Evaluating Mediterranean diet and risk of chronic disease in cohort studies: an umbrella review of meta-analyses

Cecilia Galbete; Lukas Schwingshackl; Carolina Schwedhelm; Heiner Boeing; Matthias Schulze

doi:10.1007/s10654-018-0427-3

Evaluating Mediterranean diet and risk of chronic disease in cohort studies: an umbrella review of meta-analyses

Galbete, Cecilia; Schwingshackl, Lukas; Schwedhelm, Carolina; Boeing, Heiner; Schulze, Matthias 2018-07-20 00:00:00 European Journal of Epidemiology (2018) 33:909–931 https://doi.org/10.1007/s10654-018-0427-3(0123456789().,-volV)(0123456789().,-volV) REVIEW Evaluating Mediterranean diet and risk of chronic disease in cohort studies: an umbrella review of meta-analyses 1,2 2,3 2,3 2,3 • • • • Cecilia Galbete Lukas Schwingshackl Carolina Schwedhelm Heiner Boeing 1,2,4 Matthias B. Schulze Received: 30 January 2018 / Accepted: 17 July 2018 / Published online: 20 July 2018 The Author(s) 2018 Abstarct Several meta-analyses have been published summarizing the associations of the Mediterranean diet (MedDiet) with chronic diseases. We evaluated the quality and credibility of evidence from these meta-analyses as well as characterized the different indices used to deﬁne MedDiet and re-calculated the associations with the different indices identiﬁed. We conducted an umbrella review of meta-analyses on cohort studies evaluating the association of the MedDiet with type 2 diabetes, cardiovascular disease, cancer and cognitive-related diseases. We used the AMSTAR (A MeaSurement Tool to Assess systematic Reviews) checklist to evaluate the methodological quality of the meta-analyses, and the NutriGrade scoring system to evaluate the credibility of evidence. We also identiﬁed different indices used to deﬁne MedDiet; tests for subgroup differences were performed to compare the associations with the different indices when at least 2 studies were available for different deﬁnitions. Fourteen publications were identiﬁed and within them 27 meta-analyses which were based on 70 primary studies. Almost all meta-analyses reported inverse associations between MedDiet and risk of chronic disease, but the credibility of evidence was rated low to moderate. Moreover, substantial heterogeneity was observed on the use of the indices assessing adherence to the MedDiet, but two indices were the most used ones [Trichopoulou MedDiet (tMedDiet) and alternative MedDiet (aMedDiet)]. Overall, we observed little difference in risk associations comparing different MedDiet indices in the subgroup meta-analyses. Future prospective cohort studies are advised to use more homogenous deﬁnitions of the MedDiet to improve the comparability across meta-analyses. Keywords Mediterranean diet Chronic diseases Umbrella review Meta-analyses Cohort studies Heterogeneity Introduction olive oil consumption in Greece, the high ﬁsh intake in the Dalmatian area (Croatia), and the high vegetable intake in The Seven Countries Study observed in the 1960s a lower Italy. Later on, the dietary components considered to have cardiovascular mortality in the participating countries a beneﬁcial effect on health were combined in one index around the Mediterranean area [1]. Ancel Keys attributed and published as MedDiet index [2]. Apart from the this observation to the traditional diets such as the high inﬂuence of the Mediterranean diet (MedDiet) on risk of cardiovascular disease (CVD), several metabolic diseases have been studied for a possible favourable role, including & Lukas Schwingshackl type 2 diabetes (T2D), cognitive-related diseases, and dif- lukas.schwingshackl@dife.de ferent types of cancer in the Mediterranean countries Department of Molecular Epidemiology, German Institute of [3–10]. Recently the landmark PREDIMED study has been Human Nutrition Potsdam-Rehbruecke, Nuthetal, Germany retracted and republished due to ‘‘irregularities in ran- NutriAct – Competence Cluster Nutrition Research Berlin- domisation procedures’’ [11, 12]. Similarly to the retracted Potsdam, Nuthetal, Germany paper, the new ﬁndings showed that the incidence of Department of Epidemiology, German Institute of Human combined cardiovascular events was lower among those Nutrition Potsdam-Rehbruecke, Nuthetal, Germany assigned to a MedDiet supplemented with extra-virgin Institute of Nutritional Sciences, University of Potsdam, Nuthetal, Germany 123 910 C. Galbete et al. olive oil or nuts than among those assigned to a lower-fat Methods diet [12]. The interest in the MedDiet as a whole was not This manuscript was drafted in adherence to the recom- restricted to those countries and thus, the MedDiet has been mendations of the ‘Preferred Reporting Items for System- investigated in many countries that are geographically far atic reviews and Meta-Analyses’ (PRISMA) checklist [20]. from being Mediterranean, e.g. Australia and Japan The methodological approach of this umbrella review is [13–15]. The observed results have been summarised in based on previous published umbrella reviews, which several meta-analyses, but the methods used for the esti- focused on nut and garlic intake and risk of CVD [21, 22], mation of MedDiet adherence in the different study pop- and is next explained. ulations were often heterogeneous, implying the creation of many different indices intended to reﬂect MedDiet. In fact, Data sources and search strategy even though most of the meta-analyses are consistent in their ﬁndings, the observed statistical heterogeneity within PubMed (from inception until 27th March 2018) and these varies from low to high (e.g. from 26% in the study Embase (from inception until 27th March 2018) was from Jannasch et al. [16] on MedDiet and T2D to 82% in searched for meta-analyses published in English language the meta-analysis on MedDiet and cancer from Schwing- using following search terms: (Mediterranean[tiab]) AND shackl et al. [17]). Moreover, the methodological quality (cardiovascular[tiab] OR coronary[tiab] OR myocardial[- and credibility of evidence of these meta-analyses have not tiab] OR stroke[tiab] OR mortality[tiab] OR cancer[tiab] been analysed so far. OR ‘‘neoplastic disease’’[tiab] OR tumor[tiab] OR dia- The creation of nutritional indices is a common tool betes[tiab] OR ‘‘cognitive decline’’[tiab] OR cognition[- largely used in the nutritional epidemiology research with tiab] OR dementia[tiab] OR Alzheimer disease[tiab]) AND the purpose of reﬂecting the adherence to a dietary pattern, (meta-analysis[tiab]). Additionally, reference lists of the e.g. the MedDiet, in a certain population. These are created included meta-analyses were veriﬁed for further relevant by ranking the population according to the intake of foods studies as well. considered to be in line with, or against, the dietary pattern under study. Inclusion criteria Soﬁ et al. as well as Davis et al. discussed the derived difﬁculties from the use of different scores measuring Studies were included in this umbrella review if they MedDiet adherence [18, 19]. They criticised that the use of met all of the following criteria: (1) meta-analysis of cohort different population-speciﬁc cut-off values for the con- studies, (2) evaluating the