchs/data-
linkage/mortality-public.htm#. Accessed 1 February 2019.
23. Durrleman S, Simon R. Flexible regression models with cubic splines. Stat Med 1989;8:551-
Page 24 of 58
https://mc.manuscriptcentral.com/bmj
BMJ
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
Confidential: For Review Only
25
61.
24. Aune D, Sen A, Prasad M, et al. BMI and all cause mortality: systematic review and non-
linear dose-response meta-analysis of 230 cohort studies with 3.74 million deaths
among 30.3 million participants. BMJ 2016;353:i2156. doi: 10.1136/bmj.i2156.
25. Pan X-F, Yuan J-M, Koh W-P, Pan A. Weight change in relation to mortality in middle-aged
and elderly Chinese: the Singapore Chinese Health Study. Int J Obes (Lond) 2018:1.
doi: 10.1038/s41366-018-0259-y.
26. Dietz WH. Obesity and Excessive Weight Gain in Young Adults: New Targets for Prevention.
JAMA 2017;318:241-42. doi: 10.1001/jama.2017.6119.
27. Cohen SS, Signorello LB, Cope EL, et al. Obesity and all cause mortality among black
adults and white adults. Am J Epidemiol 2012;176:431-42. doi: 10.1093/aje/kws032
28. Droyvold WB, Lund Nilsen TI, Lydersen S, et al. Weight change and mortality: the Nord-
Trondelag Health Study. J Intern Med 2005;257:338-45. doi: 10.1111/j.1365-
2796.2005.01458.x.
29. Elliott AM, Aucott LS, Hannaford PC, Smith WC. Weight change in adult life and health
outcomes. Obes Res 2005;13:1784-92. doi: 10.1038/oby.2005.217.
30. Ferrucci L, Alley D. Obesity, disability, and mortality: a puzzling link. Arch Intern Med
2007;167:750-1. doi: 10.1001/archinte.167.8.750.
31. Park SY, Wilkens LR, Maskarinec G, Haiman CA, Kolonel LN, Marchand LL. Weight change
in older adults and mortality: the Multiethnic Cohort Study. Int J Obes (Lond)
2017;42:205-12. doi: 10.1038/ijo.2017.188.
32. Walston J, Hadley EC, Ferrucci L, et al. Research agenda for frailty in older adults: toward
Page 25 of 58
https://mc.manuscriptcentral.com/bmj
BMJ
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
Confidential: For Review Only
26
a better understanding of physiology and etiology: summary from the American
Geriatrics Society/National Institute on Aging Research Conference on Frailty in Older
Adults. J Am Geriatr Soc 2006;54:991-1001. doi: 10.1111/j.1532-5415.2006.00745.x.
33. Mulligan AA, Lentjes MA, Luben RN, Wareham NJ, Khaw K-T. Weight change and 15 year
mortality: results from the European Prospective Investigation into Cancer in Norfolk
(EPIC-Norfolk) cohort study. Eur J Epidemiol 2018;33:37-53. doi: 10.1007/s10654-017-
0343-y.
34. Casey VA, Dwyer JT, Berkey CS, Coleman KA, Gardner J, Valadian I. Long-term memory
of body weight and past weight satisfaction: a longitudinal follow-up study. Am J Clin
Nutr 1991;53:1493-98.
35. Perry GS, Byers TE, Mokdad AH, Serdula MK, Williamson DF. The validity of self-reports
of past body weights by US adults. Epidemiology 1995:61-66.
36. Stokes A, Ni Y. Validating a summary measure of weight history for modeling the health
consequences of obesity. Ann Epidemiol 2016;26:821-26. e2. doi:
10.1016/j.annepidem.2016.10.005.
37. Koster A, Harris TB, Moore SC, et al. Joint associations of adiposity and physical activity
with mortality: the National Institutes of Health-AARP Diet and Health Study. Am J
Epidemiol 2009;169:1344-51. doi: 10.1093/aje/kwp053.
38. Ekelund U, Ward HA, Norat T, et al. Physical activity and all cause mortality across levels
of overall and abdominal adiposity in European men and women: the European
Prospective Investigation into Cancer and Nutrition Study (EPIC). Am J Clin Nutr
2015;101:613-21. doi: 10.3945/ajcn.114.100065.
Page 26 of 58
https://mc.manuscriptcentral.com/bmj
BMJ
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
Confidential: For Review Only
27
Page 27 of 58
https://mc.manuscriptcentral.com/bmj
BMJ
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
Confidential: For Review Only
28
Figure Legends
Fig 1 Associations between weight change patterns across adulthood and risk of all cause mortality stratified by baseline age, smoking status and sex in NHANES 1988-2014.
Risk estimates were adjusted for baseline age (not adjusted in subgroup analysis by age), sex (not adjusted in subgroup analysis by sex), race/ethnicity, education level, household income level, marital status, drinking and smoking status (not adjusted in subgroup analysis by smoking status) and family history of diabetes and heart attack. P for interaction was <0.001, 0.95, 0.01 by baseline age, sex and smoking status respectively in age 25 years to ten years before baseline. P for interaction was <0.001, 0.49 and 0.03 by baseline age, sex and smoking status respectively in age 25 years to baseline. P for interaction was <0.001, 0.53 and 0.01 by baseline age, sex and smoking status respectively in ten years period before baseline.
Fig 2 Dose response association between weight change across adulthood and risk of all cause mortality.
Associations were examined by multivariable Cox regression based on restricted cubic splines. Dash line represents estimates of hazard ratios and dotted line represents 95% confidence intervals. Risk estimates were adjusted for baseline age, sex, race/ethnicity, education level, household income level, marital status, drinking and smoking status and family history of diabetes and heart attack. For weight change from age 25 years to ten years before baseline or to baseline, weight at age 25 and baseline height were also adjusted. For weight change from ten years before baseline to baseline, weight at 10 years ago and baseline height were adjusted. P for overall association <0.001 in all three periods. P for non-linear association <0.001 in all three periods.
Page 28 of 58
https://mc.manuscriptcentral.com/bmj
BMJ
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
Confidential: For Review Only
29
Table 1 Baseline characteristics of study participants aged 40 or over in NHANES 1988-2014 according to patterns of weight change from age 25 years to baseline* Weight change patterns from age 25 years to baseline†
Characteristics Stable normal Maximum overweight Loss Gain Stable obese Total
No. of participants, n (%) 8529 (29.1) 12 955 (37.7) 590 (1.4) 9956 (26.9) 1750 (4.9) 33 780Age, mean (95% CI), years 56.8 (56.2 to 57.4) 57.8 (57.4 to 58.3) 59.9 (58.3 to 61.5) 56.9 (56.5 to 57.3) 53.5 (52.8 to 54.2) 57.1 (56.7 to 57.5)Women 4799 (63.3) 5523 (43.6) 201 (31.4) 5736 (56.9) 898 (47.8) 17 157 (52.9)BMI, mean (95% CI), kg/m2
At age 25 years 20.8 (20.7 to 20.8) 23.1 (23.1 to 23.2) 32.9 (32.5 to 33.3) 24.3 (24.2 to 24.3) 34.7 (34.4 to 35.0) 23.4 (23.3 to 23.5)At 10 years prior baseline 22.2 (22.1 to 22.2) 26.0 (25.9 to 26.1) 30.2 (29.6 to 30.9) 30.1 (29.9 to 30.2) 37.7 (37.1 to 38.3) 26.6 (26.5 to 26.7)Maximum 24.6 (24.5 to 24.7) 29.4 (29.2 to 29.4) 35.1 (34.5 to 35.7) 36.4 (36.2 to 36.5) 43.6 (43.0 to 44.2) 30.6 (30.5 to 30.8)At survey 22.2 (22.2 to 22.3) 27.1 (27.0 to 27.1) 26.4 (26.1 to 26.7) 34.5 (34.3 to 34.6) 39.3 (38.8 to 39.9) 28.2 (28.1 to 28.4)
Waist circumference, mean (95% CI), cm 83.6 (83.3 to 83.8) 96.9 (96.7 to 97.1) 97.1 (95.7 to 98.6) 111.9 (111.6 to 112.3) 121.8 (120.8 to 122.8) 98.3 (97.9 to 98.6)Race
Non-Hispanic White 4826 (80.6) 6678 (78.7) 267 (73.7) 4580 (74.7) 813 (76.5) 17 164 (80.0)Non-Hispanic Black 1533 (7.1) 2530 (9.0) 140 (12.1) 2574 (12.6) 538 (14.4) 7315 (9.7)Mexican American 990 (2.5) 2407 (4.7) 134 (5.9) 1918 (5.7) 282 (4.9) 5731 (4.4)Others 1180 (9.9) 1340 (7.5) 49 (8.3) 884 (7.0) 117 (4.3) 3750 (7.9)
EducationLess than high school 2529 (19.4) 4460 (23.0) 298 (36.1) 3393 (24.9) 558 (21.0) 11 238 (22.5)High school or equivalent 2105 (26.6) 3215 (28.3) 121 (29.4) 2538 (29.5) 453 (30.2) 8432 (28.2)College or above 3864 (53.7) 5257 (48.5) 168 (34.4) 4010 (45.5) 734 (48.7) 14 033 (49.0)
Household income levelBelow or at poverty 1272 (8.3) 1958 (8.8) 134 (14.6) 1652 (10.4) 329 (11.4) 5345 (9.3)Above poverty 6528 (85.0) 9883 (84.4) 408 (79.5) 7492 (82.5) 1307 (83.7) 25 618 (83.9)
Marital statusMarried 5275 (67.3) 8421 (70.5) 342 (63.9) 6186 (67.5) 1012 (66.0) 21 236 (68.5)Separated 2614 (26.1) 3666 (23.5) 195 (28.0) 3040 (26.6) 495 (21.5) 10 010 (25.0)Never married 562 (5.7) 745 (5.2) 48 (7.6) 632 (5.2) 228 (11.8) 2215 (5.6)
Alcohol drinkingNever drinker 7492 (89.5) 11221 (87.4) 459 (73.1) 8756 (88.3) 1523 (86.6) 29 451 (88.0)Ever drinker 958 (9.5) 1623 (11.9) 120 (24.1) 1138 (11.0) 217 (12.9) 4056 (11.2)
Smoking statusNever smoker 3947 (45.3) 5992 (45.2) 224 (33.3) 4995 (47.6) 913 (50.5) 16 071 (46.0)Ever smoker 2355 (28.5) 4458 (35.1) 207 (36.1) 3389 (35.3) 521 (32.2) 10 930 (33.1)
Page 29 of 58
https://mc.manuscriptcentral.com/bmj
BMJ
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
Confidential: For Review Only
30
Current smoker 2222 (26.2) 2500 (19.7) 158 (30.5) 1567 (17.1) 316 (17.3) 6763 (20.9)16 797 (49.9) Family history of chronic metabolic
diseases3729 (44.7) 6131 (47.6) 303 (53.8) 5545 (56.3) 1089 (62.3)
Self-reported chronic diseasesDiabetes 604 (4.5) 1609 (8.4) 170 (16.9) 2020 (15.9) 548 (26.4) 4951 (10.3)Hypertension 2096 (19.0) 4489 (30.6) 242 (33.6) 4740 (45.3) 922 (53.0) 12 489 (32.3)Cardiovascular diseases 1054 (8.7) 1916 (11.5) 150 (20.6) 1639 (13.8) 353 (16.3) 5112 (11.6)Chronic obstructive pulmonary diseases 797 (9.7) 986 (7.9) 65 (15.6) 998 (11.1) 182 (10.4) 3028 (9.5)Cancer 1211 (14.5) 1727 (13.4) 82 (12.2) 1141 (12.4) 176 (9.8) 4337 (13.3)*Complex survey designs are accounted for all estimates; data are presented as No. (%) unless otherwise indicated. Percentages may not add up to 100% due to missing values.†Stable normal: BMI25 <25 kg/m2 and BMIbaseline <25 kg/m2; maximum overweight: either BMI25 or BMIbaseline was 25.0-29.9 kg/m2 and the other BMI not ≥30.0 kg/m2; loss: BMI25 ≥ 30 kg/m2 and 0 < BMIbaseline < 30 kg/m2; gain: 0 < BMI25 < 30 kg/m2 and BMIbaseline ≥ 30 kg/m2; stable obese: BMI25 ≥ 30 kg/m2 and BMIbaseline ≥ 30 kg/m2.
