Accepted Manuscript Nut consumption and 5-year all-cause mortality in a Mediterranean cohort: The SUN Project A. Fernández-Montero, M. Bes-Rastrollo, M.T. Barrio-López, de la Fuente-Arrillaga C, J. Salas-Salvadó, L. Moreno-Galarraga, M.A. Martínez-González PII:
S0899-9007(14)00123-3
DOI:
10.1016/j.nut.2014.02.018
Reference:
NUT 9236
To appear in:
Nutrition
Received Date: 15 July 2013 Revised Date:
14 January 2014
Accepted Date: 6 February 2014
Please cite this article as: Fernández-Montero A, Bes-Rastrollo M, Barrio-López M, de la FuenteArrillaga C , Salas-Salvadó J, Moreno-Galarraga L, Martínez-González M, Nut consumption and 5year all-cause mortality in a Mediterranean cohort: The SUN Project, Nutrition (2014), doi: 10.1016/ j.nut.2014.02.018. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT TITLE: Nut consumption and 5-year all-cause mortality in a Mediterranean cohort: The SUN Project.
Fuente-Arrillaga
Cb ,
Salas-Salvadó
Jdc,
RI PT
AUTHORS: Fernández-Montero Aa, Bes-Rastrollo Mb, Barrio-López MTb, de la Moreno-Galarraga
SC
Martínez-González MAbc.
Le,
M AN U
Authors Affiliations a
Department of Occupational Medicine, University of Navarra Clinic, Pamplona,
Spain. b
Department of Preventive Medicine & Public Health. School of Medicine.
c
TE D
University of Navarra, Pamplona, Spain.
Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y
d
EP
Nutrición (CIBERObn), Instituto de Salud Carlos III, Madrid, Spain. The Human Nutrition Department, Hospital Universitari Sant Joan, Institut
e
AC C
d'Investigació Sanitaria Pere i Virgili, Universitat Rovira i Virgili, Reus, Spain. Pediatrics Service, Hospital Virgen del Camino, Servicio Navarro de
Salud-Osasunbidea, Pamplona, Spain.
ACCEPTED MANUSCRIPT Word count: 4817 Tables: 3
RI PT
Figure: 1
Corresponding author
SC
Dr. Alejandro Fernández Montero
M AN U
Department of Occupational Medicine, University of Navarra Clinic. Av, Pio XII, 36. 31008 Pamplona, Spain. email: [email protected]
AC C
EP
Fax: +34-948296500
TE D
Phone: +34-948255400
ACCEPTED MANUSCRIPT ABSTRACT Objective: To assess the association between nut consumption and all-cause mortality after 5-year follow-up in a Spanish cohort.
RI PT
Research Methods & Procedures: The SUN Project [Seguimiento Universidad de Navarra, University of Navarra Follow-up] is a prospective cohort study, formed by Spanish university graduates. Information is gathered by mailed
SC
questionnaires collected biennially. We followed 17,184 participants up to 5 years. Baseline nut consumption was collected by self-reported data, using a
M AN U
validated 136-item semiquatintative food frequency questionnaire (FFQ). Information on mortality was collected by a permanent contact with the SUN participants and their families, postal authorities and the National Death Index. The association between baseline nut consumption and all-cause mortality was
TE D
assessed using Cox proportional hazards model to adjust for potential confounding. Baseline nut consumption was categorized in two ways. In a first analysis we used energy-adjusted quintiles of nut consumption (measured in
EP
g/day). To adjust for total energy intake we used the residuals method. In a second analysis, subjects were categorized in four groups according to
AC C
pre-established categories of nut consumption (servings/day or servings/week). Both analyses were adjusted for potential confounding factors. Results: Participants who consumed nuts twice or more per week had a 56% lower risk of all-cause mortality than those who never or almost never consumed nuts (adjusted hazard ratio: 0.44, 95% confidence intervals: 0.23 to 0.86). Conclusion: Nut consumption was significantly associated with a reduced risk of all-cause mortality after the first five years of follow-up in the SUN Project.
