Mediterranean diet and quality of life: Baseline cross-sectional analysis of the PREDIMED-PLUS trial

RESEARCH ARTICLE Mediterranean diet and quality of life: Baseline cross-sectional analysis of the PREDIMED-PLUS trial Iñigo Galilea-Zabalza 1,2 , Pilar Buil-Cosiales 1,2,3 , Jordi Salas-Salvado ´ 2,4 , Estefanı ´a Toledo 2,3 , Carolina Ortega-Azorı ´n 2,5 , Javier Dı ´ez-Espino 1,2,3 , Zenaida Va ´zquezRuiz 2,3 , Marı ´a Dolores Zomeño 6,7 , Jesu ´s Vioque 8,9 , Jose ´Alfredo Martı ´nez 2,10 , Dora Romaguera 2,11 , Napoleo ´n Perez-Farinos 12 , Jose ´Lo ´pez-Miranda 2,13 , Ramo ´n Estruch 2,14 , Aurora Bueno-Cavanillas 7,15 , Fernando Aro ´s 2,16,17 , Josep Antoni Tur 2,18 , Francisco Tinahones 2,18 , Lluis Serra-Majem 2,19 , Alba Marcos-Delgado 7,20 , Manuel Ortega-Calvo 2,21 , Clotilde Va ´zquez 2,22 , Xavier Pinto ´ 2,23 , Josep Vidal 24,25 , Lidia Daimiel 26 , Miguel Delgado-Rodrı ´guez 7,27 , Pilar Matı ´a 28 , Dolores Corella 2,5 , Andre ´s Diaz-Lo ´pez 2,4 , Nancy Babio 4 , Miguel Angel Muñoz 2,29 , Montse Fito ´ 2,29 , Sandra Gonza ´lez-Palacios 8,9 , Itziar Abete 10 , Antonio Garcı ´a-Rios 13 , Emilio Ros 2,30 , Miguel A ´ngel Martı ´nez-Gonza ´lez 2,3,31 *, for the PREDIMED-PLUS Study Investigators ‡ 1Atencio ´n Primaria. Osasunbidea-Servicio Navarro de Salud. Pamplona, Spain, 2CIBER Fisiopatologı ´a de la Obesidad y Nutricio ´n (CIBERobn), Instituto de Salud Carlos III (ISCIII), Madrid, Spain, 3Department of Preventive Medicine and Public Health, University of Navarra-IdiSNA, Pamplona, Spain, 4Human Nutrition Unit, IISPV, Universitat Rovira i Virgili, Reus, Spain, 5Department of Preventive Medicine, University of Valencia, Valencia, Spain, 6Cardiovascular Risk and Nutrition, IMIM-Hospital del Mar Medical Research Institute, Barcelona, Spain, 7Blanquerna School of Life Sciences, Universitat Ramon Llull, Barcelona, Spain, 8CIBER Epidemiologı ´a y Salud Pu ´blica (CIBEResp), Instituto de Salud Carlos III (ISCIII), Madrid, Spain, 9Nuritional Epidemiology Unit, Miguel Hernandez University, ISABIAL-FISABIO, Alicante, Spain, 10 Department of Nutrition and Food Sciences, Physiology and Toxicology, University of Navarra, Pamplona, Spain, 11 Health Research Institute of the Balearic Islands (IdISBa), University Hospital Son Espases, Palma, Spain, 12 School of Nursing, University of Ma ´laga, Ma ´laga, Spain, 13 Department of Internal Medicine, Reina Sofia University Hospital, University of Co ´rdoba-IMIBIC, Co ´rdoba, Spain, 14 Department of Internal Medicine, IDIBAPS, Hospital Clinic, University of Barcelona, Barcelona, Spain, 15 Department of Preventive Medicine, University of Granada, Granada, Spain, 16 Department of Cardiology OSI ARABA. University Hospital Araba, Vitoria, Spain, 17 University of the Basque Country UPV/EHU, Vitoria-Gasteiz. Spain, 18 Department of Endocrinology, University Hospital, University of Ma ´laga, Ma ´laga, Spain, 19 Institute for Biomedical Research, University of Las Palmas de Gran Canaria, Las Palmas, Spain, 20 Instituto de Biomedicina (IBIOMED); Universidad de Leo ´n, Leo ´n, Spain, 21 Department of Family Medicine, Distrito Sanitario Atencion Primaria, Centro de Salud Las Palmeritas, Sevilla, Spain, 22 Department of Endocrinology, Fundacio ´n Jime ´nez-Dı ´az, Madrid, Spain, 23 Lipids and Vascular Risk Unit, Internal Medicine, Hospital Universitario de Bellvitge, Hospitalet de Llobregat, Barcelona, Spain, 24 CIBER Diabetes y enfermedades metabo ´licas (CIBERdem), Instituto de Salud Carlos III (ISCIII), Madrid, Spain, 25 Department of Endocrinology, IDIBAPS, Hospital Clinic, University of Barcelona, Barcelona, Spain, 26 Nutritional Genomics and Epigenomics Group, IMDEA Food, CEI UAM + CSIC, Madrid, Spain, 27 Division of Preventive Medicine, University of Jae ´n, Jae ´n, Spain, 28 Instituto de Investigacio ´n Sanitaria del Hospital Clı ´nico San Carlos, Madrid, Spain, 29 Lipids and Cardiovascular Epidemiology Research Unit, Institut Municipal d’Investigacio ´Mèdica (IMIM), Barcelona, Spain, 30 Lipid Clinic, Department of Endocrinology and Nutrition, Institut d’Investigacions Biomèdiques August Pi Sunyer (IDIBAPS), Hospital Clı ´nic, Barcelona, Spain, 31 Department of Nutrition, Harvard T. H. Chan School of Public Health, Boston, United State of America ‡ Complete membership of the author group can be found in the Acknowledgments. *[email protected] PLOS ONE | https://doi.org/10.1371/journal.pone.0198974 June 18, 2018 1 / 18 a1111111111 a1111111111 a1111111111 a1111111111 a1111111111 OPEN ACCESS Citation: Galilea-Zabalza I, Buil-Cosiales P, SalasSalvado ´J, Toledo E, Ortega-Azorı ´n C, Dı ´ez-Espino J, et al. (2018) Mediterranean diet and quality of life: Baseline cross-sectional analysis of the PREDIMED-PLUS trial. PLoS ONE 13(6): e0198974. https://doi.org/10.1371/journal. pone.0198974 Editor: Sabine Rohrmann, University of Zurich, SWITZERLAND Received: February 20, 2018 Accepted: May 28, 2018 Published: June 18, 2018 Copyright: ©2018 Galilea-Zabalza et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Data Availability Statement: All relevant data are within the paper and its Supporting Information files. Funding: This project is funded by the European Research Council (Advanced Research Grant 2013-2018; 340918) granted to MAM-G, the Spanish Ministry of Health - Instituto de Salud Carlos III (ISCIII) for the periods 2014-2016, 20152017, 2017-2019 and 2018-2020, through the Fondo de Investigacio ´n