association of scores used for sumption of the food groups considered to be part of the assessing adherence to a MedDiet or considered by the MedDiet hampered the further clinical and public health authors as reﬂecting a MedDiet type diet, (3) study popu- applications. But this is not the only discrepancy observed lation: C 18 years, (4) study endpoints include overall among the different scores; both authors mentioned also cancer mortality and/or incidence, CVD or coronary heart the inconsistencies observed in the classiﬁcation of the disease (CHD) mortality and/or incidence, stroke, food groups. However, this point has not been deeply myocardial infarction (MI), acute myocardial infarction investigated and could be one of the reasons for the high (AMI) type 2 diabetes, Alzheimer’s disease (AD), mild statistical heterogeneity found in several of the published cognitive impairment (MCI), or dementia. meta-analyses. Thus, by the present complementary umbrella review, in a ﬁrst step, we aimed to evaluate the Methodological quality methodological quality and the credibility of evidence generated by all available meta-analyses evaluating the The methodological quality was evaluated using a modiﬁed association between adherence to a MedDiet and major version of the AMSTAR (A MeaSurement Tool to Assess chronic diseases (T2D, CVD, cancer and cognitive-related systematic Reviews) [23] checklist, which has been disorders) in cohort studies. In a second step, we aimed to recently established to evaluate the methodological quality enumerate and characterize the different deﬁnitions used to of meta-analyses and systematic reviews on the Mediter- assess adherence to the MedDiet in the studies gathered in ranean diet and CVD outcomes and is based on 14 items the meta-analyses, and to emulate the associations on (maximum score of 22) [24]. These are grouped within four chronic diseases with the different dietary MedDiet different domains; (1) ‘‘a priori design’’, which includes adherence indices. two questions, (2) Literatures search and duplicate effort, which includes ﬁve different questions, (3) coding of studies, including two questions, and (4) analysis and 123 Evaluating Mediterranean diet and risk of chronic disease in cohort studies: an umbrella… 911 interpretation, which includes four different questions. The incorporated both within and between study variability original AMSTAR checklist has been previously used to [28]. To evaluate the weighting of each study, the choose high quality systematic reviews and meta-analysis standard error for the logarithm HR/RR/OR of each to build the Dietary Guidelines for Americans 2015–2020 study was calculated and regarded as the estimated [25]. variance of the logarithm HR/RR/OR, using an inverse variance method [28]. Credibility of the evidence To detect discrepancies between the different types of MedDiet adherence scores for an outcome a test for sub- To evaluate credibility of evidence for the association group differences was performed based on a random effects between adherence to MedDiet and risk of the included model (ﬁxed effects model used for the sensitivity outcomes we applied the NutriGrade scoring system (max analysis). 10 points) which comprises the following items for cohort For the summary random effects, we estimated for each studies [26]: (1) risk of bias/study quality/study limitations, meta-analysis the 95% prediction interval (PI), which fur- (2) precision, (3) heterogeneity, (4) directness, (5) publi- ther accounts for the degree of between-study hetero- cation bias, (6) funding bias, (7) effect size, and (8) dose– geneity and gives a range for which we are 95% conﬁdent response. Based on this scoring system we recommend four that the effect in a new study examining the same associ- categories to judge credibility of meta-evidence: high, ation lies within [29]. moderate, low, and very low taking into account the fol- All analyses were conducted using the Review Manager lowing cut-points: C 8 points (high meta-evidence), by the Cochrane Collaboration (version 5.3) and Stata 14.2 6–7.99 points (moderate meta-evidence), 4–5.99 (low (Stata-Corp, College Station, TX. USA). meta-evidence), and 0–3.99 (very low meta-evidence). Identification of different MedDiet scores Results Within the meta-analyses included in this study the dif- The study characteristics of the meta-analyses are sum- ferent scores used in the primary studies were carefully marized in Table 1. A total of 14 publications reporting 27 evaluated. The nine food groups referred to by Tri- meta-analyses on the association of the MedDiet with the chopoulou et al. [27], and usually quoted for the creation of risk of any of the major chronic diseases (T2D, CVD, the MedDiet score were considered as the basis (fruit, cancer, or cognitive-related diseases) were included in the vegetables, legumes, cereals, meat, dairy products, ﬁsh, present umbrella review [16, 17, 19, 30–40]. Among all the alcohol and, healthy fats), and for each primary study we meta-analyses 70 primary studies were included carefully identiﬁed the foods reported to be included within [2, 7, 13, 27, 41–106]. Several different endpoints have the different food groups. Thus, the scores were considered been evaluated: T2D, CVD incidence and/or mortality, to be different when: (1) different food groups were CHD incidence, different types of stroke incidence and/or included, (2) food groups were comprised of different food mortality, MI incidence, MCI incidence, AD incidence, items, and (3) different speciﬁc cut-off values within the and dementia incidence. Four meta-analyses were found food items were applied. This last point was particularly evaluating the association between adherence to the Med- relevant for the different cut-off values used to deﬁne Diet and risk of T2D [16, 30, 31, 40], among which 11 ‘‘moderate alcohol intake’’. primary studies were considered [7, 43, 46, 50, 61, 74, 76, 79, 82, 83, 98]. Comparing the highest versus lowest Statistical analysis adherence category an inverse association between 13% (RR 0.87, 95% CI 0.82, 0.97) and 23% (RR 0.77, 95% CI If at least two cohort studies were included in a meta- 0.66, 0.89) for the risk of T2D was observed. Regarding the analysis for at least two speciﬁc MedDiet adherence different CVD endpoints a total of 12 meta-analyses within scores identiﬁed (e.g. tMedDiet, aMedDiet, sMedDiet) 5 publications were identiﬁed [19, 32–35], and within these a new meta-analysis was carried out to estimate and 31 primary studies were included [2, 13, 41, 44, 47, 49, 51, compare the associations between these scores for the 52, 56, 59, 60, 67, 71, 72, 75, 77, 78, 80, 85–87, 89–93, included outcomes. These new meta-analyses were 96, 100, 103–105]. A 2-point increase in adherence to the performed by combining the multivariable adjusted MedDiet score was associated with a 10% (RR 0.90, 95% RRs, HR of the highest compared with the lowest CI 0.86, 0.94) lower risk of CVD incidence/mortality MedDiet adherence category, or 2-point increase in [19, 34]. Comparing the highest versus lowest category of MedDiet adherence score based on a random