ACCEPTED MANUSCRIPT
AC C
EP
TE D
M AN U
SC
RI PT
KEY WORDS: nut consumption, total mortality, SUN Project
ACCEPTED MANUSCRIPT INTRODUCTION Macronutrient and micronutrient profiles of tree nuts are likely to explain the beneficial health effects of nut consumption observed in many epidemiological studies (1). In spite of the high fat content and relatively high energy density of
RI PT
nuts, randomized trials have consistently shown that nut consumption decreases LDL-Cholesterol concentrations (2) and reduces the incidence of major cardiovascular events (3). However, very few epidemiologic studies have been
SC
conducted on the relationship between nut consumption and mortality. In fact, when we conducted this assessment we did not find any published study that had
M AN U
specifically assessed this association in a Mediterranean population, although Mediterranean countries are characterized by a relatively high nut consumption (4). The PREDIMED trial conducted in Spain (an intervention study using nut consumption in a context of a Mediterranean dietary pattern) found a protective
TE D
effect on hard cardiovascular clinical events, but the effect of nuts on all-cause mortality was not statistically significant (3). The widespread nut consumption seen in Mediterranean countries represents an
EP
ideal setting to explore this association. We assessed the association between nut consumption and all-cause mortality after a 5-year follow-up period in a
AC C
Mediterranean cohort.
MATERIALS AND METHODS Study Population The SUN Project [Seguimiento Universidad de Navarra, University of Navarra Follow-up] is a prospective cohort study, formed by Spanish university graduates.
ACCEPTED MANUSCRIPT The objectives, design and methods of the SUN study have been previously published (5-7). The cohort began in December 1999 and the recruitment of participants is permanently open (constantly including new participants). Information is
RI PT
gathered biennially by mailed questionnaires. All participants included in the SUN cohort have university studies. Thus, a better control of confounding by education-related variables is achieved (i.e. the restriction procedure to control
SC
confounding is applied), which makes the interpretation of results easier and adds validity to the high-quality information derived from their questionnaires
M AN U
(8,9). In addition, several validation studies of this self-reported data have been published, including anthropometric data (10), physical activity questionnaires (11), the diagnosis of hypertension (12) and the specific criteria used for metabolic syndrome definition (13,14), assesing a good quality of this
TE D
self-reported data.
The present analyses took place in December 2012. At this time the SUN cohort
EP
included 21,474 participants. To ensure that all participants had the opportunity to answer the 2-year follow-up questionnaire, we considered eligible only
AC C
participants who had answered the baseline questionnaire before March 2010. Among the remaining 20,572 subjects, 1,953 were outside the pre-specified limits of total energy intake (4,000 kcal / d in men and 3,500 kcal / d in women), and were thus excluded, leaving 18,619 subjects. Eight percent of these participants were lost to follow up (retention rate: 92%), therefore 17,184 subjects were included in the final analyses (Figure 1).
ACCEPTED MANUSCRIPT This study was conducted according to the guidelines established in the Helsinki declaration, and all procedures involving human subjects were approved by the institutional review board of the University on Navarra. Informed consent was implied once the baseline questionnaire was filled-in and returned.
RI PT
Assessment of non-dietary variables
At baseline, information about non-dietary variables was also collected, such as medical history, sociodemographic variables, anthropometric indexes, lifestyle
SC
and health-related habits. Assessment of dietary exposure and nuts consumption
M AN U
We used a 136-item semi-quantitative FFQ previously validated in Spain (15-17) to assess food consumption. Specific questions on nut intake included walnuts, almonds, hazelnuts, and peanuts, as this four nuts are the most frequently consumed by Spanish population. The semi-quantitative FFQ defined 50 gr. of
TE D
peeled nuts as a typical nut serving. During the study, a dietician was in charge of updating the nutrient data bank (18-19). Assessment of Mortality
EP
The primary endpoint was defined as all-cause mortality, including any death occurring between the baseline questionnaire reception and the first five-year
AC C
period of follow-up for each participant. We decided to censor at 5 year the follow-up period to avoid the assumption of an inappropriately long induction period.
A thorough monitoring of participants is carried out in the SUN Study to identify each new participant death. In order to get information from participants who have not responded to any of the follow-up questionnaires, they are contacted by postal mail, email or telephone annually. In the baseline questionnaires three
ACCEPTED MANUSCRIPT different contact addresses are always requested, and participants are asked to communicate their change of address. More than 85% of the deaths identified in the cohort were reported by participants´ relatives, by professional associations or by ordinary mail. The National Death Index was also consulted to verify every
RI PT
death. In the study mortality was grouped into three groups including cardiovascular mortality, mortality due to cancer and non-cardiovascular
SC
non-cancer mortality.