para la Salud (FIS), which Abstract We assessed if a 17-item score capturing adherence to a traditional Mediterranean diet (MedDiet) was associated with better health-related quality of life among older Spanish men and women with overweight or obesity harboring the metabolic syndrome. We analyzed baseline data from 6430 men and women (age 55–70 years) participating in the PREDIMED-Plus study. PREDIMED-Plus is a multi-centre randomized trial testing an energyrestricted MedDiet combined with promotion of physical activity and behavioral therapy for primary cardiovascular prevention compared to a MedDiet alone. Participants answered a 36-item questionnaire about health-related quality of life (HRQoL) and a 17-item questionnaire that assessed adherence to an MedDiet. We used ANCOVA and multivariableadjusted linear regression models to compare baseline adjusted means of the quality of life scales according to categories of adherence to the MedDiet. Higher adherence to the MedDiet was independently associated with significantly better scores in the eight dimensions of HRQoL. Adjusted differences of >= 3 points between the highest and the lowest dietary adherence groups to the MedDiet were observed for vitality, emotional role, and mental health and of >= 2 points for the other dimensions. In conclusion, this study shows a positive association between adherence to a MedDiet and several dimensions of quality of life. Introduction Even though numerous studies have linked a high-quality dietary pattern with lower incidence of chronic diseases [1], particularly cardiovascular disease [2,3], the effect of high-quality dietary patterns on health-related quality of life (HRQL) is still not well known [4–7]. Self-perceived HRLQ is a relevant variable because it could be a predictor of chronic disease and mortality in the long term [8–9] and it is likely to be influenced by an overall high-quality dietary pattern. During the last 2 decades, the use of patient-reported outcome measures represents a strong shift in medicine, because previously the main reliance was on clinical measurements and biomarkers instead of self-reported information. In this context, self-reported quality of life is considered as the extent to which the life of a person is felt as comfortable or satisfying. Quality of life has more to do with happiness, convenience, well-being and easiness in life than with wealth, power or hierarchical/professional roles. According to the US government goals “Healthy People 2020”, health-related quality of life (HRQL) is a “multi-dimensional concept that includes domains related to physical, mental, emotional, and social functioning. It goes beyond direct measures of population health, life expectancy, and causes of death, and focuses on the impact health status has on quality of life” (www.healthypeople.gov). The most frequently used tool to appraise HRQL is the short-form 36 questionnaire. HRQL can be partly determined by dietary patterns. Studying dietary patterns instead of individual foods or nutrients is the state-of-the-art in current nutritional epidemiology, because complete dietary patterns provide a more realistically picture of food consumption habits while capturing the synergistic or antagonistic effects that foods and nutrients may have when they are consumed together [10]. In the context of overall dietary patterns, the traditional Mediterranean diet (MedDiet) has been found to be associated with better HRQL in the Moli-sani Project, a population-based cohort study in Italy [11]. Smaller cross-sectional studies conducted in Spain [12–13] have also shown positive associations between adherence to the Mediterranean diet and quality of life PLOS ONE | https://doi.org/10.1371/journal.pone.0198974 June 18, 2018 2 / 18 is co-funded by the European Regional Development Fund (four coordinated FIS grants lead by Jordi Salas-Salvado ´and Josep Vidal, including the following projects: PI13/00673, PI13/ 00492, PI13/00272, PI13/01123, PI13/00462, PI13/00233, PI13/02184, PI13/00728 PI13/01090 PI13/01056, PI14/01722, PI14/00636, PI14/00618, PI14/00696, PI14/01206, PI14/01374, PI14/01919, PI14/00853, PI16/00743 PI16/00501, PI17/ 000508), by a Recercaixa grant 2013 (2013ACUP00194), by a grant from the Consejerı ´a de Salud de la Junta de Andalucı ´a (PI0458/2013), and a SEMERGEN grant. None of these funding sources plays any role in the design, collection, analysis, or interpretation of the data or in the decision to submit manuscripts for publication. Competing interests: The authors have declared that no competing interests exist. MedDiet and HRQL. In the SUN Project [14], a Spanish multipurpose prospective cohort study including more than 11,000 middle-aged university graduates, a significant direct association between higher baseline adherence to the MedDiet and better physical and mental health dimensions of HRQL was reported after a 4-year follow-up. In general, studies have found better HRQL associated with higher adherence to the Mediterranean diet, but the dimensions of health categories differ among studies. In some studies, the beneficial association was observed for the physical dimensions [7,14], whereas in others improvements were observed only for mental dimensions [11,13,15]. The ascertainment of the reasons for these differences and the mechanisms involved is still a matter of investigation. HRQL is becoming more important with