effects adherence to the MedDiet the risk of CVD was reduced by model using the DerSimonian–Laird method, which approximately 19% (RR 0.81, 95% CI 0.74, 0.88) to 27% 123 912 C. Galbete et al. (RR 0.73, 95% CI 0.66, 0.80). Similar results were reported (moderate conﬁdence for the effect estimate: further for CHD (RR 0.72, 95% CI 0.60, 0.86), MI (RR 0.67, 95% research could add information on the conﬁdence and may CI 0.54, 0.83), AMI (RR 0.74, 95% CI 0.66, 0.83), and change the effect estimate). stroke (RR 0.77, 95% CI 0.67, 0.90). No association was observed between adherence to the MedDiet and haemor- Description of the different scores rhagic stroke. Regarding overall cancer incidence and/or mortality four meta-analyses were identiﬁed within three A total of 70 primary studies were included within the 27 publications [17, 19, 36], and within these a total of 27 meta-analyses, where 34 different scores meant to reﬂect primary studies were identiﬁed [27, 42, 45, 48, the MedDiet were applied [2, 7, 13, 27, 41–106]. A detailed 53–55, 57–59, 62, 68–70, 72, 73, 75, 78, 80, 84, 94, 96, 97, description of the different deﬁnitions is shown in Table 2. 99–102]. Two meta-analyses considering overall cancer Within the 34 different deﬁnitions gathered from the mortality and one meta-analysis including overall cancer included studies, two main ones could be extracted; the incidence were found [17, 36], whereas in another meta- ﬁrst one made reference to the deﬁnitions derived from the analysis conducted by Soﬁ et al. [19] cancer mortality and one created in 2003 by Trichopoulou et al. [27] (tMedDiet), incidence were combined. Comparing the highest versus which, after the careful evaluation was considered as dif- lowest adherence to MedDiet category a 14% (RR 0.86, ferent from the ﬁrst one used by Trichipoulou et al. [2]. The 95% CI 0.81, 0.91) (4% reduction for cancer incidence) Trichopoulou deﬁnition from 2003 included nine food reduced risk of cancer mortality was reported, whereas a groups, ﬁve were postulated to be in line with it (vegeta- 2-point increase in the MedDiet score was associated with bles, fruits and nuts, cereals, legumes, and ﬁsh), and two a 5% (RR 0.95 95% CI 0.93, 0.97) reduced risk of cancer were in disagreement with it (dairy products and meat). mortality/incidence. Regarding cognitive-related disorders Alcohol intake in moderation was also considered as part three studies meta-analysed the observed effects of Med- of the MedDiet, as well as a higher intake of monounsat- Diet with different outcomes: MCI, AD and dementia urated fats (MUFA) in relation to saturated fats (SFA). [37–39]. A total of 6 meta-analyses were conducted Fourteen studies out of the 70 identiﬁed were using this [37–39]. Comparing highest versus lowest category of deﬁnition to assess adherence to the MedDiet adherence to the MedDiet up to 31% (RR 0.69, 95% CI [7, 27, 41–52]. Nine other deﬁnitions, used in 18 studies, 0.57, 0.84) risk reduction for MCI was observed and 40% were relatively similar to this one (labelled from tMedDiet (RR 0.60, 95% CI 0.48, 0.77) reduction for AD. No asso- 1 to tMedDiet 9) [13, 53–68, 106]. The differences among ciation was observed for incident dementia. these dietary pattern scores were observed in the cut-off Almost all included meta-analyses showed a signiﬁcant values considered to deﬁne moderate alcohol intake as well inverse association between higher adherence to a MedDiet as in how healthy fat intake was reﬂected. Regarding this and risk of chronic diseases. Estimating 95% prediction last point two of these deﬁnitions, tMedDiet 4 and 5 intervals, however, the null value was excluded only in [13, 58–62], considered intake of olive oil instead of the some of the associations (CVD incidence, CVD inci- MUFA: SFA ratio. This modiﬁcation has been commonly dence/mortality, CHD/AMI incidence mortality, unspeci- used in those studies conducted in non-Mediterranean ﬁed stroke incidence/mortality, AD incidence, and MCI countries, where the intake of MUFA could be mainly incidence). This implies that most meta-analyses indicated represented by the fat intake from meat rather than olive high degrees of statistical heterogeneity and/or were based oil. Another variation of this deﬁnition, tMedDiet 1 on a limited number of studies. [53–55], included the intake of polyunsaturated fatty acids (PUFA) together with MUFA. Methodological quality The second main deﬁnition observed referred to the one created by Fung et al. [71], the alternative MedDiet index In total, the overall methodological quality of the included (aMedDiet). The authors modiﬁed the original score cre- meta-analyses was rated as moderate (Table 1). On aver- ated by Trichopoulou et al. by considering some eating age, the meta-analyses achieved a mean of 16.5 points behaviours that were associated with lower risk of chronic (75% of the maximum score). disease. Thus, the authors separated into two different groups fruits and nuts, eliminated the dairy group, included Credibility of the evidence whole grain products only, as well as only red and pro- cessed meat. Nine studies used this deﬁnition and ﬁve other The NutriGrade credibility of evidence judgement varied studies used a deﬁnition relatively similar to this one between low (low conﬁdence for the effect estimate: fur- [69–77]. The main difference was observed in how alcohol ther research provides important information on the con- intake in moderation was deﬁned, and also one of these ﬁdence and likely change the effect estimate) and moderate 123 Evaluating Mediterranean diet and risk of chronic disease in cohort studies: an umbrella… 913 Table 1 General and speciﬁc characteristics of the included meta-analysis References Outcome and No. Sample Follow- Predictive NutriGrade Modiﬁed Included Results re-analyses RR (95% Results re-analyses RR (95% summary of the studies size, up Interval grading AMSTAR MedDiet- CI) and test for subgroup CI) and test for subgroup estimates RR included cases (years) (95% CI) [26] rating [24] scores* (ref.) differences (random effects differences (ﬁxed effects (95% CI) model) model) Jannasch et al. T2D incidence 6 cohort 183,392, 10–20 (0.77, Low 18/22 tMedDiet: High versus low adherence High versus low adherence [16] studies 17,561 1.00) [7, 50] RR: 0.87 (0.82, RR (tMedDiet): 0.87 (0.81, RR (tMedDiet): 0.87 (0.81, 0.97) tMedDiet 4: 0.93) 0.93) [61] I = 26% RR (aMedDiet): 0.88 (0.75, RR (aMedDiet): 0.89 (0.84, aMedDiet: 1.04) 0.98) [74] Test for subgroup differences Test for subgroup aMedDiet 2: (tMedDiet vs aMedDiet): differences (tMedDiet vs [79] aMedDiet): p = 0.83 aMedDiet 4: p = 0.51 [82] Schwingshackl T2D incidence 8 cohort 129,647, 3.2–20 (0.61, Moderate 17/22 tMedDiet: High versus low adherence High versus low adherence et al. [40] studies 19,463 1.11) [46, 50] RR: 0.83 RR (tMedDiet): 0.86 (0.74, RR (tMedDiet): 0.88 (0.81, tMedDiet 4: 1.01) 0.95) (0.74, 0.92) [61] RR (aMedDiet): 0.82 (0.68, RR (aMedDiet): 0.79 (0.71, I = 56% aMedDiet: 1.00) 0.87) [76] Test for subgroup differences Test for subgroup aMedDiet 2: (tMedDiet vs aMedDiet): differences (tMedDiet vs [79] aMedDiet): p = 0.70 aMedDiet 4: p = 