Page 30 of 58
https://mc.manuscriptcentral.com/bmj
BMJ
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
Confidential: For Review Only
31
Table 2 Hazard ratios (95% CI) of all cause and cause specific mortality with weight change patterns across adulthood among 36 812 participants in NHANES 1988-2014*
Weight change patterns†
Cause of death Stable normal Maximum overweight Loss Gain Stable obeseFrom age 25 years to ten years before baseline All cause
No. of deaths/Person-years 3094/133 393 3849/127 257 160/3724 1837/54 404 524/16 220Age-adjusted mortality rate‡ 26.4 (25.5 to 27.3) 27.8 (26.9 to 28.6) 38.3 (32.2 to 44.4) 30.2 (28.8 to 31.6) 39.1 (35.6 to 42.5)Model 1 1.00 1.05 (0.98 to 1.12) 1.42 (1.06 to 1.92) 1.30 (1.18 to 1.42) 1.85 (1.63 to 2.09)Model 2 1.00 1.08 (1.01 to 1.15) 1.28 (0.92 to 1.79) 1.33 (1.22 to 1.45) 1.93 (1.72 to 2.16)
Cardiovascular diseasesNo. of deaths 745 1096 44 515 162Model 1 1.00 1.18 (1.04 to 1.35) 1.24 (0.84 to 1.83) 1.48 (1.24 to 1.76) 2.45 (1.89 to 3.16)Model 2 1.00 1.21 (1.06 to 1.39) 1.10 (0.74 to 1.64) 1.52 (1.28 to 1.81) 2.52 (1.97 to 3.23)
CancerNo. of deaths 789 872 27 380 90Model 1 1.00 0.96 (0.83 to 1.12) 1.10 (0.60 to 2.02) 1.20 (0.97 to 1.49) 1.07 (0.81 to 1.43)Model 2 1.00 1.01 (0.88 to 1.17) 0.98 (0.51 to 1.88) 1.26 (1.02 to 1.56) 1.16 (0.87 to 1.55)
Other causesNo. of deaths 1560 1881 89 942 272Model 1 1.00 1.03 (0.94 to 1.12) 1.69 (1.12 to 2.55) 1.27 (1.13 to 1.43) 2.03 (1.67 to 2.49)Model 2 1.00 1.05 (0.96 to 1.14) 1.53 (0.99 to 2.38) 1.29 (1.15 to 1.44) 2.08 (1.71 to 2.54)
From age 25 years to baselineAll cause
No. of deaths/Person-years 2677/87 892 3915/131 968 264/4923 2302/98 464 423/15 156Age-adjusted mortality rate‡ 29.1 (28.0 to 30.2) 27.8 (26.9 to 28.7) 45.2 (39.5 to 50.8) 26.0 (24.9 to 27.2) 36.3 (32.6 to 40.1)Model 1 1.00 0.91 (0.84 to 0.99) 1.38 (1.10 to 1.73) 1.08 (0.99 to 1.17) 1.68 (1.48 to 1.92)Model 2 1.00 0.94 (0.86 to 1.03) 1.21 (0.93 to 1.58) 1.11 (1.01 to 1.21) 1.81 (1.59 to 2.05)
Cardiovascular diseasesNo. of deaths 687 1071 80 629 125Model 1 1.00 0.99 (0.84 to 1.17) 1.35 (0.95 to 1.91) 1.19 (1.02 to 1.38) 2.13 (1.61 to 2.82)Model 2 1.00 1.01 (0.86 to 1.20) 1.18 (0.83 to 1.69) 1.21 (1.05 to 1.40) 2.24 (1.71 to 2.94)
CancerNo. of deaths 604 919 47 545 73Model 1 1.00 0.92 (0.79 to 1.07) 1.04 (0.67 to 1.62) 1.05 (0.92 to 1.21) 1.05 (0.75 to 1.48)Model 2 1.00 0.97 (0.83 to 1.14) 0.91 (0.57 to 1.46) 1.11 (0.96 to 1.28) 1.18 (0.84 to 1.66)
Other causes
Page 31 of 58
https://mc.manuscriptcentral.com/bmj
BMJ
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
Confidential: For Review Only
32
No. of deaths 1386 1925 137 1128 225Model 1 1.00 0.87 (0.80 to 0.96) 1.57 (1.18 to 2.08) 1.05 (0.94 to 1.17) 1.84 (1.48 to 2.28)Model 2 1.00 0.89 (0.82 to 0.98) 1.38 (1.00 to 1.90) 1.07 (0.96 to 1.20) 1.94 (1.56 to 2.40)
From ten years before baseline to baseline All cause
No. of deaths/Person-years 2362/81 771 3924/131 762 852/16 428 1137/58 251 1652/56 972Age-adjusted mortality rate‡ 28.7 (27.5 to 29.9) 27.8 (26.9 to 28.7) 40.5 (37.7 to 43.4) 25.3 (23.7 to 26.9) 29.7 (28.2 to 31.2)Model 1 1.00 0.93 (0.85 to 1.02) 1.46 (1.27 to 1.68) 1.07 (0.95 to 1.20) 1.27 (1.15 to 1.40)Model 2 1.00 0.96 (0.88 to 1.04) 1.44 (1.28 to 1.61) 1.09 (0.95 to 1.25) 1.33 (1.22 to 1.45)
Cardiovascular diseasesNo. of deaths 605 1058 270 318 455Model 1 1.00 0.92 (0.79 to 1.08) 1.68 (1.33 to 2.13) 1.13 (0.93 to 1.37) 1.40 (1.15 to 1.69)Model 2 1.00 0.95 (0.80 to 1.11) 1.66 (1.32 to 2.09) 1.15 (0.94 to 1.41) 1.45 (1.22 to 1.73)
CancerNo. of deaths 567 892 138 273 354Model 1 1.00 0.91 (0.76 to 1.10) 1.13 (0.85 to 1.51) 0.95 (0.75 to 1.21) 1.14 (0.95 to 1.35)Model 2 1.00 0.96 (0.80 to 1.15) 1.13 (0.86 to 1.48) 0.99 (0.78 to 1.27) 1.24 (1.03 to 1.48)
Other causesNo. of deaths 1190 1974 444 546 843Model 1 1.00 0.94 (0.85 to 1.04) 1.51 (1.25 to 1.82) 1.11 (0.95 to 1.29) 1.28 (1.13 to 1.46)Model 2 1.00 0.96 (0.87 to 1.07) 1.46 (1.23 to 1.74) 1.13 (0.96 to 1.33) 1.33 (1.17 to 1.50)
*Complex survey designs are considered for all estimates. A total of 3382, 3032, 2230 participants were excluded in analyses from age 25 years to ten years before baseline, age 25 years to baseline, ten years before baseline to baseline respectively due to missing values of BMI at both times. Model 1 were adjusted for baseline age, sex, race/ethnicity. Model 2 were additionally adjusted for additionally adjusted for education level, household income level, marital status, drinking and smoking status (never, ever, current) and family history of diabetes and heart attack.†Weight change patterns were defined by BMI at two time points. Stable normal participants had BMI <25.0 kg/m2 at both times, maximum overweight participants had BMI in 25.0-29.9 kg/m2 at either time but not ≥30.0 kg/m2 at the other time, weight loss participants had BMI ≥30.0 kg/m2 at younger age while <30.0 kg/m2 later, weight gain participants had BMI <30.0 kg/m2 at younger age while ≥30.0 kg/m2 later, and stable obese participants had BMI ≥30.0 kg/m2 at both times. ‡Mortality rates per 1000 person-years, directly standardized to the age distribution of the entire study population
Page 32 of 58
https://mc.manuscriptcentral.com/bmj
BMJ
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
Confidential: For Review Only
33
Table 3 Hazard ratios of all cause and cause specific mortality with absolute weight change groups across adulthood in 36 812 participants in NHANES 1988-2014*
Weight change in three life periodsCause of death Weight loss ≥2.5 kg Weight loss <2.5
or gain <2.5 kg 2.5 kg ≤ Weight gain <10.0 kg 10 kg ≤ Weight gain <20 kg Weight gain ≥20 kg
From age 25 years to ten years before baselineAll cause
No. of deaths 762 2152 2661 2191 1698 Age-adjusted mortality rate† 37.2 (34.5 to 39.8) 30.0 (28.7 to 31.3) 26.2 (25.2 to 27.2) 26.2 (25.1 to 27.3) 31.1 (29.6 to 32.7) Model 1 1.30 (1.11 to 1.53) 1.00 0.90 (0.82 to 0.99) 0.95 (0.86 to 1.05) 1.17 (1.05 to 1.30) Model 2 1.07 (0.92 to 1.25) 1.00 0.97 (0.87 to 1.07) 1.06 (0.95 to 1.18) 1.28 (1.15 to 1.42)