the steady increase in life expectancy and could inform general practitioners and policy makers for decision-making. Collecting sound evidence on the link between high adherence to an MedDiet and HRQL among older individuals at high risk of cardiovascular disease is especially appealing from a public health perspective. In this context, the primary aim of our study was to assess whether baseline adherence to a MedDiet was cross-sectionally associated with better baseline HRQL in the participants of the PREDIMED-Plus randomized trial. Methods Study design and participants We performed a cross-sectional analysis of the participants in the PREDIMED-Plus study, a multi-centre randomized trial. PREDIMED-Plus aims to evaluate the effect of an energyrestricted MedDiet associated with physical exercise and behavioral therapy compared to a traditional Mediterranean diet alone for the primary prevention of cardiovascular disease in Spain (http://medpreventiva.es/QufSWn). The trial was approved by de Institutional Review Board of all the recruitment centers where the study was conducted (CEI Provincial de Ma ´laga, CEI de los Hospitales Universitarios Virgen Macarena y Virgen del Rocio, CEI de la Universidad de Navarra, CEI de las Illes Balears, CEIC del Hospital Clinic de Barcelona, CEIC del Parc de Salut Mar, CEIC del Hospital Universitari Sant Joan de Reus, CEI del Hospital Universitario San Cecilio, CEIC de la Fundacion Jimenez Dıaz, CEIC Euskadi, CEI en Humanos de la Universidad de Valencia, CEIC del Hospital Universitario de Gran Canaria Doctor Negrın, CEIC del Hospital Universitario de Bellvitge, CEI de Cordoba, CEI de Instituto Madrileño De Estudios Avanzados, CEIC del Hospital Clınico San Carlos, CEI Provincial de Malaga, CEI de las Illes Balears, CCEI de la Investigacion Biomedica de Andalucıa and CEIC de Leon. Participants signed a written informed consent form. The trial was registered in 2014 at the International Standard Randomized Controlled Trial (ISRCTN89898870) and it was funded by the European Research Council (Advanced Research Grant (http://medpreventiva.es/N37jk1). Participants in the PREDIMED-Plus trial are men aged between 55–75 years and women aged between 60–75 years, with a body mass index (BMI) between 27 and 40 kg/m 2 and disclosing the metabolic syndrome [16], but no cardiovascular disease at enrollment. The recruitment took place between September 2013 and December 2016. During that period, 6874 participants were recruited and randomized. For the present analysis, we included all participants who had answered the adapted HRQL questionnaire validated for the Spanish population [14,15], and the 17-item questionnaire of adherence to a MedDiet (Table 1). In total, 6768 participants answered to the SF-36, but only 5416 among them completed all the items of the questionnaire. As some participants left blank only some items of the questionnaire, we imputed for these 1352 participants the missing items using their average score for the other items belonging to that same dimension. Thus, we included information on 6430 participants (Fig 1). Mediterranean diet and quality of life PLOS ONE | https://doi.org/10.1371/journal.pone.0198974 June 18, 2018 3 / 18 Diet The traditional Mediterranean diet is characterized by the use of olive oil as main culinary fat and, consequently, a high intake of fat from vegetable sources and of fruits, vegetables, legumes, nuts and fish, and a low intake of red meat and sweets. In the 17-item screener shown in Table 1 that we developed to assess adherence to a MedDiet, an adequate consumption of typical traditional Mediterranean foods adds one point and low consumption of foods not characteristic of the MedDiet diet also adds one point. In this 17-item questionnaire we took into account the need for weight loss among these overweight/obese participants and included several items (#4, #5, #6–8, #11, #15–16) specifically tailored to improve the ability of the MedDiet to attain long-term sustainable weight loss. An, in fact, an inverse relationship was observed between better adherence to the 17-item MedDiet screener and total energy intake (Fig 2). All participants completed the 17-item screener in the baseline visit. Health-related quality of life We used an adapted version of previously published questionnaires of HRQL that were validated for the Spanish population [7,14]. This questionnaire has been extensively used in Spain as an accurate way to measure self-perceived HRQL (https://goo.gl/Uyn5u6,https://goo.gl/ Gs31ua). It allows studying different dimensions that can be grouped in an aggregated Table 1. Mediterranean diet used in the intervention arm of the PREDIMED-PLUS trial: 17-point questionnaire to assess adherence. Questions Criteria for 1 point Do you use only extra-virgin olive oil for cooking, salad dressings, and spreads? Yes How many fruit units (including natural fruit juices) do you consume per day? 3 How many servings of vegetables/garden produce do you consume per day? [1 serving: 200 g (consider side dishes as half a serving)] 2 (1 portion raw or in a salad) How many servings of white bread do you consume per day? (1 serving: 75 g) 1 How many times per week do you consume whole grain cereals and pasta? 