Statistical Analysis
M AN U
In a first analysis, we used the residuals method proposed by Willett (20) to adjust baseline nut consumption (g/d) for total energy intake. The energy-adjusted consumption of nuts was then categorized into quintiles, considering the lowest quintile as the reference category. We estimated hazard ratios (HR) and their
TE D
95% confidence interval (CI) for total mortality during the first five years of follow-up, using Cox regression models. In successive degrees of adjustment, HRs were estimated after adjusting a) only for sex and age, and b) for other
EP
additional potential confounding factors including baseline body mass index (BMI), smoking (never smokers, former smokers, and current smokers in 3
AC C
categories =35 cig/d), alcohol (g/d), adherence to the Mediterranean diet (0 to 9 Trichopoulou score), use of special diets (dichotomous), marital status (3 categories), baseline hypercholesterolemia (dichotomous), hypertension (dichotomous), physical activity (quintiles), time of television watching (continuous), baseline presence of cancer, cardiovascular disease or diabetes (all dichotomous).
ACCEPTED MANUSCRIPT In a second analysis we fitted the same Cox regression models, but we used as exposure
baseline
nut
consumption
categorized
in
servings/day
or
servings/week instead of quintiles of energy-adjusted nut consumption. In these models, total energy intake was introduced only as a covariate in the standard
RI PT
multivariate model. Taking into account the observed distribution of nut consumption at baseline, nut intake was grouped into four categories of consumption: never or almost never, one to three times per month, once a week,
SC
or at least two times per week. The models were adjusted for the same variables as stated above.
M AN U
In both analyses, tests for linear trend were computed by fitting a continuous variable assigning each individual the median level of nut consumption of their respective category (in g/d or servings/d). As sensitivity analyses, we estimated the full-adjusted HR for the consumption of nuts (servings/d or servings/wk) after
TE D
modifying several assumptions: (1) using age instead of time from recruitment to the cohort as the underlying time variable; (2) restricting the analysis only to participants who were health professionals; (3) excluding subjects with cancer,
EP
cardiovascular disease or both at baseline; (4) censoring early or late deaths at various intervals in order to adopt different assumptions on the induction period;
AC C
(5) adopting different limits for allowable total energy intake. Robust standard errors were always used in Cox models. All P-values were 2-sided, P
S0899-9007(14)00123-3
DOI:
10.1016/j.nut.2014.02.018
Reference:
NUT 9236
To appear in:
Nutrition
Received Date: 15 July 2013 Revised Date:
14 January 2014
Accepted Date: 6 February 2014
Please cite this article as: Fernández-Montero A, Bes-Rastrollo M, Barrio-López M, de la FuenteArrillaga C , Salas-Salvadó J, Moreno-Galarraga L, Martínez-González M, Nut consumption and 5year all-cause mortality in a Mediterranean cohort: The SUN Project, Nutrition (2014), doi: 10.1016/ j.nut.2014.02.018. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT TITLE: Nut consumption and 5-year all-cause mortality in a Mediterranean cohort: The SUN Project.
Fuente-Arrillaga
Cb ,
Salas-Salvadó
Jdc,
RI PT
AUTHORS: Fernández-Montero Aa, Bes-Rastrollo Mb, Barrio-López MTb, de la Moreno-Galarraga
SC
Martínez-González MAbc.
Le,
M AN U
Authors Affiliations a
Department of Occupational Medicine, University of Navarra Clinic, Pamplona,
Spain. b
Department of Preventive Medicine & Public Health. School of Medicine.
c
TE D
University of Navarra, Pamplona, Spain.
Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y
d
EP
Nutrición (CIBERObn), Instituto de Salud Carlos III, Madrid, Spain. The Human Nutrition Department, Hospital Universitari Sant Joan, Institut
e
AC C
d'Investigació Sanitaria Pere i Virgili, Universitat Rovira i Virgili, Reus, Spain. Pediatrics Service, Hospital Virgen del Camino, Servicio Navarro de
Salud-Osasunbidea, Pamplona, Spain.