Cardiovascular diseases No. of deaths 211 565 703 618 465 Model 1 1.17 (0.96 to 1.43) 1.00 0.82 (0.70 to 0.96) 0.85 (0.72 to 1.00) 1.11 (0.96 to 1.30) Model 2 0.90 (0.75 to 1.10) 1.00 0.88 (0.74 to 1.05) 0.96 (0.80 to 1.15) 1.26 (1.08 to 1.47)Cancer No. of deaths 170 510 662 453 363 Model 1 1.34 (1.05 to 1.72) 1.00 0.94 (0.79 to 1.11) 0.96 (0.77 to 1.11) 1.14 (0.91 to 1.44) Model 2 1.19 (0.92 to 1.53) 1.00 0.99 (0.83 to 1.19) 1.04 (0.83 to 1.31) 1.21 (0.96 to 1.53)Other causes No. of deaths 381 1077 1296 1120 870 Model 1 1.37 (1.10 to 1.72) 1.00 0.95 (0.83 to 1.09) 1.02 (0.91 to 1.15) 1.23 (1.09 to 1.40) Model 2 1.12 (0.89 to 1.42) 1.00 1.02 (0.88 to 1.18) 1.14 (1.01 to 1.29) 1.35 (1.19 to 1.53)From age 25 years to baselineAll cause No. of deaths 1801 1059 2027 2417 2277 Age-adjusted mortality rate† 44.4 (42.2 to 46.6) 29.1 (27.3 to 30.9) 26.5 (25.4 to 27.7) 25.6 (24.6 to 26.6) 25.7 (24.5 to 26.8) Model 1 1.44 (1.26 to 1.64) 1.00 0.97 (0.86 to 1.09) 0.91 (0.82 to 1.02) 1.09 (0.98 to 1.21) Model 2 1.21 (1.06 to 1.38) 1.00 1.01 (0.90 to 1.13) 0.99 (0.89 to 1.10) 1.16 (1.05 to 1.28)Cardiovascular disease No. of deaths 506 296 563 622 605 Model 1 1.18 (0.96 to 1.46) 1.00 0.88 (0.72 to 1.08) 0.84 (0.71 to 0.99) 1.01 (0.83 to 1.22) Model 2 0.95 (0.75 to 1.19) 1.00 0.92 (0.76 to 1.13) 0.92 (0.79 to 1.08) 1.11 (0.92 to 1.34)Cancer
No. of deaths 394 210 475 572 537Model 1 1.67 (1.35 to 2.07) 1.00 1.08 (0.89 to 1.31) 1.03 (0.85 to 1.26) 1.16 (0.98 to 1.37)Model 2 1.48 (1.17 to 1.86) 1.00 1.12 (0.93 to 1.34) 1.10 (0.89 to 1.36) 1.20 (1.01 to 1.42)
Page 33 of 58
https://mc.manuscriptcentral.com/bmj
BMJ
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
Confidential: For Review Only
34
Other causes No. of deaths 901 553 989 1223 1135 Model 1 1.50 (1.25 to 1.79) 1.00 0.98 (0.83 to 1.15) 0.92 (0.79 to 1.08) 1.13 (0.98 to 1.30) Model 2 1.26 (1.03 to 1.53) 1.00 1.02 (0.87 to 1.19) 1.00 (0.86 to 1.16) 1.20 (1.06 to 1.37)From ten years before baseline to baselineAll cause No. of deaths 3853 2205 2184 1115 570 Age-adjusted mortality rate† 38.5 (37.2 to 39.7) 25.5 (24.4 to 26.6) 23.6 (22.6 to 24.6) 25.4 (23.7 to 27.1) 28.5 (25.3 to 31.6) Model 1 1.49 (1.36 to 1.64) 1.00 0.99 (0.91 to 1.07) 1.14 (1.04 to 1.25) 1.68 (1.43 to 1.97) Model 2 1.30 (1.17 to 1.44) 1.00 1.01 (0.93 to 1.09) 1.12 (1.02 to 1.23) 1.57 (1.31 to 1.87)Cardiovascular disease No. of deaths 1106 613 567 267 153 Model 1 1.37 (1.12 to 1.67) 1.00 1.03 (0.86 to 1.23) 1.02 (0.80 to 1.31) 1.82 (1.35 to 2.44) Model 2 1.16 (0.94 to 1.44) 1.00 1.04 (0.88 to 1.23) 0.99 (0.78 to 1.25) 1.70 (1.25 to 2.31)Cancer No. of deaths 773 478 562 281 130 Model 1 1.45 (1.24 to 1.71) 1.00 1.02 (0.86 to 1.21) 1.07 (0.90 to 1.29) 1.36 (1.01 to 1.82) Model 2 1.29 (1.09 to 1.53) 1.00 1.04 (0.87 to 1.25) 1.06 (0.88 to 1.29) 1.24 (0.93 to 1.66)Other causes No. of deaths 1974 1114 1055 567 287 Model 1 1.57 (1.41 to 1.75) 1.00 0.95 (0.84 to 1.07) 1.24 (1.09 to 1.42) 1.80 (1.41 to 2.30) Model 2 1.38 (1.22 to 1.54) 1.00 0.97 (0.86 to 1.09) 1.23 (1.07 to 1.41) 1.70 (1.32 to 2.19)
*Complex survey designs were taken into account for all estimates. A total of 3382, 3032, 2230 participants were excluded in analyses from age 25 years to ten years before baseline, age 25 years to baseline, ten years before baseline to baseline respectively due to missing values of BMI at both times. Model 1 were adjusted for baseline age, sex and race/ethnicity. In analyses from age 25 years to ten years before baseline and age 25 years to baseline, model 2 were adjusted for baseline age, sex, race/ethnicity, height, weight at age 25, education level, household income level, marital status, drinking and smoking status (never, ever, current) and family history of diabetes and heart attack. In analysis from ten years before baseline to baseline, model 2 were adjusted for baseline age, sex, race/ethnicity, height, weight at ten years ago, education level, household income level, marital status, drinking and smoking status (never, ever, current) and family history of diabetes and heart attack. †Mortality rates per 1000 person-years, directly standardized to the age distribution of the entire study population
Page 34 of 58
https://mc.manuscriptcentral.com/bmj
BMJ
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
Confidential: For Review Only
Fig 1 Associations between weight change patterns across adulthood and risk of all cause mortality stratified by baseline age, smoking status and sex in NHANES 1988-2014.
Risk estimates were adjusted for baseline age (not adjusted in subgroup analysis by age), sex (not adjusted in subgroup analysis by sex), race/ethnicity, education level, household income level, marital status,
drinking and smoking status (not adjusted in subgroup analysis by smoking status) and family history of diabetes and heart attack. P for interaction was <0.001, 0.95, 0.01 by baseline age, sex and smoking status
respectively in age 25 years to ten years before baseline. P for interaction was <0.001, 0.49 and 0.03 by baseline age, sex and smoking status respectively in age 25 years to baseline. P for interaction was <0.001,
0.53 and 0.01 by baseline age, sex and smoking status respectively in ten years period before baseline.
230x148mm (96 x 96 DPI)
Page 35 of 58
https://mc.manuscriptcentral.com/bmj
BMJ
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
Confidential: For Review Only
Fig 2 Dose response association between weight change across adulthood and risk of all cause mortality.
Associations were examined by multivariable Cox regression based on restricted cubic splines. Dash line represents estimates of hazard ratios and dotted line represents 95% confidence intervals. Risk estimates
were adjusted for baseline age, sex, race/ethnicity, education level, household income level, marital status, drinking and smoking status and family history of diabetes and heart attack. For weight change from age 25 years to ten years before baseline or to baseline, weight at age 25 and baseline height were also adjusted. For weight change from ten years before baseline to baseline, weight at 10 years ago and baseline height
were adjusted. P for overall association <0.001 in all three periods. P for non-linear association <0.001 in all three periods.