0.11 [82] CA: [98] MedDiet 1: [83] Koloverou T2D incidence 9 cohort 135,168, 3.2–20 (0.62, Low 16/22 tMedDiet: High versus low adherence High versus low adherence et al. [30] studies 19,609 1.15) [43, 46, 50] RR: 0.77 RR (tMedDiet): 0.88 (0.76, RR (tMedDiet): 0.88 (0.81, tMedDiet 4: 1.02) 0.95) (0.66, 0.89) [61] RR (aMedDiet): 0.83 (0.67, RR (aMedDiet): 0.79 (0.71, I = 58% aMedDiet: 1.04) 0.89) [76] Test for subgroup differences Test for subgroup aMedDiet 2: (tMedDiet vs aMedDiet): differences (tMedDiet vs [79] aMedDiet): p = 0.66 aMedDiet 4: p = 0.12 [82] CA: [98] MedDiet 1: [83] 914 C. Galbete et al. Table 1 continued References Outcome and No. Sample Follow- Predictive NutriGrade Modiﬁed Included Results re-analyses RR (95% Results re-analyses RR summary of the studies size, up Interval grading AMSTAR MedDiet- CI) and test for subgroup (95% CI) and test for estimates RR (95% included cases (years) (95% CI) [26] rating [24] scores* (ref.) differences (random effects subgroup differences (ﬁxed CI) model) effects model) Esposito T2D incidence 6 cohort 95,384, 3.2–20 (0.50, Low 17/22 MedDiet 1: High versus low adherence High versus low adherence et al. studies 7129 1.26) [83] RR: 0.80 (0.68, 0.93) RR (tMedDiet): 0.46 (0.09, RR (tMedDiet): 0.87 (0.77, [31] tMedDiet: 2.21) 0.98) I = 64% [46, 50] RR (aMedDiet): 0.82 (0.68, RR (aMedDiet): 0.79 (0.71, 0.87) aMedDiet 2: 1.00) [79] Test for subgroup differences Test for subgroup aMedDiet: (tMedDiet vs aMedDiet): differences (tMedDiet vs [76] aMedDiet): p = 0.47 aMedDiet 4: p = 0.21 [82] Rosato CHD/AMI 9 cohort 392,283, 4.9–20 (0.50, Moderate 14/22 MedDiet 6: NA NA et al. incidence/mortality studies 4256 0.99) [90] [32] RR: 0.74 (0.66, tMedDiet 4: 0.83) [60] I = 27% tMedDiet: [44, 47] tMedDiet 2: [56] MedDiet 3: [85] mMedDiet: [96] aMedDiet: [77] MedDiet 7: [91] Unspeciﬁed stroke 5 cohort 107,074, No (0.61, Low tMedDiet: NA NA incidence/mortality studies 1210 follow- 0.98) [41, 49, 51] RR: 0.77 (0.67, up to aMedDiet: 0.90) 20 [77] I =0% MedDiet 3: [85] MedDiet 8: [93] Evaluating Mediterranean diet and risk of chronic disease in cohort studies: an umbrella… 915 Table 1 continued References Outcome and No. Sample Follow- Predictive NutriGrade Modiﬁed Included Results re-analyses RR (95% Results re-analyses RR (95% summary of the studies size, up Interval grading AMSTAR MedDiet- CI) and test for subgroup CI) and test for subgroup estimates RR (95% included cases (years) (95% CI) [26] rating [24] scores* (ref.) differences (random effects differences (ﬁxed effects CI) model) model) Ischemic stroke 5 cohort 181,295, 6.5–20 (0.67, Low tMedDiet: NA NA studies 2997 1.00) [41] RR: 0.82 (0.73, 0.92) tMedDiet 2: I =0% [56] tMedDiet 8: [67] aMedDiet: [71] MedDiet 7: [91] Haemorrhagic stroke 4 cohort 178,727, 6.5–20 (0.36, Low tMedDiet: NA NA RR: 1.01 (0.74, studies 737 2.82) [41] 1.37) tMedDiet 8: I = 36% [67] aMedDiet: [71] MedDiet 7: [91] Unspeciﬁed CVD 11 831,642, 4.9–20 (0.62, Moderate tMedDiet: High versus low adherence High versus low adherence incidence/mortality cohort 56 695 1.06) [47, 52] RR (tMedDiet): 0.69 (0.54, RR (tMedDiet): 0.70 (0.58, RR: 0.81 (0.74, studies tMedDiet 2: 0.89) 0.86) 0.88) [56] RR (aMedDiet): 0.83 (0.74, RR (aMedDiet): 0.81 (0.79, I = 80% tMedDiet 4: 0.94) 0.84) [59] Test for subgroup differences Test for subgroup differences aMedDiet: (tMedDiet vs aMedDiet): (tMedDiet vs aMedDiet): [72, 75, 77] p = 0.18 p = 0.17 MedDiet 3: [85] MedDiet 4: [87] MedDiet 7: [92] mMedDiet: [96] 916 C. Galbete et al. Table 1 continued References Outcome and No. Sample Follow- Predictive NutriGrade Modiﬁed Included Results re-analyses RR (95% Results re-analyses RR (95% summary of the studies size, up Interval grading AMSTAR MedDiet- CI) and test for subgroup CI) and test for subgroup estimates RR included cases (years) (95% CI) [26] rating [24] scores* (ref.) differences (random effects differences (ﬁxed effects (95% CI) model) model) Grosso CVD incidence 13 274,023, 2–20 (0.57, Moderate 16/22 tMedDiet: High versus low adherence High versus low adherence et al. cohort 11,688 0.92) [44, 47, 49] RR: 0.73 (0.66, RR (tMedDiet): 0.71 (0.60, RR (tMedDiet): 0.72 (0.63, [33] studies 0.80) tMedDiet 2: 0.85) 0.82) [56] I = 36% RR (MedDiet 3): 0.80 (0.66, RR (MedDiet 3): 0.83 (0.74, tMedDiet 4: 0.97) 0.92) [60] RR (sMedDiet): 0.22 (0.06, RR (sMedDiet): 0.21 (0.12, aMedDiet: 0.82) 0.37) [71] Test for subgroup differences Test for subgroup differences iMedDiet: (tMedDiet vs MedDiet 3 vs (tMedDiet vs MedDiet 3 vs [41] sMedDiet): sMedDiet): MedDiet 5: p = 0.13 p \ 0.01 [89] MedDiet 3: [85, 86] MAI: [105] sMedDiet: [103, 104] Evaluating Mediterranean diet and risk of chronic disease in cohort studies: an umbrella… 917 Table 1 continued References Outcome and No. Sample Follow- Predictive NutriGrade Modiﬁed Included Results re-analyses RR (95% Results re-analyses RR (95% summary of the studies size, up Interval grading AMSTAR MedDiet- CI) and test for subgroup CI) and test for subgroup estimates RR included cases (years) (95% CI) [26] rating [24] scores* (ref.) differences (random effects differences (ﬁxed effects (95% CI) model) model) CVD mortality 14 786,279, 5.8–40 (0.53, Low tMedDiet: RR (tMedDiet): 0.76 (0.68, RR (tMedDiet): 0.76 (0.68, cohort 9563 1.06) [44, 49] 0.85) 0.85) RR: 0.75 studies tMedDiet 4: RR (aMedDiet): 0.77 (0.68, RR (aMedDiet): 0.77 (0.71, (0.68, 0.83) [13, 59] 0.86) 0.84) I = 75% aMedDiet: Test for subgroup differences Test for subgroup differences [71] (tMedDiet vs aMedDiet): (tMedDiet vs aMedDiet): aMedDiet 1: p = 0.93 p = 0.93 [78] aMedDiet 3: [80] MAI: [105] MedDiet 3: [85] MedDiet 5: [89] rmMedDiet: [100] MedDiet 6: [90] mMedDiet: [96] CHD incidence 4 cohort 153,502, 4.9–20 (0.38, Low tMedDiet: NA NA studies 2910 1.36) [44, 47] RR: 0.72 tMedDiet 4: (0.60, 0.86) [60] I =NA aMedDiet: [71] MI incidence 3 cohort 44,428, 9–14 (0.17, Low tMedDiet 2: NA NA studies 1364 2.70) [56] RR: 0.67 (0.54, 0.83) MedDiet 3: [85] I =NA MedDiet 5: [89] 918 C. Galbete et al. Table 1 continued References Outcome and No. Sample Follow- Predictive NutriGrade Modiﬁed Included Results re-analyses RR (95% Results re-analyses RR summary of the studies size, up Interval grading AMSTAR MedDiet- CI) and test for subgroup (95% CI) and test for estimates RR (95% included cases (years) (95% CI) [26] rating [24] scores* (ref.) differences (random effects subgroup differences (ﬁxed CI) model) effects model) Stroke incidence 5 cohort 159,995, 7.9–20 (0.37, Low tMedDiet 2: NA NA studies 2444 1.56) [56] RR: 0.76 (0.60, 0.96) aMedDiet: I = 52% [71] MedDiet 3: [85] MedDiet 5: [89] iMedDiet: [41] Martinez- CVD 12 671,005, 4.9–40 (0.79, Low 11/22 tMedDiet: Per 2-point increase Per 2-point increase Gonzalez incidence/mortality cohort 15,909 1.03) [44, 47, 49] RR(tMedDiet): 0.87 (0.81, RR(tMedDiet): 0.87 (0.82, and Bes- studies RR: 0.90 (0.86, 0.94) tMedDiet 2: 0.93) 0.92) Rastrollo [56] I = 78% RR(aMedDiet): 0.91 (0.88, RR(aMedDiet): 0.91 (0.89, [34] tMedDiet 4: 0.95) 0.94) [60] Test for subgroup differences Test for subgroup aMedDiet: (tMedDiet vs aMedDiet): differences (tMedDiet vs [71] aMedDiet): p = 0.22 aMedDiet 1: p = 0.14 [78] mMedDiet: [96] rmMedDiet: [100] MAI: [105] MedDiet 5: [89] MedDiet 3: [85] Evaluating Mediterranean diet and risk of chronic disease in cohort studies: an umbrella… 919 Table 1 continued References Outcome and No. Sample Follow- Predictive NutriGrade Modiﬁed Included Results re-analyses RR (95% Results re-analyses RR (95% summary of the studies size, up Interval grading AMSTAR MedDiet- CI) and test for subgroup CI) and test for subgroup estimates RR (95% included cases (years) (95% CI) [26] rating [24] scores* (ref.) differences (random effects differences (ﬁxed effects CI) model) model) Soﬁ et al. CVD 14 752,293, 4.5–20 (0.83, Moderate 14/22 MedDiet: [2] Per 2-point increase Per 2-point increase [19] incidence/mortality cohort 16,631 0.97) tMedDiet: RR (tMedDiet): 0.87 (0.83, RR (tMedDiet): 0.87 (0.83, studies RR: 0.90 (0.87, 0.92) [44, 47, 49] 0.91) 0.91) I = 38% tMedDiet 2: RR (aMedDiet): 0.92 (0.89, RR (aMedDiet): 0.92 (0.89, 0.94) [56] 0.94) tMedDiet 4: Test for subgroup differences Test for subgroup differences [59, 60] (tMedDiet vs aMedDiet): (tMedDiet vs aMedDiet): aMedDiet: p = 0.08 p = 0.06 [71] aMedDiet 1: [78] MedDiet 3: [85] MedDiet 4: [87] iMedDiet: [41] mMedDiet: [96] rmMedDiet: [100] 920 C. Galbete et al. Table 1 continued References Outcome and No. Sample Follow- Predictive NutriGrade Modiﬁed Included Results re-analyses RR Results re-analyses RR summary of the studies size, cases up Interval grading AMSTAR MedDiet- (95% CI) and test for (95% CI) and test for estimates RR (95% included (years) (95% CI) [26] rating [24] scores* (ref.) subgroup differences subgroup differences (ﬁxed CI) (random effects model) effects model) Cancer 14 2,720,221, 7.9–16 (0.88, Moderate tMedDiet: Per 2-point increase RR Per 2-point increase RR incidence/mortality cohort 83,111 1.02) [42, 45] (tMedDiet): 0.96 (0.94, (tMedDiet): 0.96 (0.96, studies 0.99) 0.97) RR: 0.95 (0.93, 0.97) tMedDiet 1: [53–55] RR (aMedDiet): 0.93 (0.93, RR (aMedDiet): 0.95 (0.93, I = 65% 0.98) 0.98) tMedDiet 4: [58, 59] Test for subgroup Test for subgroup differences (tMedDiet vs differences (tMedDiet vs tMedDiet 5: aMedDiet): aMedDiet): [62] p = 0.76 p = 0.42 aMedDiet: [69, 70] aMedDiet 1: [78] mMedDiet: [96] rmMedDiet: [100] iMedDiet: [97] Psaltopoulou Stroke 4 cohort 152,843, 7.9–20 (0.68, Low 19/22 tMedDiet: NA NA et al. [35] studies 2560 1.03) [41] RR: 0.84 (0.74, 0.95) tMedDiet 2: I =0% [56] aMedDiet: [71] MedDiet 3: [85] Evaluating Mediterranean diet and risk of chronic disease in cohort studies: an umbrella… 921 Table 1 continued References Outcome and No. Sample Follow- Predictive NutriGrade Modiﬁed Included Results re-analyses RR (95% Results re-analyses RR summary of the studies size, cases up Interval grading AMSTAR MedDiet- CI) and test for subgroup (95% CI) and test for estimates RR included (years) (95% CI) [26] rating [24] scores* (ref.) differences (random effects subgroup differences (ﬁxed (95% CI) model) effects model) Schwingshackl Cancer mortality 14 1,363,136, 6.3–40 (0.70, Moderate 18/22 tMedDiet: High versus low adherence High versus low adherence et al. [17] cohort 54,569 1.05) [45, 48] RR: 0.86 RR (tMedDiet): 0.92 (0.74, RR (tMedDiet): 0.83 (0.78, studies (0.81–0.91) tMedDiet 3: 1.15) 0.88) [57] I = 82% RR (aMedDiet): 0.80 (0.78, RR (aMedDiet): 0.80 (0.78, tMedDiet 9: 0.83) 0.83) [68] Test for subgroup Test for subgroup aMedDiet: differences (tMedDiet vs differences (tMedDiet vs [72, 73, 75] aMedDiet): aMedDiet): aMedDiet 3: p = 0.22 p = 0.31 [80] mMedDiet: [96] rmMedDiet: [100] MedDiet 2: [84] MedDiet 9: [94] FA: [99] Bloomﬁeld Cancer mortality 13 991,306, 5.8–40 (0.72, Low 15/22 tMedDiet: High versus low adherence High versus low adherence et al. [36] cohort 49,819 1.04) [27, 45] RR: 0.86 RR (tMedDiet): 0.92 (0.64, RR (tMedDiet): 0.84 (0.69, studies tMedDiet 3: 1.31) 1.02) (0.82, 0.91) [57] RR (aMedDiet): 0.81 (0.78, RR (aMedDiet): 0.81 (0.78, I = 77% aMedDiet: 0.85) 0.83) [72, 73, 75] Test for subgroup Test for subgroup aMedDiet 3: differences (tMedDiet vs differences (tMedDiet vs [80] aMedDiet): aMedDiet): mMedDiet: p = 0.48 p = 0.68 [96] FA: [99] rmMedDiet: [100] MedDiet 2: [84] AHEI: [102] 922 C. Galbete et al. Table 1 continued References Outcome and No. Sample Follow- Predictive NutriGrade Modiﬁed Included Results re-analyses RR (95% CI) Results re-analyses RR (95% summary of the studies size, up Interval grading AMSTAR MedDiet- and test for subgroup differences CI) and test for subgroup estimates RR (95% included cases (years) (95% CI) [26] rating [24] scores* (random effects model) differences (ﬁxed effects CI) (ref.) model) Cancer incidence 3 cohort 591, 8.7–24 (0.87, Low tMedDiet NA NA studies 002, 1.05) 1: [53] RR: 0.96 (0.95, 48,683 0.97) AHEI: [101] I =0% Wu and MCI incidence RR: 5 cohort 27,667, 2.2–12 (0.70, Moderate 18/22 tMedDiet NA NA Sun [37] 0.83 (0.75, 0.93) studies 2376 1.00) 6: [63, 64] I =0% tMedDiet 8: [106] aMedDiet 3: [81] MedDiet 4: [88] AD incidence RR: 5 cohort 7609, 4–12 (0.41, Moderate tMedDiet NA NA 0.60 (0.48, 0.77) studies 838 0.89) 6: [64, 65] I =0% tMedDiet 7: [66] MedDiet4: [88] MedDiet 10: [95] Dementia RR: 1.07 3 cohort 9811, 5–12 (0.17, Low tMedDiet NA NA (0.81,1.42) studies 632 6.61) 7: [66] I =0% aMedDiet 3: [81] MedDiet 4: [88] Cao et al. MCI incidence 4 cohort 766, 2.2–5 (0.49, Low 10/22 tMedDiet NA NA [38] studies 6294 0.96) 6: RR: 0.69 (0.57, [63–65] 0.84) tMedDiet I =1% 7: [66] Singh MCI incidence RR: 2 cohort 2626, 2.2–4.5 NA Low 17/22 tMedDiet NA NA et al. 0.73 (0.56, 0.96) studies 438 6: [39] [63, 64] I =0% Evaluating Mediterranean diet and risk of chronic disease in cohort studies: an umbrella… 923 deﬁnitions, aMedDiet 4 [82], included the food group high fat-dairy products as not being in line with the MedDiet. Apart from these two main groups of deﬁnitions we identiﬁed 16 other scores used to assess MedDiet adher- ence in 24 reports [41, 83–105]. A great variability was observed among these different deﬁnitions (see Table 2). In addition, some of the meta-analyses here evaluated included also studies in which MedDiet adherence specif- ically was not intended to be assessed. This is for example the case of the meta-analyses from Bloomﬁeld et al. [36] evaluating the effects of the MedDiet on cancer mortality and incidence. There, the authors also included two reports in which the Alternative Healthy Eating Index (AHEI) was assessed and not the MedDiet [101, 102]. In their meta- analysis on cancer mortality Bloomﬁeld et al. also included the study of Menotti et al. [99], in which two dietary pat- terns were identiﬁed by means of factor analysis. Particu- larly, the authors observed a dietary pattern characterized by high consumption of bread, pasta, potatoes, vegetables, ﬁsh, and oil and by lower consumption of milk, sugar, fruit, and alcoholic beverages and argued this was similar to the MedDiet dietary pattern. Similarly, two of the meta-anal- yses here identiﬁed evaluating the effects of MedDiet on the onset of T2D [30, 40] included the study of Brunner et al. [98], in which dietary patterns were obtained by cluster analysis. In this study one of the clusters identiﬁed was strong and positively correlated with