5 How many servings of red meat, hamburgers, or meat products (ham, sausage, etc.) do you consume per week? (1 serving: 100–150 g) 1 How many servings of butter, margarine, or cream do you consume per week? (1 serving: 12 g) <1 How many sugary beverages or sugar-sweetened fruit juices do you drink per week? <1 How many servings of legumes do you consume per week? (1 serving: 150 g) 3 How many servings of fish or shellfish do you consume per week? (1 serving: 100–150 g of fish or 4–5 units or 200 g of shellfish) 3 How many times per week do you consume commercial sweets or pastries (not homemade), such as cakes, cookies, sponge cake, or custard? <3 How many servings of nuts (including peanuts) do you consume per week? (1 serving: 30 g) 3 Do you preferentially consume chicken, turkey or rabbit instead of beef, pork hamburgers or sausages? Yes How many times per week do you consume vegetables, pasta, rice or other dishes seasoned with sofrito (sauce made with tomato and onion, leek or garlic and simmered in olive oil)? 2 Do you preferentially add non-caloric artificial sweeteners to beverages (such as coffee or tea) instead of sugar? Yes How many times per week do you consume non-whole grain pasta or white rice? <3 How many glasses of wine do you drink per day? (1 glass: 100 ml) 2–3 for men 1–2 for women https://doi.org/10.1371/journal.pone.0198974.t001 Mediterranean diet and quality of life PLOS ONE | https://doi.org/10.1371/journal.pone.0198974 June 18, 2018 4 / 18 physical dimension and an aggregated mental dimension. Specifically, the 36 items measure eight multi-item dimensions: physical functioning, role limitations due to physical health problems (role-physical), bodily pain, general health perceptions, vitality, social functioning, role limitations due to emotional problems (role emotional) and mental health. The first four domains deal with physical aspects, and the next four reflect psychological features. For each parameter, scores are coded, summed and transformed to a scale from 0 (the worst possible condition) to 100 (the best possible condition). This questionnaire is a useful tool to compare health status that varies according to different healthy lifestyles and diseases [17]. The HQRL was completed during the baseline visit. Other covariates Only participants with metabolic syndrome were included in the PREDIMED-Plus trial. After an overnight fasting, blood samples were collected at the initial screening visits. Aliquots of serum and EDTA plasma were immediately processed, coded and stored at -80˚C in a central Fig 1. Flow-chart of participants in the PREDIMED Plus trial. HRQL: Health related quality of life. https://doi.org/10.1371/journal.pone.0198974.g001 Mediterranean diet and quality of life PLOS ONE | https://doi.org/10.1371/journal.pone.0198974 June 18, 2018 5 / 18 laboratory until analysis. Serum glucose, triglyceride, total and high-density lipoprotein (HDL) cholesterol levels were measured by routine laboratory tests using standard enzymatic methods. Blood pressure was measured using a validated semiautomatic oscillometer (Omron HEM-705CP, Netherlands) after 5 minutes of rest in-between measurements. Height, waist circumference and weight were measured at baseline by trained staff. Body-mass index was calculated as weight (kg) over height squared (m 2 ). All anthropometric variables were determined in duplicate, except for blood pressure (in triplicate). The cut-off points used to define metabolic syndrome (>= 3 criteria over 5 criteria) were fasting glucose>= 100 mg/dl, triglycerides>= 150 mg/dl, HDL<40 mg/dl in men or <50 in women and blood pressure >= 130/85 mm Hg. In the Caucasian population, the cut-off point defining the abdominal obesity criterion for metabolic syndrome was >= 80 cm in women and >= 94 cm in men. In the South American population, the value is the same for women but for men It was >= 90 cm. Information about age, sex, physical activity (measured in METs-minutes/week), civil status and educational level was collected with a general questionnaire prior to randomization. Fig 2. Mean energy intake according to adherence to the Mediterranean diet. https://doi.org/10.1371/journal.pone.0198974.g002 Mediterranean diet and quality of life PLOS ONE | https://doi.org/10.1371/journal.pone.0198974 June 18, 2018 6 / 18 For measuring physical activity, we used the short form of the Minnesota Leisure Time Physical Activity Questionnaire validated for the Spanish population [18,19]. We defined cases of high blood pressure, diabetes, history of depression, chronic lung disease and cancer as the respective diagnosis received by a physician. Statistical analysis According to the 17-item questionnaire, we categorized baseline adherence to the MedDiet into approximate quartiles, defining the four groups as “Low” (0–6 points), “Low to Moderate” (7–8 points), “Moderate to High” (9–10 points), and “High (11–17)”. Baseline characteristics were described as means (standard deviations) for quantitative traits and as proportions for qualitative traits according to the baseline adherence to categories of the MedDiet. We compared the means in each HRQL dimension (and the 2 aggregated dimensions) across the four levels of adherence to the MedDiet with ANCOVA models and calculated the between-group differences with linear regression models. We fitted three different models for each dimension provided by the HRQL questionnaire. The first model was adjusted for sex, age and recruitment centre. A second model included additional adjustments for body-mass index, physical activity (METs-min/week), smoking