151x298mm (96 x 96 DPI)
Page 36 of 58
https://mc.manuscriptcentral.com/bmj
BMJ
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
Confidential: For Review Only
Page 37 of 58
https://mc.manuscriptcentral.com/bmj
BMJ
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
Confidential: For Review Only
Supplementary tables/figures
Table S1 Weight change patterns across adulthood in NHANES 1988-2014
Table S2 Characteristics of 36 812 study participants aged 40 years or over in NHANES1988-2014 according to weight change from age 25 years to ten years before
baseline
Table S3 Characteristics of 36 812 study participants aged 40 years or over in NHANES1988-2014 according to weight change in the ten year period before baseline
Table S4 Hazard ratios of all cause mortality with obesity status at three age points among 36 812 participants in NHANES 1988-2014
Table S5 Hazard ratios of all cause mortality with weight change patterns stratified by study period
Table S6 Hazard ratios of all cause and cause specific mortality with weight change patterns across adulthood in 36 812 participants in NHANES 1988-2014 with further
adjustment of disease status
Table S7 Hazard ratios of all cause mortality with weight change patterns among 36 812 stratified by age at death in NHANES 1988-2014
Table S8 Hazard ratios of all cause mortality with weight change patterns after excluding participants who were underweight in NHANES 1988-2014
Table S9 Hazard ratios of all cause and cause specific mortality with weight change patterns across adulthood among 31 077 participants after excluding deaths within the
first three years of follow-up in NHANES 1988-2014
Table S10 Hazard ratios of all cause and cause specific mortality with absolute weight change groups across adulthood in 36 812 participants in NHANES 1988-2014 with
Page 38 of 58
https://mc.manuscriptcentral.com/bmj
BMJ
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
Confidential: For Review Only
further adjustment of disease status
Figure S1 Flow chart of inclusion and exclusion of participants
Figure S2 Associations between fine weight change patterns across adulthood and all cause mortality in NHANES 1988-2014
Figure S3 Dose response associations between weight change across adulthood and risk of mortality in the NHANES 1988-2014
Page 39 of 58
https://mc.manuscriptcentral.com/bmj
BMJ
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
Confidential: For Review Only
Table S1 Weight change patterns across adulthood in NHANES 1988-2014From age 25 yearsto ten years before baseline From age 25 years to baseline From ten years before baseline
to baselineAbsolute weight change, median (IQR), kg 6.80 (1.81, 13.6) 11.70 (4.10, 21.07) 3.67 (-1.61, 10.13)Stable Normal
No. of participants 12 201 8529 7785Percent (%) 42.3 29.1 26.9
Maximum overweight No. of participants 12 804 12 955 12 932Percent (%) 36.1 37.7 37.2
Loss No. of participants 403 590 1982Percent (%) 1.2 1.4 4.2
Gain No. of participants 6104 9956 5502Percent (%) 15.3 26.9 15.4
Stable obese No. of participants 1918 1750 6381Percent (%) 5.2 4.9 16.3
Page 40 of 58
https://mc.manuscriptcentral.com/bmj
BMJ
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
Confidential: For Review Only
Table S2 Baseline characteristics of study participants aged 40 or over in NHANES1988-2014 according to patterns of weight change from age 25 years to ten years before baseline a
Weight change patterns bCharacteristics Stable normal Maximum overweight Loss Gain Stable obese Total
No. of participants, n (%) 12 201 (42.3) 12 804 (36.1) 403 (1.2) 6104 (15.3) 1918 (5.2) 33 430Age, mean (95% CI), years 55.0 (54.5, 55.5) 58.7 (58.3, 59.2) 57.9 (56.6, 59.2) 59.8 (59.3, 60.2) 54.3 (53.6, 54.9) 57.1 (56.7, 57.4)Women 7350 (64.9) 5292 (40.7) 158 (37.3) 3154 (51.1) 925 (45.6) 16 879 (52.7)BMI, mean (95% CI), kg/m2
At age 25 years. 20.9 (20.8, 20.9) 23.9 (23.8, 24.0) 33.2 (32.6, 33.8) 25.1 (25.0, 25.2) 34.6 (34.3, 34.9) 23.5 (23.4, 23.5) At 10 years prior baseline 22.2 (22.1, 22.2) 27.0 (27.0, 27.1) 26.8 (26.3, 27.2) 33.8 (33.6, 34.0) 38.2 (37.7, 38.6) 26.6 (26.5, 26.7) Maximum 26.0 (25.9, 26.2) 31.0 (30.9, 31.1) 35.7 (34.8, 36.5) 37.6 (37.4, 37.8) 43.1 (42.6, 43.7) 30.6 (30.5, 30.8) At survey 24.4 (24.3, 24.5) 28.8 (28.7, 28.9) 29.3 (28.4, 30.2) 34.0 (33.8, 34.2) 38.1 (37.6, 38.5) 28.2 (28.1, 28.4)
Waist circumference, mean (95% CI), cm 88.5 (88.2, 88.9) 100.9 (100.7, 101.2) 103.0 (101.3, 104.7) 111.6 (111.1, 112.1) 119.6 (118.6, 120.6) 98.2 (97.9, 98.6)
RaceNon-Hispanic White 6489 (79.0) 6569 (78.3) 208 (78.0) 2923 (76.0) 869 (75.4) 17 058 (78.1)Non-Hispanic Black 2465 (8.4) 2575 (9.4) 83 (9.5) 1498 (12.1) 589 (14.8) 7210 (9.7)Mexican American 1664 (3.2) 2367 (4.9) 79 (4.4) 1187 (5.6) 327 (5.1) 5624 (4.3)Others 1583 (9.4) 1293 (7.4) 33 (8.1) 496 (6.3) 133 (4.7) 3538 (7.9)
Education levelLess than high school 3555 (19.6) 4345 (23.2) 174 (28.4) 2265 (26.9) 665 (23.0) 11 004 (22.3)High school or equivalent 3120 (27.7) 3159 (28.3) 94 (29.0) 1535 (29.4) 473 (29.9) 8381 (28.3)College or above 5498 (52.4) 5273 (48.2) 134 (42.6) 2293 (43.4) 772 (47.0) 13 970 (49.2)
Household income levelBelow or at poverty 1883 (9.1) 1887 (8.5) 82 (11.6) 1021 (10.2) 377 (12.2) 5250 (9.2)Above poverty 9284 (84.2) 9849 (84.7) 296 (84.9) 4589 (83.0) 1407 (82.3) 25 425 (84.1)
Marital statusMarried 7648 (68.4) 8337 (70.5) 245 (67.2) 3735 (66.0) 1100 (65.3) 21 065 (68.6)Separated 3573 (24.9) 3612 (23.6) 125 (25.3) 1990 (28.6) 563 (22.5) 9683 (24.9)Never married 868 (5.8) 720 (5.1) 30 (6.9) 331 (4.7) 238 (11.5) 2187 (5.7)
Alcohol drinkingNever drinker 10765 (89.4) 11095 (87.3) 314 (73.0) 5316 (87.4) 1651 (85.9) 29 141 (88.0)Ever drinker 1330 (9.8) 1609 (11.9) 82 (25.2) 746 (11.9) 252 (13.2) 4019 (11.2)
Smoking statusNever smoker 5685 (45.3) 6031 (45.4) 146 (35.6) 3029 (48.2) 976 (49.2) 15 867 (45.9)
Page 41 of 58
https://mc.manuscriptcentral.com/bmj
BMJ
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
Confidential: For Review Only
Ever smoker 3514 (30.5) 4450 (35.7) 166 (40.3) 2145 (34.5) 563 (31.7) 10 838 (33.1)Current smoker 2994 (24.2) 2319 (18.9) 91 (24.1) 929 (17.3) 378 (19.1) 6711 (21.0)
Family history of chronic metabolic diseases
5570 (47.0) 6236 (48.6) 220 (60.1) 3451 (57.2) 1163 (60.5) 16 640 (50.0)Self-reported chronic diseases
Diabetes 707 (4.0) 1753 (10.0) 92 (12.5) 1712 (22.3) 628 (27.3) 4892 (10.3)Hypertension 3098 (21.2) 4877 (34.9) 146 (30.5) 3241 (50.1) 1013 (53.1) 12 375 (32.4)Cardiovascular diseases 1250 (7.4) 2061 (13.2) 90 (20.3) 1268 (17.6) 414 (16.7) 5083 (11.7)Chronic obstructive pulmonary diseases
1099 (9.4) 993 (8.1) 48 (17.1) 660 (12.2) 197 (10.3) 2997 (9.5)Cancer 1442 (12.7) 1771 (14.1) 54 (13.9) 836 (14.3) 202 (9.6) 4305 (13.3)
a Complex survey designs are considered for all estimates; percentages may not add up to 100% due to missing values. b From age 25 years to ten years before baseline, stable normal: BMI25 < 25 kg/m2 and BMI10prior < 25 kg/m2; maximum overweight: either BMI25 or BMI10prior was 25.0-29.9 kg/m2 and the other BMI not ≥30.0 kg/m2; loss: BMI25 ≥ 30 kg/m2 and 25 ≤ BMI10prior < 30 kg/m2; gain: 25 ≤ BMI25 < 30 kg/m2 and BMI10prior≥ 30 kg/m2; stable obese: BMI25 ≥ 30 kg/m2 and BMI10prior ≥ 30 kg/m2.