the intake of fruit, vegetables, rice, pasta, and wine, and thus named Mediterranean-like cluster. Test for subgroup differences comparing different types of MedDiet adherence scores Several of the included meta-analyses reported moderate to high statistical heterogeneity, which could be related to the different indices applied. Once we identiﬁed the different scores used in the primary studies and considered these as similar enough, if at least two cohort studies were included in a meta-analysis for at least two different MedDiet scores, we combined the studies applying similar scores in a new meta-analysis and tested for possible subgroup dif- ferences in between the different scores. Comparing the tMedDiet versus the aMedDiet score suggested no evidence for subgroup differences (p [ 0.10) for T2D as outcome in the random effects model (Table 1). In the meta-analysis by Bloomﬁeld et al. on cancer mor- tality, an inverse association was observed with aMedDiet (RR 0.81, 95% CI 0.78, 0.85), while no association with the tMedDiet was found (RR 0.92, 95% CI 0.64, 1.31). However, as in the re-analysis of the work from Soﬁ et al. for cancer mortality/incidence, no evidence for subgroup differences were observed in the study from Bloomﬁeld et al. Regarding CVD, a marginal difference in the Table 1 continued References Outcome and No. Sample Follow- Predictive NutriGrade Modiﬁed Included Results re-analyses RR (95% CI) Results re-analyses RR (95% summary of the studies size, up Interval grading AMSTAR MedDiet- and test for subgroup differences CI) and test for subgroup estimates RR (95% included cases (years) (95% CI) [26] rating [24] scores* (random effects model) differences (ﬁxed effects CI) (ref.) model) AD incidence RR: 2 cohort 3668, 4–5 NA Low tMedDiet NA NA 0.64 (0.46, 0.89) studies 328 7: [66] I =0% tMedDiet 6: [65] T2D type 2 diabetes, CVD cardiovascular disease, CHD coronary heart disease, MI myocardial infarction, AMI acute myocardial infarction, MCI mild cognitive impairment, AD Alzheimer’s disease, FA factor analysis, AHEI Alternative Healthy Eating Index, MAI Mediterranean Adequacy Index, CA cluster analysis *This makes reference to the indices identiﬁed in Table 2 924 C. Galbete et al. subgrouping (test for subgroup difference p = 0.06) was exploratory methods [98, 99] to other scores not explicitly observed when reanalysing the meta-analysis by Soﬁ et al. created to assess MedDiet, such as the Alternative Healthy [19], where the tMedDiet showed a stronger inverse asso- Eating Index [101, 102]. ciation (RR 0.87, 95% CI 0.83, 0.91) compared to studies The tMedDiet score was used for the ﬁrst time by Tri- using the aMedDiet score (RR 0.92, 95% CI 0.89, 0.94). chopoulou et al. [27] in the EPIC-Greece cohort in 2003, Nevertheless, no statistically signiﬁcant subgroup differ- while the aMedDiet score was created and used for the ﬁrst ences were observed in any of the other meta-analyses. The time by Fung et al. [70] in the Nurses’ Health Study. This ﬁxed effects sensitivity analyses conﬁrmed mainly the second one was a literature-updated version according to results of the random effects meta-analysis. published evidence. As stated before, for most of the Unfortunately, in the case of the meta-analyses on analyses here conducted, similar associations were cognitive-related diseases it was not possible to test for observed when applying one or the other score. In the sub-group differences due to the small number of studies meta-analysis by Bloomﬁeld et al. differences in the esti- included. mates were observed but the test for subgroup differences was not signiﬁcant. These observed differences could be due to the selection of healthier items included in the Discussion aMedDiet score compared to the tMedDiet. This is the case, for example, of whole grains; the most recent meta- In this umbrella review of meta-analyses, we summarized analyses observed an inverse dose–response association of the ﬁndings from prospective cohort studies and investi- whole grains with cancer mortality [107, 108]. The evi- gated the different scores used to assess MedDiet and their dence regarding the health implications of dairy products is implications on the risk of major chronic diseases (T2D, controversial. A recent meta-analysis observed in a non- CVD, cancer and cognitive-related diseases). We observed linear dose–response model that low intake of total dairy that a higher adherence to the MedDiet was associated with products could be protective against cancer-related deaths lower incidence of T2D, lower incidence/mortality of [109]. Concerning meat and processed meat, the World CVD, and lower incidence/mortality of cancer; the credi- Cancer Research Fund International recommends an aver- bility of this evidence ranged from low to moderate. Low age consumption under 300 g a week, and to limit as much credibility of the evidence implies that the conﬁdence in as possible the intake of processed meat [110]. The same the effect estimate was low and that further research will report stated that processed meat has been particularly provide important evidence on the conﬁdence and likely associated with an increased risk of colorectal and stomach change the effect estimate, while moderate credibility non-cardia cancers. Finally, the inclusion of two food means that further research could add evidence on the groups for fruits and nuts instead of combining them into conﬁdence and may change the effect estimate [26]. Two one attributes a higher weight of these food items presumed scores assessing adherence to the MedDiet were manly to have a beneﬁcial effect on health. These two food applied in cohort studies (tMedDiet and aMedDiet). groups, as well as whole grains, are rich in ﬁbre, nutrient Overall, we observed little difference in risk associations particularly associated with lower risk of colorectal cancer comparing tMedDiet versus aMedDiet indices in the sub- [111]. In any case, our analyses are restricted to overall group meta-analysis. In the meta-analysis by Soﬁ et al. cancer mortality; the broad consideration of overall cancer [19], which assessed the effect of the MedDiet on the risk and this approach could complicate possible conclusions of CVD incidence/mortality, some differences were and interpretations due to the different nature and aetiology observed; in this case, both MedDiet scores associated with of the different cancer sites. Still, no difference has been lower risk, but the effects observed for the tMedDiet score observed for T2D and CVD even though foods like whole were stronger. grains and red meat have been also shown to be associated with these diseases [112–116]. Mediterranean diet scores and health Some other limitations should be mentioned. In the ﬁrst associations place, our analyses have been restricted to the ones already performed by the authors and this could complicate the Within the large variety of indices attempting to reﬂect comparisons. For example, some of the authors combined adherence to the MedDiet two scores could be identiﬁed incidence and mortality in one outcome while other pre- which were applied more frequently; the tMedDiet