ACCEPTED MANUSCRIPT Word count: 4817 Tables: 3
RI PT
Figure: 1
Corresponding author
SC
Dr. Alejandro Fernández Montero
M AN U
Department of Occupational Medicine, University of Navarra Clinic. Av, Pio XII, 36. 31008 Pamplona, Spain. email: [email protected]
AC C
EP
Fax: +34-948296500
TE D
Phone: +34-948255400
ACCEPTED MANUSCRIPT ABSTRACT Objective: To assess the association between nut consumption and all-cause mortality after 5-year follow-up in a Spanish cohort.
RI PT
Research Methods & Procedures: The SUN Project [Seguimiento Universidad de Navarra, University of Navarra Follow-up] is a prospective cohort study, formed by Spanish university graduates. Information is gathered by mailed
SC
questionnaires collected biennially. We followed 17,184 participants up to 5 years. Baseline nut consumption was collected by self-reported data, using a
M AN U
validated 136-item semiquatintative food frequency questionnaire (FFQ). Information on mortality was collected by a permanent contact with the SUN participants and their families, postal authorities and the National Death Index. The association between baseline nut consumption and all-cause mortality was
TE D
assessed using Cox proportional hazards model to adjust for potential confounding. Baseline nut consumption was categorized in two ways. In a first analysis we used energy-adjusted quintiles of nut consumption (measured in
EP
g/day). To adjust for total energy intake we used the residuals method. In a second analysis, subjects were categorized in four groups according to
AC C
pre-established categories of nut consumption (servings/day or servings/week). Both analyses were adjusted for potential confounding factors. Results: Participants who consumed nuts twice or more per week had a 56% lower risk of all-cause mortality than those who never or almost never consumed nuts (adjusted hazard ratio: 0.44, 95% confidence intervals: 0.23 to 0.86). Conclusion: Nut consumption was significantly associated with a reduced risk of all-cause mortality after the first five years of follow-up in the SUN Project.
ACCEPTED MANUSCRIPT
AC C
EP
TE D
M AN U
SC
RI PT
KEY WORDS: nut consumption, total mortality, SUN Project
ACCEPTED MANUSCRIPT INTRODUCTION Macronutrient and micronutrient profiles of tree nuts are likely to explain the beneficial health effects of nut consumption observed in many epidemiological studies (1). In spite of the high fat content and relatively high energy density of
RI PT
nuts, randomized trials have consistently shown that nut consumption decreases LDL-Cholesterol concentrations (2) and reduces the incidence of major cardiovascular events (3). However, very few epidemiologic studies have been
SC
conducted on the relationship between nut consumption and mortality. In fact, when we conducted this assessment we did not find any published study that had
M AN U
specifically assessed this association in a Mediterranean population, although Mediterranean countries are characterized by a relatively high nut consumption (4). The PREDIMED trial conducted in Spain (an intervention study using nut consumption in a context of a Mediterranean dietary pattern) found a protective
TE D
effect on hard cardiovascular clinical events, but the effect of nuts on all-cause mortality was not statistically significant (3). The widespread nut consumption seen in Mediterranean countries represents an
EP
ideal setting to explore this association. We assessed the association between nut consumption and all-cause mortality after a 5-year follow-up period in a
AC C
Mediterranean cohort.
MATERIALS AND METHODS Study Population The SUN Project [Seguimiento Universidad de Navarra, University of Navarra Follow-up] is a prospective cohort study, formed by Spanish university graduates.
ACCEPTED MANUSCRIPT The objectives, design and methods of the SUN study have been previously published (5-7). The cohort began in December 1999 and the recruitment of participants is permanently open (constantly including new participants). Information is
RI PT
gathered biennially by mailed questionnaires. All participants included in the SUN cohort have university studies. Thus, a better control of confounding by education-related variables is achieved (i.e. the restriction procedure to control
SC
confounding is applied), which makes the interpretation of results easier and adds validity to the high-quality information derived from their questionnaires
M AN U
(8,9). In addition, several validation studies of this self-reported data have been published, including anthropometric data (10), physical activity questionnaires (11), the diagnosis of hypertension (12) and the specific criteria used for metabolic syndrome definition (13,14), assesing a good quality of this
TE D
self-reported data.
The present analyses took place in December 2012. At this time the SUN cohort
EP
included 21,474 participants. To ensure that all participants had the opportunity to answer the 2-year follow-up questionnaire, we considered eligible only
AC C
participants who had answered the baseline questionnaire before March 2010. Among the remaining 20,572 subjects, 1,953 were outside the pre-specified limits of total energy intake (4,000 kcal / d in men and 3,500 kcal / d in women), and were thus excluded, leaving 18,619 subjects. Eight percent of these participants were lost to follow up (retention rate: 92%), therefore 17,184 subjects were included in the final analyses (Figure 1).