status (never smoker / former smoker/ current smoker), marital status (single / married / divorced / widowed), highest level of education attained (primary school or less / Secondary studies / College graduate). A third model was also adjusted for comorbidities that have been associated with poorer quality of life such as high blood pressure (yes/no), diagnosis of type-2 diabetes (yes/no) history of depression (yes/no), chronic lung disease (yes/no) and cancer (yes/no). We also assessed the linear trends for the association between baseline adherence to the MedDiet and the different dimensions of the HRQL, for this aim, we tested the 17-item score as a continuous quantitative variable included in the multivariable-adjusted models. We considered a two-tailed value of 0.05 as threshold for statistical significance. We conducted all the analyses with Stata (Stata/SE 15.1 StataCorp College Station, Texas). Results Baseline characteristics of the PREDIMED-Plus participants are shown in Table 2 according to categories of baseline adherence to the MedDiet. Mean age ranged from 64.2 years in the “Low” adherence group to 65.5 years in the “High” adherence group. In the “High” adherence group there were more women and participants with diabetes, and higher levels of physical activity (METs-min/week). There were also less former smokers and a lower prevalence of hypertension, and the average body-mass index was slightly lower. Tables 3and 4show the mean scores in the different dimensions of HRQL according to categories of baseline adherence to the MedDiet. In the fully adjusted models, we observed that a higher adherence to the MedDiet was associated with better scores in all dimensions of HQRL. When the individual dimensions were aggregated, a higher adherence to the MedDiet was also associated with a better score in the aggregated mental and physical dimension. Fig 3 shows mean differences and confidence intervals in the different individual and aggregated dimensions for the categories of increasing adherence to the MedDiet diet compared to the lowest category. Differences of at least three points between the high and the low adherence groups were observed for vitality, emotional role and mental health and of at least two points for the other dimensions in the fully adjusted models. Mediterranean diet and quality of life PLOS ONE | https://doi.org/10.1371/journal.pone.0198974 June 18, 2018 7 / 18 Discussion We found a direct association between baseline adherence to an MedDiet and all dimensions of health-related quality of life. Beyond merely statistically significant differences, clinically meaningful associations were also observed, because we found differences greater than three points in three of them, belonging to mental health dimensions [20–23]. Our results are consistent with previous findings. [7,11–13] On the other hand, Henriquez-Sanchez et al [14] observed a positive relationship between adherence to the MedDiet and four physical health categories of HRQL in highly educated and younger subjects in their longitudinal assessment of the SUN cohort, although there were no significant associations with most of the mental health dimensions. While the SUN study and Table 2. Baseline characteristics of the participants in the PREDIMED-Plus trial according to baseline categories (roughly quartiles) of adherence to the traditional Mediterranean diet. Adherence to the Mediterranean diet Low Low-medium Medium-high High Score [MedDiet (0 to 17)] 0–6 7–8 9–10 11–17 N1567 1730 1647 1486 Energy consumption (Kcal/d) 2553(670) 2404(636) 2347(575) 2312(583) Age (years) 64 (5) 65 (5) 65 (5) 66 (5) Female sex (%) 37.4 47.6 50.5 56.5 Body-mass index (Kg/m 2 )32.9 (3.4) 32.8 (3.5) 32.8 (3.4) 32.4 (3.4) Physical activity (METs-min/week) 2187(2189) 2360(2159) 2644(2431) 2972(2628) Diabetes at baseline (%) 22.2 27.6 28.8 29.5 Depression at baseline (%) 18.6 21.1 20.5 22.1 Hypertension at baseline (%) 84.8 84.0 84.0 81.2 History of cancer (%) 7.3 7.4 6.6 7.5 History of lung disease (%) 4.3 4.1 4.7 4.5 Smoking status (%) Current smoker 15.7 13.6 10.9 9.6 Former smoker 44.9 43.5 42.9 44.4 Never smoker 39.4 42.9 46.1 46.1 Marital status (%) Married 77.5 77.2 77.4 74.4 Single 5.2 4.5 5.2 5.5 Divorced 7.4 8.1 7.7 8.8 Widowed/widower 9.8 10.2 9.8 11.4 Maximum attained educational level (%) Primary school or less 46.7 49.9 48.3 47.8 Secondary school 32.0 31.0 28.4 26.4 College or higher 21.3 19.1 22.3 25.8 Anti-platelet therapy (%) 13.6 14.7 16.7 17.4 Blood-pressure lowering therapy (%) 78.2 77.3 77.6 76.2 Lipid lowering therapy (%) 49.6 49.8 49.8 51.6 Insulin therapy (%) 4.2 4.5 5.1 4.9 Metformin therapy (%) 18.6 23.1 24.0 24.0 Other oral antidiabetic therapy (%) 15.4 20.2 20.1 19.5 MedDiet: Mediterranean diet Data are presented as mean (standard deviation) or percentage. https://doi.org/10.1371/journal.pone.0198974.t002 Mediterranean diet and quality of life PLOS ONE | https://doi.org/10.1371/journal.pone.0198974 June 18, 2018 8 / 18 Table 3. Adjusted means for each of the 8 dimensions of health-related quality of life by baseline categories of adherence to a traditional Mediterranean diet. The PREDIMED-Plus trial. Physical Role Adherence to tde traditional Mediterranean diet <7 7–9 9–10 11–17 P for trend N 1567 1730 1647 1486 Age & sex adjusted 73.84 (72.08 to 75.60) 75.75 (74.13 to 77.37) 77.25 (75.59 to 78.91) 77.63 (75.84 to 79.42) <0.001 Multivariable