Page 42 of 58
https://mc.manuscriptcentral.com/bmj
BMJ
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
Confidential: For Review Only
Table S3 Baseline characteristics of study participants aged 40 or over in NHANES1988-2014 according to weight change patterns in ten years period before baseline a
Weight change patterns bCharacteristics Stable normal Maximum overweight Loss Gain Stable obese Total
No. of participants, n (%) 7785 (26.9) 12 932 (37.2) 1982 (4.2) 5502 (15.4) 6381 (16.3) 34 582Age, mean (95% CI), years 56.3 (55.7, 56.9) 58.1 (57.6, 58.6) 61.6 (60.5, 62.6) 54.9 (54.4, 55.4) 57.7 (57.3, 58.2) 57.2 (56.8, 57.6)Women 4370 (63.4) 5578 (44.3) 867 (42.7) 3273 (58.6) 3457 (52.2) 17 545 (52.8)BMI, mean (95% CI), kg/m2
At age 25 years 20.8 (20.7, 20.9) 23.0 (22.9, 23.1) 25.8 (25.4, 26.1) 23.7 (23.6, 23.9) 27.9 (27.6, 28.2) 23.4 (23.3, 23.5)At 10 years prior baseline 21.6 (21.6, 21.7) 25.5 (25.5, 25.6) 32.9 (32.6, 33.2) 26.8 (26.7, 26.9) 35.5 (35.2, 35.7) 26.6 (26.5, 26.7)Maximum 24.2 (24.1, 24.3) 28.9 (28.9, 29.0) 34.4 (34.1, 34.7) 34.7 (34.5, 34.8) 40.1 (39.9, 40.4) 30.6 (30.5, 30.8)At survey 22.1 (22.0, 22.2) 26.8 (26.7, 26.8) 27.5 (27.3, 27.6) 33.3 (33.2, 33.5) 36.9 (36.7, 37.1) 28.2 (28.1, 28.3)
Waist circumference, mean (95% CI), cm 83.1 (82.9, 83.4) 96.2 (96.0, 96.4) 98.9 (98.3, 99.4) 109.4 (109.0, 109.9) 117.1 (116.7, 117.6) 98.2 (97.9, 98.5)
RaceNon-Hispanic White 4422 (80.6) 6670 (78.5) 865 (73.2) 2419 (73.5) 2999 (75.8) 17 375 (77.6)Non-Hispanic Black 1399 (7.0) 2433 (8.7) 484 (13.7) 1457 (13.0) 1704 (12.9) 7477 (9.8)Mexican American 862 (2.4) 2394 (4.7) 468 (6.8) 1094 (5.9) 1174 (5.4) 5992 (4.5)Others 1102 (10.0) 1435 (8.1) 165 (6.3) 532 (7.7) 504 (5.8) 3738 (8.1)
EducationLess than high school 2273 (19.1) 4506 (23.3) 946 (35.4) 1849 (24.6) 2236 (24.7) 11 810 (23.1)High school or equivalent 1922 (26.4) 3152 (28.1) 443 (27.4) 1396 (29.0) 1619 (29.8) 8532 (28.0)College or above 3560 (54.2) 5243 (48.4) 586 (37.0) 2250 (46.3) 2514 (45.3) 14 153 (48.6)
Household income levelBelow or at poverty 1179 (8.4) 1948 (8.6) 427 (14.3) 959 (11.2) 1091 (10.2) 5604 (9.5)Above poverty 5942 (84.9) 9812 (84.2) 1365 (78.2) 4082 (81.8) 4788 (83.2) 25 989 (83.6)
Marital statusMarried 4812 (67.2) 8387 (70.3) 1128 (62.3) 3423 (68.2) 3845 (65.7) 21 595 (68.1)Separated 2355 (25.8) 3660 (23.5) 725 (31.7) 1622 (25.0) 1993 (26.6) 10 355 (25.2)Never married 548 (6.2) 760 (5.3) 116 (5.5) 398 (6.0) 491 (7.0) 2313 (5.9)
Alcohol drinkingNever drinker 6845 (89.6) 11220 (87.5) 1654 (82.3) 4813 (87.3) 5625 (88.4) 30 157 (88.0)Ever drinker 856 (9.3) 1597 (11.7) 304 (16.3) 651 (12.0) 717 (10.9) 4125 (11.2)
Smoking statusNever smoker 3576 (45.6) 6043 (45.0) 901 (45.5) 2689 (46.1) 3324 (49.8) 16 533 (46.1)
Page 43 of 58
https://mc.manuscriptcentral.com/bmj
BMJ
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
Confidential: For Review Only
Ever smoker 2123 (28.3) 4406 (35.1) 634 (30.1) 1807 (35.4) 2149 (34.3) 11 119 (32.9)Current smoker 2082 (26.1) 2476 (19.9) 446 (24.4) 1004 (18.5) 907 (15.9) 6915 (20.9)
17 062 (49.6) Family history of chronic metabolic diseases
3288 (43.5) 6012 (47.6) 1058 (52.0) 2994 (54.6) 3710 (59.0)
Self-reported chronic diseasesDiabetes 413 (3.5) 1487 (7.7) 614 (23.5) 791 (11.2) 1847 (23.8) 5152 (10.4)Hypertension 1725 (17.3) 4342 (29.8) 961 (44.5) 2297 (40.3) 3454 (52.2) 12 779 (32.3)Cardiovascular diseases 855 (7.6) 1883 (11.5) 509 (22.1) 780 (12.2) 1248 (16.1) 5257 (11.8)
3089 (9.5)Chronic obstructive pulmonary diseases
715 (9.6) 969 (7.8) 217 (12.4) 516 (10.2) 672 (11.5)
Cancer 1059 (14.0) 1729 (13.6) 286 (14.7) 551 (11.5) 776 (12.5) 4401 (13.2)a Complex survey design factors were taken into account for all estimates; percentages may not add up to 100% due to missing values.b From ten years before baseline to baseline, stable normal: BMI10prior < 25 kg/m2 and BMIbaseline < 25 kg/m2; max overweight: either BMI10prior or BMIbaseline was 25.0-29.9 kg/m2 and the other BMI not ≥30.0 kg/m2; losing: BMI10prior ≥ 30 kg/m2 and 25 ≤ BMIbaseline < 30 kg/m2; gaining: 25 ≤ BMI10prior < 30 kg/m2 and BMIbaseline ≥ 30 kg/m2; stable obese: BMI10prior ≥ 30 kg/m2 and BMIbaseline ≥ 30 kg/m2.
Page 44 of 58
https://mc.manuscriptcentral.com/bmj
BMJ
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
Confidential: For Review Only
Table S4 Hazard ratios of all cause mortality with adiposity status at different age points among 36 812 participants in NHANES 1988-2014 aStandard BMI groupsUnderweight Normal weight Overweight Obese
BMI at age 25 yearsMean (95% CI) 17.5 (17.4, 17.6) 21.9 (21.8, 21.9) 26.8 (26.8, 26.9) 34.3 (34.0, 34.6)No. of participants 1902 21 841 7814 2358No. of deaths/person-years 455/21 174 6175/225 062 2323/73 018 696/20 201Model 1 1.00 (0.89, 1.12) 1.00 1.19 (1.11, 1.27) 1.65 (1.45, 1.87)Model 2 0.98 (0.86, 1.12) 1.00 1.17 (1.09, 1.25) 1.43 (1.24, 1.65)
BMI at ten years before baselineMean (95% CI) 17.4 (17.3, 17.6) 22.4 (22.4, 22.5) 27.2 (27.2, 27.3) 34.9 (34.8, 35.1)No. of participants 547 12 651 13 119 8401No. of deaths/person-years 125/6034 3376/137 158 3971/129 407 2524/73 664Model 1 1.53 (1.23, 1.91) 1.00 1.06 (1.00, 1.13) 1.42 (1.32, 1.53)Model 2 1.52 (1.20, 1.92) 1.00 1.02 (0.95, 1.09) 1.22 (1.13, 1.32)
BMI at baselineMean (95% CI) 17.4 (17.3, 17.5) 22.6 (22.5, 22.6) 27.3 (27.3, 27.4) 35.2 (35.1, 35.4)No. of participants 547 9827 13 216 12 461No. of deaths/person-years 275/4282 3347/98 960 3923/135 093 2955/120 644Model 1 1.76 (1.45, 2.13) 1.00 0.92 (0.85, 0.99) 1.16 (1.07, 1.25)Model 2 1.75 (1.42, 2.15) 1.00 0.89 (0.82, 0.96) 1.02 (0.94, 1.11)
Baseline waist quartile Q1 Q2 Q3 Q4Mean (95% CI) 81.3 (81.2, 81.5) 94.1 (94.0, 94.1) 103.0 (102.9, 103.1) 118.6 (118.3, 118.9)No. of participants 8600 8587 8704 8597No. of deaths/person-years 2453/91 738 2446/89 923 2554/86 128 2332/78 984Model 1 1.12 (1.03, 1.22) 1.00 1.11 (1.02, 1.22) 1.39 (1.24, 1.55)Model 2 1.16 (1.06, 1.27) 1.00 1.10 (1.00, 1.20) 1.23 (1.10, 1.37)
a Complex survey designs are considered for all estimates. A total of 2897, 2094, 761, 2324 participants were excluded due to missing values of adiposity indicator at specific age point respectively. Model 1 were adjusted for baseline age, sex, race, education level, marital status, income level, drinking status, smoking status (never, ever, current) and family history of chronic metabolic diseases. Model 2 were additionally adjusted for baseline history of diabetes, hypertension, cardiovascular diseases, cancer and chronic obstructive pulmonary diseases based on model 1.