ACCEPTED MANUSCRIPT This study was conducted according to the guidelines established in the Helsinki declaration, and all procedures involving human subjects were approved by the institutional review board of the University on Navarra. Informed consent was implied once the baseline questionnaire was filled-in and returned.
RI PT
Assessment of non-dietary variables
At baseline, information about non-dietary variables was also collected, such as medical history, sociodemographic variables, anthropometric indexes, lifestyle
SC
and health-related habits. Assessment of dietary exposure and nuts consumption
M AN U
We used a 136-item semi-quantitative FFQ previously validated in Spain (15-17) to assess food consumption. Specific questions on nut intake included walnuts, almonds, hazelnuts, and peanuts, as this four nuts are the most frequently consumed by Spanish population. The semi-quantitative FFQ defined 50 gr. of
TE D
peeled nuts as a typical nut serving. During the study, a dietician was in charge of updating the nutrient data bank (18-19). Assessment of Mortality
EP
The primary endpoint was defined as all-cause mortality, including any death occurring between the baseline questionnaire reception and the first five-year
AC C
period of follow-up for each participant. We decided to censor at 5 year the follow-up period to avoid the assumption of an inappropriately long induction period.
A thorough monitoring of participants is carried out in the SUN Study to identify each new participant death. In order to get information from participants who have not responded to any of the follow-up questionnaires, they are contacted by postal mail, email or telephone annually. In the baseline questionnaires three
ACCEPTED MANUSCRIPT different contact addresses are always requested, and participants are asked to communicate their change of address. More than 85% of the deaths identified in the cohort were reported by participants´ relatives, by professional associations or by ordinary mail. The National Death Index was also consulted to verify every
RI PT
death. In the study mortality was grouped into three groups including cardiovascular mortality, mortality due to cancer and non-cardiovascular
SC
non-cancer mortality.
Statistical Analysis
M AN U
In a first analysis, we used the residuals method proposed by Willett (20) to adjust baseline nut consumption (g/d) for total energy intake. The energy-adjusted consumption of nuts was then categorized into quintiles, considering the lowest quintile as the reference category. We estimated hazard ratios (HR) and their
TE D
95% confidence interval (CI) for total mortality during the first five years of follow-up, using Cox regression models. In successive degrees of adjustment, HRs were estimated after adjusting a) only for sex and age, and b) for other
EP
additional potential confounding factors including baseline body mass index (BMI), smoking (never smokers, former smokers, and current smokers in 3
AC C
categories =35 cig/d), alcohol (g/d), adherence to the Mediterranean diet (0 to 9 Trichopoulou score), use of special diets (dichotomous), marital status (3 categories), baseline hypercholesterolemia (dichotomous), hypertension (dichotomous), physical activity (quintiles), time of television watching (continuous), baseline presence of cancer, cardiovascular disease or diabetes (all dichotomous).
ACCEPTED MANUSCRIPT In a second analysis we fitted the same Cox regression models, but we used as exposure
baseline
nut
consumption
categorized
in
servings/day
or
servings/week instead of quintiles of energy-adjusted nut consumption. In these models, total energy intake was introduced only as a covariate in the standard
RI PT
multivariate model. Taking into account the observed distribution of nut consumption at baseline, nut intake was grouped into four categories of consumption: never or almost never, one to three times per month, once a week,
SC
or at least two times per week. The models were adjusted for the same variables as stated above.
M AN U
In both analyses, tests for linear trend were computed by fitting a continuous variable assigning each individual the median level of nut consumption of their respective category (in g/d or servings/d). As sensitivity analyses, we estimated the full-adjusted HR for the consumption of nuts (servings/d or servings/wk) after
TE D
modifying several assumptions: (1) using age instead of time from recruitment to the cohort as the underlying time variable; (2) restricting the analysis only to participants who were health professionals; (3) excluding subjects with cancer,
EP
cardiovascular disease or both at baseline; (4) censoring early or late deaths at various intervals in order to adopt different assumptions on the induction period;
AC C
(5) adopting different limits for allowable total energy intake. Robust standard errors were always used in Cox models. All P-values were 2-sided, P