used in ferred to assess these separately. Moreover, the deﬁnitions 32 studies [7, 13, 27, 41–68, 106], and the aMedDiet used for the scores here identiﬁed were restricted to the ones in 14 studies [69–82]. Nineteen other deﬁnitions were previously identiﬁed by the authors conducting the meta- found within the remaining 24 studies [41, 83–105]. These analyses we have here evaluated. Thus, other scores used to were very disperse; from dietary patterns derived by assess adherence to the MedDiet could not have been 123 Evaluating Mediterranean diet and risk of chronic disease in cohort studies: an umbrella… 925 Table 2 Description of the different scores identiﬁed representing MedDiet Vegetables Legumes Fruits/nuts Cereals Fish Meat Dairy products Alcohol Fat intake Extras Cited MedDiet 1 1 2 3 – 1 1 n.d. 1 – [2] tMedDiet 1 1 1 1 1 1 1 1 1 – [7, 27, 41–52] tMedDiet 1 1 1 1 1 1 1 1 1 4 – [53–55] tMedDiet 2 1 1 2 1 1 1 1 3 1 – [56] tMedDiet 3 1 1 1 1 1 1 1 4 1 – [57] tMedDiet 4 1 1 1 1 1 1 1 1 2 – [13, 58–61] tMedDiet 5 1 1 1 1 1 1 1 – 2 – [62] tMedDiet 6 1 1 2 1 1 1 1 16 1 – [63–65] tMedDiet 7 1 1 2 1 1 1 1 14 1 – [66] tMedDiet 8 1 1 2 1 1 1 1 17 1 – [67, 106] tMedDiet 9 1 1 2 1 1 1 1 1 1 [68] aMedDiet 1 1 2, 3 2 1 2 – 5 1 – [69–77] aMedDiet 1 1 1 2, 3 2 1 2 – 15 1 – [78] aMedDiet 2 1 1 2, 3 2 1 2 – 6 1 – [79] aMedDiet 3 1 1 2, 3 2 1 2 – 7 1 – [80, 81] aMedDiet 4 1 1 2, 3 2 1 2 2 6 1 – [82] MedDiet 1 2, 3 – 2 2 1 – – – 2 – [83] MedDiet 2 1, 4 – 2 2 1 3 3 8 3 – [84] MedDiet 3 1 2 2 1 1 1 1 13 4 – [85, 86] MedDiet 4 5* * 2 3 1 1 1 1 6 – [87, 88] MedDiet 5 1 – 2 1 1 4 1 2 4 – [89] MedDiet 6 1 2 2 2 1 2, 5 2 14 5 – [90] MedDiet 7 8** 2 ** 2 1 2 11 5 11 – [91, 92] MedDiet 8 1, 8 2, 3 1 2 1 3, 6, 9, 10 3 – 2 2, 5-10 [93] MedDiet 9 1 – 2, 3 9 1 2, 3 12 5 1 4 [94] MedDiet 10 1 1 2 2 1 2, 5 2 18 2 3 [95] mMedDiet 6 3 – 1 1 1 1 – 1 – [96] iMedDiet 7 1 2 4 1 6 4 9 2 1, 2 [41, 97] CA 1 – 2 5, 6 – – 5, 6 8, 10 – – [98] FA 1 – – 4, 7 1 – – – 7 3 [99] rmMedDiet 6 – 4 2 1 1 1 2 4 – [100] AHEI 1 2 5 2 – 2 – 11 8–10 2, 4 [101, 102] 926 C. Galbete et al. Table 2 (continued) Vegetables Legumes Fruits/nuts Cereals Fish Meat Dairy products Alcohol Fat intake Extras Cited sMedDiet 1 1 1 2 1 2, 5, 7 2, 7 12 2 3 [103, 104] MAI 1 1 2 1 1 1, 7 8–10 8 2 2, 3, 5 [105] Vegetables (?); 1: vegetables; 2: raw vegetables; 3: cooked vegetables; 4; salad; 5: vegetables ? legumes; 6: vegetables ? potatoes; 7: Mediterranean vegetables (raw tomatoes, leafy vegetables, onion and garlic, salad, fruiting vegetables); 8: vegetables ? fruits (excl. potatoes and fruit juices) Legumes (?); 1: legumes; 2; legumes ? nuts; 3: legumes ? nuts ? seeds Fruits/nuts (?); 1: fruits ? nuts; 2: fruits; 3: nuts; 4; fruits ? juices; 5: fresh fruit only Cereals (?); 1: cereals; 2: whole grain cereals; 3; cereals ? potatoes; 4: pasta; 5: whole grain bread; 6: pasta ? rice; 7: bread; 8: reﬁned cereals (-); 9: max score = 3rd quintile of intake (bread, rice and white potatoes) Fish (?); 1: ﬁsh (and seafood) Meat; 1: meat and meat products (-); 2: red and processed meat (-); 3: white meat (?); 4: meat, meat products and egg (-); 5: poultry (-); 6: red meat (-); 7: eggs (-); 8: preferred white meat over red meat and processed meat; 9: organ meat (-); 10: egg (?) Dairy products; 1: dairy products (-); 2: high-fat dairy products (-); 3: dairy products (?); 4: butter (-); 5: full-cream milk (-); 6: butter (?); 7: low-fat dairy products (?); 8: Butter, margarine or cream; 9: milk; 10: cheese; 11: fermented dairy products (?); 12: max. score 3rd quintile of intake Alcohol; 1: max. score = women 5–25 g/d, men 10–50 g/d; 2: max. score C sex-speciﬁc median; 3: max. score [ 0 drinks/wk B 2 drinks/d; 4: max. score = women B 1 drink/d, men B 2 drinks/d; 5: max. score = women 5–15 g/d, men 10–25 g/d; 6: max score = 5–15 g/d; 7: max. score = women 5–15 g/d, men 10–15 g/d; 8: wine; 9: max. score C 0–12 g/d; 10: beer (CA); 11: max. score = women 0.5–1.5 drinks/d, men 0.5–2.0 drinks/d; 12: max. socre \ 3 glasses/d = 5 points and min. score [ 7 glasses/d or none = 0 points; 13: max. score C 1 drink/month; 14: max. score to those in the second quintile of alcohol intake; 15: max. score = 5–25 g/day for everybody; 16: max. sore = [ 0–30 g/d; 17: max. score = women 1–7 drinks/wk, men 1–14 drinks/ wk; 18: max. score 1–300 ml/d Fats; 1: MUFA:SFA ratio; 2: Olive oil; 3: MUFA; 4: (MUFA ? PUFA):SFA ratio; 5: PUFA ? MUFA; 6: PUFA:SFA ratio; 7: Oils; 8: trans fatty acids; 9: EPA ? DHA fatty acids; 10: PUFA; 11: olive oil and/or rapeseed oil as main sources of fat Extras; 1: potatoes (-); 2; sugar-sweetened beverages (-); 3: potatoes (?); 4: Sodium (-); 5: confectionary; 6: fruit juices and drinks; 7: pickled food; 8: deep fried food; 9; salty snacks; 10: pizza CA, cluster analysis; FA, factor analysis; AHEI, Alternative Healthy Eating Index; MAI, Mediterranean Adequacy Index; (-), not in line with the MedD; (?), in line with the MedD; MUFA, monosaturated fatty acids; SFA, saturated fatty acids; PUFA, polyunsaturated fatty acids; EPA, eicosapentaenoic acid; DHA, docosahexaenoic acid; n.d., not deﬁned Evaluating Mediterranean diet and risk of chronic disease in cohort studies: an umbrella… 927 identiﬁed. This is the case, for example of the Mediter- Compliance with ethical standards ranean diet pyramid [117]. On the other hand, other sources Conflict of interest The authors declare that they have no conflict of of heterogeneity due to the construction of the scores have interest. not been evaluated here. Moreover, umbrella reviews are limited by their primary objective. In our case we targeted Open Access This article is distributed under the terms of the Creative meta-analyses on prospective observational studies and Commons Attribution 4.0 International License (http://creative commons.org/licenses/by/4.0/), which permits unrestricted use, dis- thus, no randomized controlled trials were included. Also, tribution, and reproduction in any medium, provided you give only studies included within the identiﬁed meta-analyses appropriate credit to the original author(s) and the source, provide a have been here evaluated; any other potentially relevant link to the Creative Commons license, and indicate if changes were study could not have been included. 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Publisher: Springer Journals
Copyright: Copyright © 2018 by The Author(s)
Subject: Medicine & Public Health; Epidemiology; Public Health; Infectious Diseases; Cardiology; Oncology
ISSN: 0393-2990
eISSN: 1573-7284
DOI: 10.1007/s10654-018-0427-3
pmid: 30030684
Publisher site: See Article on Publisher Site

Abstract