Page 45 of 58
https://mc.manuscriptcentral.com/bmj
BMJ
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
Confidential: For Review Only
Table S5 Hazard ratios of all cause mortality with weight change patterns stratified by study period aWeight change patterns bStratified by study period Stable Normal Maximum overweight Loss Gain Stable obese
From age 25 years to ten years before baselineNHANES 1988-2014
No. of deaths/person years 3094/133 393 3849/127 257 160/3724 1837/54 404 524/16 220HR (95% CI) 1.00 1.08 (1.01, 1.15) 1.28 (0.92, 1.79) 1.33 (1.22, 1.45) 1.93 (1.72, 2.16)
NHANES Ⅲ (1988-1994)No. of deaths/person years 1777/65 057 2023/54 490 81/1555 891/20 638 241/5700HR (95% CI) 1.00 1.09 (1.01, 1.17) 1.21 (0.80, 1.84) 1.40 (1.25, 1.57) 1.98 (1.70, 2.30)
NHAENS 1999-2014No. of deaths/person-years 1317/68 336 1826/72 767 79/2169 946/33 766 283/10 520HR (95% CI) 1.00 1.05 (0.96, 1.15) 1.57 (1.18, 2.08) 1.25 (1.13, 1.38) 1.83 (1.56, 2.16)
From age 25 years to baselineNHANES 1988-2014
No. of deaths/person years 2677/87 892 3915/131 968 264/4923 2302/98 464 423/15 156HR (95% CI) 1.00 0.94 (0.86, 1.03) 1.21 (0.93, 1.58) 1.11 (1.01, 1.21) 1.81 (1.59, 2.05)
NHANES Ⅲ (1988-1994)No. of deaths/person years 1515/43 435 2114/59 845 122/2059 1173/39 153 204/5277HR (95% CI) 1.00 0.94 (0.85, 1.05) 1.10 (0.77, 1.57) 1.18 (1.06, 1.32) 1.89 (1.59, 2.24)
NHAENS 1999-2014No. of deaths/person-years 1162/44 457 1801/72 123 142/2864 1129/59 312 219/9878HR (95% CI) 1.00 0.93 (0.85, 1.03) 1.53 (1.24, 1.89) 0.99 (0.90, 1.08) 1.62 (1.35, 1.95)
From ten years before baseline to baselineNHANES 1988-2014
No. of deaths/person years 2362/81 771 3924/131 762 852/16 428 1137/58 251 1652/56 972HR (95% CI) 1.00 0.96 (0.88, 1.04) 1.44 (1.28, 1.61) 1.09 (0.95, 1.25) 1.33 (1.22, 1.45)
NHANES sⅢ (1988-1994)HR (95% CI) 1371/40 942 2126/60 056 427/6886 612/24 403 810/20 852Multivariable-adjusted HR (95% CI) 1.00 0.95 (0.86, 1.06) 1.45 (1.22, 1.72) 1.16 (0.96, 1.39) 1.41 (1.26, 1.58)
NHAENS 1999-2014No. of deaths/person years 991/40 829 1798/71 706 425/9542 525/33 848 842/36 120HR (95% CI) 1.00 0.97 (0.88, 1.07) 1.45 (1.23, 1.70) 0.98 (0.87, 1.11) 1.22 (1.11, 1.35)
a Complex survey designs are considered for all estimates. A total of 3382, 3032, 2230 participants were excluded in analyses from age 25 years to ten years before baseline, age 25 years to baseline, ten years before baseline to baseline respectively due to missing values of BMI at both times. Risk estimates were adjusted for baseline age, sex,
Page 46 of 58
https://mc.manuscriptcentral.com/bmj
BMJ
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
Confidential: For Review Only
race/ethnicity, education level, household income level, marital status, drinking and smoking status (never, ever, current) and family history of diabetes and heart attack.b Weight change patterns were defined by BMI at two time points. Stable normal participants had BMI <25.0 kg/m2 at both times, maximum overweight participants had BMI in 25.0-29.9 kg/m2 at either time but not ≥30.0 kg/m2 at the other time, weight loss participants had BMI ≥30.0 kg/m2 at younger age while <30.0 kg/m2 later, weight gain participants had BMI <30.0 kg/m2 at younger age while ≥30.0 kg/m2 later, and stable obese participants had BMI ≥30.0 kg/m2 at both times.
Page 47 of 58
https://mc.manuscriptcentral.com/bmj
BMJ
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
Confidential: For Review Only
Table S6 Hazard ratios of all cause and cause specific mortality with weight change patterns across adulthood in 36 812 participants in NHANES 1988-2014 with further adjustment of disease status a
Weight change patternsCause of death Stable normal Maximum overweight Loss Gain Stable obeseFrom age 25 years to ten years before baselineAll cause
No. of deaths/Person-years 3094/133 393 3849/127 257 160/3724 1837/54 404 524/16 220HR (95% CI) 1.00 1.04 (0.97, 1.11) 1.19 (0.82, 1.73) 1.16 (1.06, 1.27) 1.56 (1.35, 1.79)
Cardiovascular diseasesNo. of deaths 745 1096 44 515 162HR (95% CI) 1.00 1.14 (0.99, 1.31) 1.06 (0.69, 1.63) 1.28 (1.06, 1.54) 1.98 (1.51, 2.59)
CancerNo. of deaths 789 872 27 380 90HR (95% CI) 1.00 1.01 (0.87, 1.17) 0.94 (0.48, 1.82) 1.22 (0.98, 1.53) 1.11 (0.86, 1.45)
Other causesNo. of deaths 1560 1881 89 942 272HR (95% CI) 1.00 1.04 (0.96, 1.14) 1.49 (0.93, 2.37) 1.26 (1.12, 1.42) 1.98 (1.62, 2.43)
From age 25 years to baselineAll cause
No. of deaths/Person-years 2677/87 892 3915/131 968 264/4923 2302/98 464 423/15 156HR (95% CI) 1.00 0.93 (0.85, 1.01) 1.09 (0.81, 1.47) 1.00 (0.92, 1.10) 1.47 (1.27, 1.70)
Cardiovascular diseasesNo. of deaths 687 1071 80 629 125HR (95% CI) 1.00 0.97 (0.82, 1.15) 1.09 (0.75, 1.60) 1.05 (0.91, 1.22) 1.74 (1.31, 2.30)
CancerNo. of deaths 604 919 47 545 73HR (95% CI) 1.00 0.98 (0.83, 1.15) 0.88 (0.55, 1.42) 1.10 (0.96, 1.26) 1.14 (0.83, 1.56)
Other causesNo. of deaths 1386 1925 137 1128 225HR (95% CI) 1.00 0.90 (0.82, 0.98) 1.32 (0.94, 1.87) 1.05 (0.93, 1.18) 1.85 (1.50, 2.28)
From ten years before baseline to baselineAll cause
No. of deaths/Person-years 2362/81 771 3924/131 762 852/16 428 1137/58 251 1652/56 972HR (95% CI) 1.00 0.93 (0.84, 1.02) 1.23 (1.10, 1.38) 1.00 (0.87, 1.14) 1.13 (1.03, 1.24)
Cardiovascular diseases
Page 48 of 58
https://mc.manuscriptcentral.com/bmj
BMJ
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
Confidential: For Review Only
No. of deaths 605 1058 270 318 455HR (95% CI) 1.00 0.89 (0.76, 1.06) 1.40 (1.11, 1.79) 1.03 (0.84, 1.26) 1.18 (0.98, 1.42)
CancerNo. of deaths 567 892 138 273 354HR (95% CI) 1.00 0.96 (0.80, 1.16) 1.09 (0.83, 1.43) 0.99 (0.78, 1.25) 1.20 (1.01, 1.44)
Other causesNo. of deaths 1190 1974 444 546 843HR (95% CI) 1.00 0.96 (0.86, 1.06) 1.41 (1.19, 1.68) 1.09 (0.92, 1.29) 1.29 (1.13, 1.47)
a For all cause mortality, risk estimates were adjusted for baseline age, sex, race/ethnicity, education level, household income level, marital status, drinking and smoking status (never, ever, current), family history of diabetes and heart attack and baseline history of diabetes, hypertension, cardiovascular diseases, cancer and chronic obstructive pulmonary diseases. For cardiovascular disease mortality, risk estimates were adjusted for baseline age, sex, race/ethnicity, education level, household income level, marital status, drinking and smoking status (never, ever, current), family history of diabetes and heart attack and baseline history of diabetes, hypertension, cancer and chronic obstructive pulmonary diseases. For cancer mortality, risk estimates were adjusted for baseline age, sex, race/ethnicity, education level, household income level, marital status, drinking and smoking status (never, ever, current), family history of diabetes and heart attack and baseline history of diabetes, hypertension, cardiovascular diseases and chronic obstructive pulmonary diseases. For other-causes mortality, risk estimates were adjusted for baseline age, sex, race/ethnicity, education level, household income level, marital status, drinking and smoking status (never, ever, current), family history of diabetes and heart attack and baseline history of cardiovascular diseases and cancer.