adjusted 174.49 (72.73 to 76.26) 76.17 (74.56 to 77.78) 77.08 (75.43 to 78.73) 76.64 (74.84 to 78.43) 0.064 Multivariable adjusted 2 74.39 (72.66 to 76.14) 76.15 (74.56 to 77.74) 77.07 (75.44 to 78.70) 76.78 (75.01 to 78.56) 0.043 Bodily Pain <7 7–9 9–10 11–17 P for trend Age & sex adjusted 60.82 (59.53 to 62.14) 61.42 (60.22 to 62.61) 62.56 (61.33 to 63.78) 64.16 (62.85 to 65.49) <0.001 Multivariable adjusted 161.26 (59.96 to 62.55) 61.75 (60.56 to 62.93) 62.47 (61.25 to 63.68) 63.44 (62.11 to 64.75) 0.011 Multivariable adjusted 2 61.15 (59.87 to 62.43) 61.74 (60.57 to 62.90) 62.49 (61.29 to 63.68) 63.53 (62.23 to 64.83) 0.006 General Health <7 7–9 9–10 11–17 P for trend Age & sex adjusted 60.70 (59.76 to 61.64) 61.77 (60.91 to 62.63) 62.85 (61.97 to 63.73) 64.03 (63.08 to 64.98) <0.001 Multivariable adjusted 161.28 (60.36 to 62.22) 62.10 (61.25 to 62.94) 62.68 (61.81 to 63.55) 63.21 (62.27 to 64.16) 0.002 Multivariable adjusted 2 60.93 (60.03 to 61.84) 62.10 (61.27 to 62.92) 62.82 (61.98 to 63.68) 63.42 (62.50 to 64.34) <0.001 Physical function <7 7–9 9–10 11–17 P for trend Age & sex adjusted 74.54 (73.61 to 75.47) 75.15 (74.30 to 76.01) 76.53 (75.65 to 77.41) 78.53 (77.58 to 79.47) <0.001 Multivariable adjusted 175.20 (74.30 to 76.10) 75.59 (74.77 to 76.41) 76.39 (75.55 to 77.24) 77.47 (76.56 to 78.39) <0.001 Multivariable adjusted 2 75.16 (74.27 to 76.04) 75.59 (74.78 to 76.40) 76.39 (75.56 to 77.21) 77.53 (76.63 to 78.43) <0.01 Vitality <7 7–9 9–10 11–17 P for trend Age & sex adjusted 61.05 (60.00 to 62.10) 62.88 (61.92 to 63.45) 64.17 (63.18 to 65.16) 66.09 (65.03 to 67.16) <0.001 Multivariable adjusted 161.80 (60.77 to 62.83) 63.27 (62.33 to 64.21) 63.94 (62.97 to 64.91) 65.10 (64.05 to 66.15) <0.001 Multivariable adjusted 2 61.59 (60.58 to 62.59) 63.28 (62.36 to 64.20) 64.00 (63.05 to 64.93) 65.26 (64.23 to 66.28) <0.001 Social function <7 7–9 9–10 11–17 P for trend Age & sex adjusted 84.21 (83.17 to 85.26) 85.58 (84.62 to 86.54) 86.37 (85.39 to 87.36) 87.53 (85.39 to 87.36) <0.001 Multivariable adjusted 184.69 (83.65 to 85.73) 85.82 (84.86 to 86.77) 86.21 (85.23 to 87.19) 86.93 (85.83 to 88.99) 0.005 Multivariable adjusted 2 84.54 (83.52 to 85.56) 85.82 (84.90 to 86.76) 86.21 (85.26 to 87.17) 87.08 (86.05 to 88.12) 0.001 Emotional role <7 7–9 9–10 11–17 P for trend Age & sex adjusted 84.09 (82.55 to 85.62) 86.64 (85.23 to 88.05) 88.04 (86.59 to 89.49) 88.26 (86.07 to 89.82) <0.001 Multivariable adjusted 184.53 (82.99 to 86.06) 86.85 (85.44 to 88.25) 87.87 (86.43 to 89.31) 87.75 (86.18 to 89.32) <0.001 Multivariable adjusted 2 84.36 (82.85 to 85.87) 86.88 (85.50 to 88.25) 87.84 (86.42 to 89.25) 87.92 (86.39 to 89.45) <0.001 Mental Health <7 7–9 9–10 11–17 P for trend Age & sex adjusted 72.37 (71.42 to 73.32) 73.89 (73.03 to 74.77) 75.13 (74.24 to 76.03) 76.28 (75.32 to 77.24) <0.001 Multivariable adjusted 172.88 (71.94 to 73.82) 74.13 (73.27 to 74.99) 74.95 (74.07 to 75.83) 75.67 (74.71 to 76.53) <0.001 Multivariable adjusted 2 72.69 (71.78 to 73.61) 74.14 (73.31 to 74.97) 74.99 (74.13 to 75.84) 75.81 (74.89 to 76.74) <0.001 Additionally adjusted for body mass index (kg/m 2 ), physical activity (METs-min/week), smoking status (never, former, current), civil status (single, married, divorced, widowed), educational level (primary school or less, secondary, college or higher) Additionally adjusted for high blood pressure, diabetes (dichotomous),depression, chronic obstructive lung disease, and cancer prevalence. https://doi.org/10.1371/journal.pone.0198974.t003 Mediterranean diet and quality of life PLOS ONE | https://doi.org/10.1371/journal.pone.0198974 June 18, 2018 9 / 18 Investigation: Iñigo Galilea-Zabalza, Pilar Buil-Cosiales, Jordi Salas-Salvado ´, Estefanı ´a Toledo, Carolina Ortega-Azorı ´n, Javier Dı ´ez-Espino, Zenaida Va ´zquez-Ruiz, Marı ´a Dolores Zomeño, Jesu ´s Vioque, Jose ´Alfredo Martı ´nez, Dora Romaguera, Napoleo ´n Perez-Farinos, Jose ´Lo ´pez-Miranda, Ramo ´n Estruch, Aurora Bueno-Cavanillas, Fernando Aro ´s, Josep Antoni Tur, Francisco Tinahones, Lluis Serra-Majem, Alba Marcos-Delgado, Manuel Ortega-Calvo, Clotilde Va ´zquez, Xavier Pinto ´, Josep Vidal, Lidia Daimiel, Miguel DelgadoRodrı ´guez, Pilar Matı ´a, Dolores Corella, Andre ´s Diaz-Lo ´pez, Nancy Babio, Miguel Angel Muñoz, Montse Fito ´, Sandra Gonza ´lez-Palacios, Itziar Abete, Antonio Garcı ´a-Rios, Emilio Ros, Miguel A ´ngel Martı ´nez-Gonza ´lez. Methodology: Pilar Buil-Cosiales, Estefanı ´a Toledo, Miguel A ´ngel Martı ´nez-Gonza ´lez. Project administration: Jordi Salas-Salvado ´, Ramo ´n Estruch, Francisco Tinahones, Dolores Corella, Montse Fito ´, Emilio Ros, Miguel A ´ngel Martı ´nez-Gonza ´lez. Resources: Estefanı ´a Toledo, Carolina Ortega-Azorı ´n, Zenaida Va ´zquez-Ruiz, Marı ´a Dolores Zomeño, Jesu ´s Vioque, Jose ´Alfredo Martı ´nez, Dora Romaguera, Napoleo ´n Perez-Farinos, Jose ´Lo ´pez-Miranda, Ramo ´n Estruch, Aurora Bueno-Cavanillas, Fernando Aro ´s, Josep Antoni Tur, Francisco Tinahones, Lluis Serra-Majem, Alba Marcos-Delgado, Manuel Ortega-Calvo, Clotilde Va ´zquez, Xavier Pinto ´, Josep Vidal, Lidia Daimiel, Miguel DelgadoRodrı ´guez, Pilar Matı ´a, Dolores Corella, Andre ´s Diaz-Lo ´pez, Nancy Babio, Miguel Angel Muñoz, Montse Fito ´, Sandra Gonza ´lez-Palacios, Itziar Abete, Antonio Garcı ´a-Rios, Emilio Ros, Miguel A ´ngel Martı ´nez-Gonza ´lez. Software: Iñigo Galilea-Zabalza, Pilar Buil-Cosiales, Estefanı ´a Toledo, Miguel