Page 49 of 58
https://mc.manuscriptcentral.com/bmj
BMJ
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
Confidential: For Review Only
Table S7 Hazard ratios of all cause mortality with weight change patterns among 36 812 stratified by age at death aWeight change patternsStable Normal Maximum overweight Loss Gain Stable obese P for interaction
From age 25 years to ten years before baseline <.0001Stratified by death age groupDead before 65y
No. of deaths 522 459 23 238 140Multivariable-adjusted HR (95% CI) 1.00 1.10 (0.91, 1.32) 1.96 (1.02, 3.79) 1.54 (1.25, 1.89) 2.10 (1.68, 2.63)
Dead between 66y and 75yNo. of deaths 558 688 29 407 132Multivariable-adjusted HR (95% CI) 1.00 1.12 (0.96, 1.31) 1.40 (0.89, 2.21) 1.06 (0.91, 1.24) 1.27 (0.95, 1.68)
Dead between 76y-85yNo. of deaths 975 1341 58 682 156Multivariable-adjusted HR (95% CI) 1.00 1.11 (0.99, 1.26) 1.02 (0.69, 1.52) 1.24 (1.09, 1.41) 1.38 (1.16, 1.66)
Dead after 85yNo. of deaths 1039 1361 50 510 96Multivariable-adjusted HR (95% CI) 1.05 (0.92, 1.21) 0.87 (0.49, 1.55) 1.29 (1.08, 1.55) 1.84 (1.41, 2.40)
From age 25 years to baselineStratified by death age group <.0001Dead before 65y
No. of deaths 335 704 44 421 120Multivariable-adjusted HR (95% CI) 1.00 0.91 (0.72, 1.16) 1.38 (0.91, 2.10) 1.24 (1.00, 1.53) 2.12 (1.64, 2.74)
Dead between 66y and 75yNo. of deaths 457 1352 55 510 107Multivariable-adjusted HR (95% CI) 1.00 0.95 (0.79, 1.13) 1.18 (0.81, 1.72) 0.86 (0.72, 1.01) 1.10 (0.79, 1.53)
Dead between 76y-85yNo. of deaths 872 1386 86 820 129Multivariable-adjusted HR (95% CI) 1.00 0.92 (0.79, 1.07) 1.03 (0.76, 1.39) 1.04 (0.92, 1.17) 1.18 (0.94, 1.47)
Dead after 85yNo. of deaths 1013 3915 79 551 67Multivariable-adjusted HR (95% CI) 1.00 1.00 (0.87, 1.15) 1.12 (0.65, 1.91) 1.13 (0.92, 1.39) 1.51 (1.13, 2.01)
From ten years before baseline to baselineStratified by death age group <.0001Dead before 65y 307 460 98 255 284
No. of deaths 1.00 0.93 (0.72, 1.19) 1.64 (1.16, 2.32) 1.21 (0.93, 1.59) 1.65 (1.31, 2.08)
Page 50 of 58
https://mc.manuscriptcentral.com/bmj
BMJ
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
Confidential: For Review Only
Multivariable-adjusted HR (95% CI)
Dead between 66y and 75y 395 685 175 238 396No. of deaths 1.00 0.97 (0.81, 1.17) 1.15 (0.88, 1.51) 0.87 (0.66, 1.15) 0.94 (0.80, 1.10)Multivariable-adjusted HR (95% CI)
Dead between 76y-85yNo. of deaths 769 1338 307 390 586Multivariable-adjusted HR (95% CI) 1.00 0.95 (0.82, 1.10) 1.37 (1.12, 1.66) 1.11 (0.94, 1.32) 1.11 (0.97, 1.27)
Dead after 85yNo. of deaths 891 1441 272 254 386Multivariable-adjusted HR (95% CI) 1.00 0.96 (0.83, 1.09) 1.40 (1.11, 1.77) 1.00 (0.77, 1.32) 1.26 (1.03, 1.53)
a Complex survey designs are considered for all estimates. Risk estimates were adjusted for baseline age, sex, race/ethnicity, education level, household income level, marital status, drinking and smoking status (never, ever, current) and family history of diabetes and heart attack.
Page 51 of 58
https://mc.manuscriptcentral.com/bmj
BMJ
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
Confidential: For Review Only
Table S8 Hazard ratios of all cause mortality with weight change patterns after excluding participants who were underweight in NHANES 1988-2014 aWeight change patternsStable Normal Maximum overweight Loss Gain Stable obese
From age 25 years to ten years before baselineAll participants
No. of deaths 3094 3849 160 1837 524HR (95% CI) 1.00 1.08 (1.01, 1.15) 1.28 (0.92, 1.79) 1.33 (1.22, 1.45) 1.93 (1.72, 2.16)
Underweight people excludedNo. of deaths 2751 3741 159 1788 524HR (95% CI) 1.00 1.09 (1.02, 1.16) 1.31 (0.94, 1.82) 1.35 (1.23, 1.47) 1.94 (1.73, 2.18)
From age 25 years to baselineAll participants
No. of deaths 2677 3915 264 2302 423HR (95% CI) 1.00 0.94 (0.86, 1.03) 1.21 (0.93, 1.58) 1.11 (1.01, 1.21) 1.81 (1.59, 2.05)
Underweight people excludedNo. of deaths 2253 3750 262 2228 423HR (95% CI) 1.00 0.97 (0.89, 1.06) 1.25 (0.96, 1.63) 1.14 (1.04, 1.25) 1.85 (1.63, 2.11)
From ten years before baseline to baselineAll participants
No. of deaths 2362 3924 852 1137 1652HR (95% CI) 1.00 0.96 (0.88, 1.04) 1.44 (1.28, 1.61) 1.09 (0.95, 1.25) 1.33 (1.22, 1.45)
Underweight people excludedNo. of deaths 2071 3887 848 1132 1652HR (95% CI) 1.00 1.00 (0.92, 1.10) 1.54 (1.37, 1.72) 1.15 (1.01, 1.32) 1.41 (1.29, 1.55)
a Complex survey designs are considered for all estimates. A total of 3382, 3032, 2230 participants were excluded in analyses from age 25 years to ten years before baseline, age 25 years to baseline, ten years before baseline to baseline respectively due to missing values of BMI at both times. Risk estimates were adjusted for baseline age, sex, race/ethnicity, education level, household income level, marital status, drinking and smoking status (never, ever, current) and family history of diabetes and heart attack.
Page 52 of 58
https://mc.manuscriptcentral.com/bmj
BMJ
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
Confidential: For Review Only
Table S9 Hazard ratios of all cause and cause specific mortality with weight change patterns across adulthood among 31 077 participants after excluding deaths within three years of follow-up in NHANES 1988-2014 a
Weight change patternsCause of death b Stable normal Maximum overweight Loss Gain Stable obese
All cause
From age 25 years to ten years before baselineNo. of deaths 2597 3118 127 1462 404Model 1 1.00 1.05 (0.97, 1.13) 1.30 (0.89, 1.88) 1.32 (1.20, 1.45) 1.98 (1.74, 2.26)Model 2 1.00 1.02 (0.94, 1.10) 1.24 (0.84, 1.84) 1.17 (1.06, 1.29) 1.64 (1.41, 1.91)From age 25 years to baseline No. of deaths 2172 3187 188 1923 343Model 1 1.00 0.93 (0.84, 1.02) 1.19 (0.86, 1.63) 1.12 (1.02, 1.24) 1.90 (1.65, 2.18)Model 2 1.00 0.92 (0.83, 1.01) 1.10 (0.78, 1.54) 1.03 (0.93, 1.14) 1.58 (1.36, 1.85)From ten years before baseline to baselineNo. of deaths 1940 3172 634 982 1335Model 1 1.00 0.93 (0.84, 1.03) 1.42 (1.23, 1.63) 1.12 (0.96, 1.31) 1.34 (1.22, 1.48)Model 2 1.00 0.91 (0.81, 1.01) 1.23 (1.08, 1.41) 1.03 (0.88, 1.20) 1.16 (1.04, 1.28)
Cardiovascular diseases
From age 25 years to ten years before baselineNo. of deaths 623 879 39 406 117Model 1 1.00 1.16 (1.00, 1.35) 1.20 (0.79, 1.81) 1.50 (1.25, 1.81) 2.56 (1.93, 3.40)Model 2 1.00 1.11 (0.95, 1.30) 1.20 (0.78, 1.84) 1.30 (1.07, 1.59) 2.09 (1.55, 2.83)From age 25 years to baseline No. of deaths 552 859 54 529 99Model 1 1.00 0.98 (0.81, 1.18) 1.11 (0.73, 1.69) 1.21 (1.04, 1.41) 2.37 (1.77, 3.17)Model 2 1.00 0.95 (0.79, 1.15) 1.07 (0.69, 1.66) 1.08 (0.92, 1.26) 1.93 (1.43, 2.60)From ten years before baseline to baselineNo. of deaths 485 858 194 279 367Model 1 1.00 0.91 (0.75, 1.09) 1.57 (1.20, 2.04) 1.14 (0.92, 1.40) 1.45 (1.19, 1.77)Model 2 1.00 0.87 (0.72, 1.05) 1.36 (1.03, 1.80) 1.03 (0.84, 1.27) 1.22 (1.00, 1.50)
Cancer
From age 25 years to ten years before baseline
Page 53 of 58
https://mc.manuscriptcentral.com/bmj
BMJ
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
Confidential: For Review Only
No. of deaths 646 684 18 294 70Model 1 1.00 1.02 (0.87, 1.20) 1.04 (0.51, 2.13) 1.26 (1.00, 1.59) 1.22 (0.86, 1.74)Model 2 1.00 1.02 (0.87, 1.20) 1.03 (0.51, 2.09) 1.23 (0.97, 1.57) 1.19 (0.85, 1.65)From age 25 years to baselineNo. of deaths 474 733 29 440 60Model 1 1.00 0.98 (0.81, 1.18) 0.86 (0.46, 1.61) 1.16 (0.97, 1.38) 1.28 (0.85, 1.92)Model 2 1.00 0.99 (0.82, 1.20) 0.86 (0.46, 1.59) 1.16 (0.98, 1.37) 1.26 (0.85, 1.86)From ten years before baseline to baselineNo. of deaths 451 697 99 227 278Model 1 1.00 0.96 (0.77, 1.19) 1.14 (0.79, 1.64) 1.06 (0.80, 1.40) 1.28 (1.04, 1.58)Model 2 1.00 0.97 (0.78, 1.20) 1.11 (0.77, 1.59) 1.07 (0.82, 1.40) 1.27 (1.03, 1.57)
Other causes
From age 25 years to ten years before baselineNo. of deaths 1328 1555 70 762 217Model 1 1.00 1.02 (0.92, 1.12) 1.48 (0.90, 2.43) 1.27 (1.12, 1.45) 2.16 (1.73, 2.69)Model 2 1.00 1.02 (0.92, 1.12) 1.44 (0.86, 2.42) 1.26 (1.10, 1.43) 2.08 (1.66, 2.60)From age 25 years to baselineNo. of deaths 1146 1595 105 954 184Model 1 1.00 0.88 (0.79, 0.98) 1.39 (0.96, 2.03) 1.09 (0.96, 1.23) 2.01 (1.59, 2.55)Model 2 1.00 0.88 (0.79, 0.99) 1.35 (0.90, 2.01) 1.07 (0.94, 1.21) 1.94 (1.54, 2.45)From ten years before baseline to baselineNo. of deaths 1004 1617 341 476 690Model 1 1.00 0.94 (0.83, 1.05) 1.47 (1.20, 1.80) 1.13 (0.96, 1.39) 1.33 (1.16, 1.53)Model 2 1.00 0.93 (0.83, 1.05) 1.44 (1.18, 1.76) 1.12 (0.93, 1.35) 1.30 (1.13, 1.50)
a Complex survey designs are considered for all estimates. Model 1 were adjusted for baseline age, sex, race/ethnicity, education level, household income level, marital status, drinking and smoking status (never, ever, current) and family history of diabetes and heart attack. b For all cause mortality, model 2 were additionally adjusted for baseline history of diabetes, hypertension, cardiovascular diseases, cancer and chronic obstructive pulmonary diseases. For CVD mortality, model 2 were additionally adjusted for baseline history of diabetes, hypertension, cancer and chronic obstructive pulmonary diseases. For cancer mortality, model 2 were additionally adjusted for baseline history of diabetes, hypertension, cardiovascular diseases and chronic obstructive pulmonary diseases. For other-causes mortality, model 2 were additionally adjusted for baseline history of cardiovascular diseases and cancer.