A ´ngel Martı ´- nez-Gonza ´lez. Supervision: Estefanı ´a Toledo, Miguel A ´ngel Martı ´nez-Gonza ´lez. Validation: Miguel A ´ngel Martı ´nez-Gonza ´lez. Visualization: Estefanı ´a Toledo, Miguel A ´ngel Martı ´nez-Gonza ´lez. Writing – original draft: Iñigo Galilea-Zabalza, Pilar Buil-Cosiales. Writing – review & editing: Jordi Salas-Salvado ´, Estefanı ´a Toledo, Carolina Ortega-Azorı ´n, Javier Dı ´ez-Espino, Zenaida Va ´zquez-Ruiz, Marı ´a Dolores Zomeño, Jesu ´s Vioque, Jose ´ Alfredo Martı ´nez, Dora Romaguera, Napoleo ´n Perez-Farinos, Jose ´Lo ´pez-Miranda, Ramo ´n Estruch, Aurora Bueno-Cavanillas, Fernando Aro ´s, Josep Antoni Tur, Francisco Tinahones, Lluis Serra-Majem, Alba Marcos-Delgado, Manuel Ortega-Calvo, Clotilde Va ´zquez, Xavier Pinto ´, Josep Vidal, Lidia Daimiel, Miguel Delgado-Rodrı ´guez, Pilar Matı ´a, Dolores Corella, Andre ´s Diaz-Lo ´pez, Nancy Babio, Miguel Angel Muñoz, Montse Fito ´, Sandra Gonza ´lez-Palacios, Itziar Abete, Antonio Garcı ´a-Rios, Emilio Ros, Miguel A ´ngel Martı ´nezGonza ´lez. References 1. Trichopoulou A, Martı ´nez-Gonza ´lez MA, Tong TY, Forouhi NG, Khandelwal S, Prabhakaran D, et al. Definitions and potential health benefits of the Mediterranean diet: views from experts around the world. BMC Med. 2014; 12:112. https://doi.org/10.1186/1741-7015-12-112 PMID: 25055810 2. Estruch R, Ros E, Salas-Salvado ´J, Covas MI, Corella D, Aro ´s F et al. Primary Prevention of Cardiovascular Disease with a Mediterranean Diet N Engl J Med 2013; 368:1279–1290. https://doi.org/10.1056/ NEJMoa1200303 PMID: 23432189 3. de Lorgeril M, Renaud S, Mamelle N, Salen P, Martin JL, Monjaud I et al. Mediterranean alpha-linolenic acid-rich diet in secondary prevention of coronary heart disease. Lancet. 1994; 343:1454–9. PMID: 7911176 Mediterranean diet and quality of life PLOS ONE | https://doi.org/10.1371/journal.pone.0198974 June 18, 2018 16 / 18 4. Ruano C, Henriquez P, Bes-Rastrollo M, Ruiz-Canela M, del Burgo CL, Sa ´nchez-Villegas A. Dietary fat Intake and quality of life: the SUN project. Nutr J. 2011; 10:121. https://doi.org/10.1186/1475-2891-10121 PMID: 22047452 5. Fransen HP, May AM, Beulens JWJ, Struijk EA, de Wit GA, Boer JMet al. Association between Lifestyle Factors and Quality-Adjusted Life Years in the EPIC-NL Cohort. PLoS ONE 2014; 9: e111480. https:// doi.org/10.1371/journal.pone.0111480 PMID: 25369457 6. Carson TL, Hidalgo B, Ard JD and Affuso O. Dietary Interventions and Quality of Life: A Systematic Review of the Literature. J Nutr Educ Behav. 2014; 46:90–101. https://doi.org/10.1016/j.jneb.2013.09. 005 PMID: 24183706 7. Pe ´rez-Tasigchana RF, Leo ´n-Muñoz LM, Lo ´pez-Garcı ´a E, Banegas JR, Rodrı ´guez-Artalejo F and Guallar-Castillo ´n P. Mediterranean Diet and Health-Related Quality of Life in Two Cohorts of CommunityDwelling Older Adults. PLoS ONE 2016; 11:e0151596. https://doi.org/10.1371/journal.pone.0151596 PMID: 27008160 8. Wannamethee G & Shaper AGSelf-assessment of health status and mortality in middle-aged British men. Int J Epidemiol 1991; 20, 239–245. PMID: 2066228 9. Heistaro S, Jousilahti P, Lahelma E, Vartiainen E and Puska P. Self rated health and mortality: a long term prospective study in eastern Finland. J Epidemiol Community Health. 2001; 55:227–232. https:// doi.org/10.1136/jech.55.4.227 PMID: 11238576 10. Hu F.B. Dietary pattern analyisis: a new direction in nutritional epidemiology. Curr Opin Lipidol 2002; 13, 3–9. PMID: 11790957 11. Bonaccio M, Di Castelnuovo A, Bonanni A, Costanzo S, De Lucia F, Pounis G, et al; Moli-sani project Investigators. Adherence to a Mediterranean diet is associated with a better health-related quality of life: a possible role of high dietary antioxidant content. BMJ Open. 2013; 3(8). pii: e00300. 12. Muñoz MA, Fı ´to M, Marrugat J, Covas MI, Schro ¨der H, on behalf of the REGICOR and HERMES investigators. Adherence to the Mediterranean diet is associated with better mental and physical health. Br J Nutr 2009; 101:1821–7. https://doi.org/10.1017/S0007114508143598 PMID: 19079848 13. Sanchez-Aguadero N, Alonso-Dominguez R, Garcia-Ortiz L, Agudo-Conde C,Rodriguez-Martin C, de Cabo-Laso A, et al; MARK Group. Diet and physical activity in people with intermediate cardiovascular risk and their relationship with the health-related quality of life: results from the MARK study. Health Qual Life Outcomes. 2016; 14:169. https://doi.org/10.1186/s12955-016-0572-x PMID: 27927210 14. Henrı ´quez Sa ´nchez P, Ruano C, de Irala J, Ruiz-Canela M, Martı ´nez-Gonza ´lez MA and Sa ´nchez-Villegas A. Adherence to the Mediterranean diet and quality of life in the SUN Project. Eur J Clin Nutr. 2012; 66:360–8. https://doi.org/10.1038/ejcn.2011.146 PMID: 21847137 15. Ruano C, Henriquez P, Martı ´nez-Gonza ´lez MA ´, Bes-Rastrollo M, Ruiz-Canela M, et al. Empirically derived dietary patterns and health-relatedquality of life in the SUN project. PLoS One. 2013; 8:e61490. https://doi.org/10.1371/journal.pone.0061490 PMID: 23658694 16. Alberti KG, Eckel RH, Grundy SM, Zimmet PZ, Cleeman JI, Donato KA, et al. Harmonizing the metabolic syndrome: a joint interimstatement of the International Diabetes Federation Task Force on Epidemiology and Prevention;National Heart, Lung, and Blood Institute; American Heart Association; World Heart Federation;International Atherosclerosis Society; and International Association for the Study of Obesity. Circulation. 