Page 54 of 58
https://mc.manuscriptcentral.com/bmj
BMJ
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
Confidential: For Review Only
Table S10 Hazard ratios (95% CI) of all cause and cause specific mortality with weight change in three life periods in 36 812 participants in NHANES 1988-2014 with further adjustment of disease status a
Weight change in three life periodsCause of death b Weight loss ≥2.5 kg Weight loss <2.5 kg
or gain <2.5 kg 2.5 kg ≤ Weight gain < 10 kg 10 kg ≤ Weight gain <20 kg Weight gain ≥20 kg
From age 25 years to ten years before baselineAll cause
No. of deaths 762 2152 2661 2191 1698 Age-adjusted mortality rate c 37.2 (34.5, 39.8) 30.0 (28.7, 31.3) 26.2 (25.2, 27.2) 26.2 (25.1, 27.3) 31.1 (29.6, 32.7)HR (95% CI) 1.12 (0.95, 1.31) 1.00 0.97 (0.87, 1.08) 0.98 (0.87, 1.10) 1.10 (0.98, 1.23)
Cardiovascular diseases No. of deaths 211 565 703 618 465
HR (95% CI) 0.96 (0.79, 1.17) 1.00 0.87 (0.73, 1.04) 0.87 (0.72, 1.05) 1.03 (0.87, 1.21)Cancer No. of deaths 170 510 662 453 363 HR (95% CI) 1.18 (0.92, 1.51) 1.00 1.00 (0.83, 1.19) 1.03 (0.81, 1.30) 1.16 (0.91, 1.49)Other causes No. of deaths 381 1077 1296 1120 870 HR (95% CI) 1.15 (0.90, 1.45) 1.00 1.02 (0.88, 1.19) 1.13 (0.99, 1.29) 1.33 (1.17, 1.51)From age 25 years to baselineAll cause No. of deaths 1801 1059 2027 2417 2277 Age-adjusted mortality rate c 44.4 (42.2, 46.6) 29.1 (27.3, 30.9) 26.5 (25.4, 27.7) 25.6 (24.6, 26.6) 25.7 (24.5, 26.8) HR (95% CI) 1.16 (1.00, 1.35) 1.00 0.97 (0.87, 1.09) 0.94 (0.84, 1.05) 1.00 (0.90, 1.11)Cardiovascular disease No. of deaths 506 296 563 622 605 HR (95% CI) 0.95 (0.75, 1.21) 1.00 0.89 (0.73, 1.09) 0.86 (0.73, 1.01) 0.93 (0.78, 1.12)Cancer
No. of deaths 394 210 475 572 537 HR (95% CI) 1.46 (1.16, 1.84) 1.00 1.12 (0.93, 1.35) 1.10 (0.89, 1.35) 1.17 (0.99, 1.39)Other causes No. of deaths 901 553 989 1223 1135 HR (95% CI) 1.26 (1.04, 1.54) 1.00 1.02 (0.87, 1.19) 1.00 (0.86, 1.16) 1.17 (1.03, 1.34)From ten years before baseline to baselineAll cause
Page 55 of 58
https://mc.manuscriptcentral.com/bmj
BMJ
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
Confidential: For Review Only
No. of deaths 3853 2205 2184 1115 570 Age-adjusted mortality rate c 38.5 (37.2, 39.7) 25.5 (24.4, 26.6) 23.6 (22.6, 24.6) 25.4 (23.7, 27.1) 28.5 (25.3, 31.6) HR (95% CI) 1.25 (1.12, 1.38) 1.00 1.00 (0.92, 1.08) 1.09 (0.98, 1.20) 1.37 (1.14, 1.66)Cardiovascular disease No. of deaths 1106 613 567 267 153 HR (95% CI) 1.14 (0.92, 1.41) 1.00 1.04 (0.88, 1.23) 0.97 (0.76, 1.22) 1.49 (1.09, 2.05)Cancer No. of deaths 773 478 562 281 130 HR (95% CI) 1.27 (1.07, 1.50) 1.00 1.04 (0.87, 1.26) 1.07 (0.88, 1.29) 1.22 (0.92, 1.62)Other causes No. of deaths 1974 1114 1055 567 287 HR (95% CI) 1.34 (1.19, 1.51) 1.00 0.96 (0.85, 1.08) 1.20 (1.04, 1.38) 1.59 (1.22, 2.08)a Complex survey designs were taken into account for all estimates. A total of 3382, 3032, 2230 participants were excluded in analyses from age 25 years to ten years before baseline, age 25 years to baseline, ten years before baseline to baseline respectively due to missing values of BMI at both times. In analyses from age 25 years to ten years before baseline and age 25 years to baseline, risk estimates were adjusted for baseline age, sex, race/ethnicity, height, weight at age 25, education level, household income level, marital status, drinking and smoking status (never, ever, current) and family history of diabetes and heart attack. In analysis from ten years before baseline to baseline, risk estimates were adjusted for baseline age, sex, race/ethnicity, height, weight at ten years ago, education level, household income level, marital status, drinking and smoking status (never, ever, current) and family history of diabetes and heart attack.b For all cause mortality, risk estimates were additionally adjusted for baseline history of diabetes, hypertension, cardiovascular diseases, cancer and chronic obstructive pulmonary diseases. For cardiovascular disease mortality, risk estimates were additionally adjusted for baseline history of diabetes, hypertension, cancer and chronic obstructive pulmonary diseases. For cancer mortality, risk estimates additionally adjusted for baseline history of diabetes, hypertension, cardiovascular diseases and chronic obstructive pulmonary diseases. For other-causes mortality, risk estimates additionally adjusted for baseline history of cardiovascular diseases and cancer based on model 2.
c Mortality rates per 1000 person-years, directly standardized to the age distribution of the entire study population.
Page 56 of 58
https://mc.manuscriptcentral.com/bmj
BMJ
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
Confidential: For Review OnlyFigure S1 Flow chart of inclusion and exclusion of study participants
Page 57 of 58
https://mc.manuscriptcentral.com/bmj
BMJ
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
Confidential: For Review Only
Figure S2 Association between fine weight change patterns across adulthood and all cause mortality in NHANES 1988-2014. All risk estimates were calculated using multivariable Cox regression adjusted for baseline age, sex, race/ethnicity, education level, household income level, marital status, drinking and smoking status and family history of diabetes and heart attack.a Only two participants were in the group so that the effect estimates were not stable and were not shown.b Only three participants were in the group so that the effect estimates were not stable and were not shown.c Only five participants were in the group so that the effect estimates were not stable and were not shown.
Page 58 of 58
https://mc.manuscriptcentral.com/bmj
BMJ
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
Confidential: For Review OnlyFigure S3 Dose response association between weight change across adulthood and risk of cause specific mortality. Associations were examined by multivariable Cox regression based on restricted cubic splines. Dash line represents estimates of hazard ratios and dotted line represents 95% confidence intervals. Risk estimates were adjusted for baseline age, sex, race/ethnicity, education level, household income level, marital status, drinking and smoking status and family history of diabetes and heart attack. For weight change from age 25 years to ten years before baseline or to baseline, weight at age 25 and baseline height were also adjusted. For weight change from ten years before baseline to baseline, weight at 10 years ago and baseline height were adjusted.
Page 59 of 58
https://mc.manuscriptcentral.com/bmj
BMJ
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960