2009; 120:1640–5. https://doi.org/10.1161/CIRCULATIONAHA.109.192644 PMID: 19805654 17. Ruano-Rodrı´guez C, Serra-Majem L and Dubois D. Assessing the impact of dietary habits on healthrelated quality of life requires contextual measurement tools. Front Pharmacol. 2015; 6:101. https://doi. org/10.3389/fphar.2015.00101 PMID: 26005420 18. Elosua R, Garcia M, Aguilar A, Molina L, Covas MI, Marrugat J. Validation of the Minnesota Leisure Time Physical Activity Questionnaire In Spanish Women. Investigators of the MARATDON Group. Med Sci Sports Exerc. 2000; 32:1431–7. PMID: 10949009 19. Elosua R, Marrugat J, Molina L, Pons S, Pujol E. Validation of the Minnesota Leisure Time Physical Activity Questionnaire in Spanish men. The MARATHOM Investigators. Am J Epidemiol. 1994; 139:1197–209. PMID: 8209878 20. Ware JE JR. and Sherbourne CD.The MOS 36-Item Short-Form Health Survey (SF-36): I. Conceptual Framework and Item Selection. Med Care. 1992; 30:473–483. PMID: 1593914 21. Ware JE JR., Kosinski M, Bjorner JB, Turner-Bowker DM, Gandek B, Maruish ME. User’s Manual for the SF-36v2VR Health Survey. 2nd ed. Lincoln, RI: Quality Metric Incorporated; 2007. 22. Samsa G, Edelman D, Rothman ML, Williams GR, Lipscomb J and Matchar D. Determining clinically important differences in health status measures: a general approach with illustration to the Health Utilities Index Mark II. Pharmacoeconomics. 1999; 15:141–155. PMID: 10351188 23. http://www.measuringimpact.org/s4-sf-36. Mediterranean diet and quality of life PLOS ONE | https://doi.org/10.1371/journal.pone.0198974 June 18, 2018 17 / 18 24. Seguı ´-Go ´mez M, de la Fuente C, Va ´zquez Z, de Irala J and Martı ´nez-Gonza ´lez MA. Cohort profile: The Seguimiento Universidad de Navarra (SUN) study. Int J Epidemiol. 2006; 35:1417–22. https://doi.org/ 10.1093/ije/dyl223 PMID: 17060332 25. Schroder H, Fito M, Estruch R, Martinez-Gonzalez MA, Corella D, Salas-Salvado J, et al. A short screener is valid for assessing Mediterranean diet adherence among older Spanish men and women. J Nutr. 2011; 141:11401145. 26. Tong TY, Wareham NJ, Khaw KT, Imamura F and Forouhi NG. Prospective association of the Mediterranean diet with cardiovascular disease incidence and mortality and its population impact in a non-Mediterranean population: the EPIC-Norfolk study. BMC Med. 2016; 14:135. https://doi.org/10.1186/ s12916-016-0677-4 PMID: 27679997 27. Martı ´nez-Gonza ´lez MA ´, Hershey MS, Zazpe I, Trichopoulou A. Transferability of the Mediterranean Diet to Non-Mediterranean Countries. What Is and What Is Not the Mediterranean Diet. Nutrients. 2017; 9: pii: E1226. 28. Martı ´nez-Gonza ´lez MA, Salas-Salvado ´J, Estruch R, Corella D, Fito ´M, Ros E; PREDIMED INVESTIGATORS. Benefits of the Mediterranean Diet: Insights From the PREDIMED Study. Prog Cardiovasc Dis. 2015; 58:50–6. https://doi.org/10.1016/j.pcad.2015.04.003 PMID: 25940230 29. Sorlie PD, Backlund E, Keller JB. US mortality by economic, demographic, and social characteristics: the National Longitudinal Mortality Study. Am J Public Health. 1995; 85:949–956. PMID: 7604919 30. Kastorini CM, Milionis HJ, Esposito K, Giugliano D, Goudevenos JA, Panagiotakos DB. The effect of Mediterranean diet on metabolic syndrome and its components: a meta-analysis of 50 studies and 534,906 individuals. J Am Coll Cardiol. 2011; 57:1299–313. https://doi.org/10.1016/j.jacc.2010.09.073 PMID: 21392646 31. Buckland G., Bach A. and Serra-Majem L. Obesity and the Mediterranean diet: a systematic review of observational and intervention studies. Obes Rev. 2008; 9:582–593. https://doi.org/10.1111/j.1467789X.2008.00503.x PMID: 18547378 32. Sa ´nchez-Villegas A, Delgado-Rodrı ´guez M, Alonso A, Schlatter J, Lahortiga F, Serra Majem L, Martı ´- nez-Gonza ´lez MA. Association of the Mediterranean dietary pattern with the incidence of depression: the Seguimiento Universidad de Navarra/University of Navarra follow-up (SUN) cohort. Arch Gen Psychiatry. 2009; 66:1090–8. https://doi.org/10.1001/archgenpsychiatry.2009.129 PMID: 19805699 33. Martı ´nez-Lapiscina EH, Clavero P, Toledo E, Estruch R, Salas-Salvado ´J, San Julia ´n Bet al. Mediterranean diet improves cognition: the PREDIMED-NAVARRA randomised trial. J Neurol Neurosurg Psychiatry. 2013; 84:1318–25. https://doi.org/10.1136/jnnp-2012-304792 PMID: 23670794 34. Galbete C, Toledo E, Toledo JB, Bes-Rastrollo M, Buil-Cosiales P, Marti A. et al. Mediterranean diet and cognitive function: the SUN project. J Nutr Health Aging. 2015; 19:305–12. https://doi.org/10.1007/ s12603-015-0441-z PMID: 25732216 35. Valls-Pedret C, Sala-Vila A, Serra-Mir M, Corella D, de la Torre R,Martı ´nez-Gonza ´lez MA ´et al. Mediterranean Diet and Age-Related Cognitive Decline: ARandomized Clinical Trial. JAMA Intern Med. 2015; 175:1094–103. https://doi.org/10.1001/jamainternmed.2015.1668 PMID: 25961184 36. Liu C, Xie B, Chou CP, Koprowski C, Zhou D, Palmer P et al. (2007). Perceived stress, depression and food consumption frequency in the college students of China Seven Cities. Physiol Behav. 92, 748– 754. https://doi.org/10.1016/j.physbeh.2007.05.068 PMID: 17585967 37. Finger JD, Tylleska ¨r T, Lampert T, Mensink GB. Dietary Behaviour and Socioeconomic Position: The Role of Physical Activity Patterns. PLoS ONE. 2013; 8: e78390. https://doi.org/10.1371/journal.pone. 0078390 PMID: 24223150 Mediterranean diet and quality of life PLOS ONE | https://doi.org/10.1371/journal.pone.0198974 June 18, 2018 18 / 18