European Journal of Epidemiology (2018) 33:909–931 https://doi.org/10.1007/s10654-018-0427-3(0123456789().,-volV)(0123456789().,-volV) REVIEW Evaluating Mediterranean diet and risk of chronic disease in cohort studies: an umbrella review of meta-analyses 1,2 2,3 2,3 2,3 • • • • Cecilia Galbete Lukas Schwingshackl Carolina Schwedhelm Heiner Boeing 1,2,4 Matthias B. Schulze Received: 30 January 2018 / Accepted: 17 July 2018 / Published online: 20 July 2018 The Author(s) 2018 Abstarct Several meta-analyses have been published summarizing the associations of the Mediterranean diet (MedDiet) with chronic diseases. We evaluated the quality and credibility of evidence from these meta-analyses as well as characterized the different indices used to deﬁne MedDiet and re-calculated the associations with the different indices identiﬁed. We conducted an umbrella review of meta-analyses on cohort studies evaluating the association of the MedDiet with type 2 diabetes, cardiovascular disease, cancer and cognitive-related diseases. We used the AMSTAR (A MeaSurement Tool to Assess systematic Reviews) checklist to evaluate the methodological quality of the meta-analyses, and the NutriGrade scoring system to evaluate the credibility of evidence. We also identiﬁed different indices used to deﬁne MedDiet; tests for subgroup differences were performed to compare the associations with the different indices when at least 2 studies were available for different deﬁnitions. Fourteen publications were identiﬁed and within them 27 meta-analyses which were based on 70 primary studies. Almost all meta-analyses reported inverse associations between MedDiet and risk of chronic disease, but the credibility of evidence was rated low to moderate. Moreover, substantial heterogeneity was observed on the use of the indices assessing adherence to the MedDiet, but two indices were the most used ones [Trichopoulou MedDiet (tMedDiet) and alternative MedDiet (aMedDiet)]. Overall, we observed little difference in risk associations comparing different MedDiet indices in the subgroup meta-analyses. Future prospective cohort studies are advised to use more homogenous deﬁnitions of the MedDiet to improve the comparability across meta-analyses. Keywords Mediterranean diet Chronic diseases Umbrella review Meta-analyses Cohort studies Heterogeneity Introduction olive oil consumption in Greece, the high ﬁsh intake in the Dalmatian area (Croatia), and the high vegetable intake in The Seven Countries Study observed in the 1960s a lower Italy. Later on, the dietary components considered to have cardiovascular mortality in the participating countries a beneﬁcial effect on health were combined in one index around the Mediterranean area [1]. Ancel Keys attributed and published as MedDiet index [2]. Apart from the this observation to the traditional diets such as the high inﬂuence of the Mediterranean diet (MedDiet) on risk of cardiovascular disease (CVD), several metabolic diseases have been studied for a possible favourable role, including & Lukas Schwingshackl type 2 diabetes (T2D), cognitive-related diseases, and dif- lukas.schwingshackl@dife.de ferent types of cancer in the Mediterranean countries Department of Molecular Epidemiology, German Institute of [3–10]. Recently the landmark PREDIMED study has been Human Nutrition Potsdam-Rehbruecke, Nuthetal, Germany retracted and republished due to ‘‘irregularities in ran- NutriAct – Competence Cluster Nutrition Research Berlin- domisation procedures’’ [11, 12]. Similarly to the retracted Potsdam, Nuthetal, Germany paper, the new ﬁndings showed that the incidence of Department of Epidemiology, German Institute of Human combined cardiovascular events was lower among those Nutrition Potsdam-Rehbruecke, Nuthetal, Germany assigned to a MedDiet supplemented with extra-virgin Institute of Nutritional Sciences, University of Potsdam, Nuthetal, Germany 123 910 C. Galbete et al. olive oil or nuts than among those assigned to a lower-fat Methods diet [12]. The interest in the MedDiet as a whole was not This manuscript was drafted in adherence to the recom- restricted to those countries and thus, the MedDiet has been mendations of the ‘Preferred Reporting Items for System- investigated in many countries that are geographically far atic reviews and Meta-Analyses’ (PRISMA) checklist [20]. from being Mediterranean, e.g. Australia and Japan The methodological approach of this umbrella review is [13–15]. The observed results have been summarised in based on previous published umbrella reviews, which several meta-analyses, but the methods used for the esti- focused on nut and garlic intake and risk of CVD [21, 22], mation of MedDiet adherence in the different study pop- and is next explained. ulations were often heterogeneous, implying the creation of many different indices intended to reﬂect MedDiet. In fact, Data sources and search strategy even though most of the meta-analyses are consistent in their ﬁndings, the observed statistical heterogeneity within PubMed (from inception until 27th March 2018) and these varies from low to high (e.g. from 26% in the study Embase (from inception until 27th March 2018) was from Jannasch et al. [16] on MedDiet and T2D to 82% in searched for meta-analyses published in English language the meta-analysis on MedDiet and cancer from Schwing- using following search terms: (Mediterranean[tiab]) AND shackl et al. [17]). Moreover, the methodological quality (cardiovascular[tiab] OR coronary[tiab] OR myocardial[- and credibility of evidence of these meta-analyses have not tiab] OR stroke[tiab] OR mortality[tiab] OR cancer[tiab] been analysed so far. OR ‘‘neoplastic disease’’[tiab] OR tumor[tiab] OR dia- The creation of nutritional indices is a common tool betes[tiab] OR ‘‘cognitive decline’’[tiab] OR cognition[- largely used in the nutritional epidemiology research with tiab] OR dementia[tiab] OR Alzheimer disease[tiab]) AND the purpose of reﬂecting the adherence to a dietary pattern, (meta-analysis[tiab]). Additionally, reference lists of the e.g. the MedDiet, in a certain population. These are created included meta-analyses were veriﬁed for further relevant by ranking the population according to the intake of foods studies as well. considered to be in line with, or against, the dietary pattern under study. Inclusion criteria Soﬁ et al. as well as Davis et al. discussed the derived difﬁculties from the use of different scores measuring Studies were included in this umbrella review if they MedDiet adherence [18, 19]. They criticised that the use of met all of the following criteria: (1) meta-analysis of cohort different population-speciﬁc cut-off values for the con- studies, (2) evaluating the association of scores used for sumption of the food groups considered to be part of the assessing adherence to a MedDiet or considered by the MedDiet hampered the further clinical and public health authors as reﬂecting a MedDiet type diet, (3) study popu- applications. But this is not the only discrepancy observed lation: C 18 years, (4) study endpoints include overall among the different scores; both authors mentioned also cancer mortality and/or incidence, CVD or coronary heart the inconsistencies observed in the classiﬁcation of the disease (CHD) mortality and/or incidence, stroke, food groups. However, this point has not been deeply myocardial infarction (MI), acute myocardial infarction investigated and could be one of the reasons for the high (AMI) type 2 diabetes, Alzheimer’s disease (AD), mild statistical heterogeneity found in several of the published cognitive impairment (MCI), or dementia. meta-analyses. Thus, by the present complementary umbrella review, in a ﬁrst step, we aimed to evaluate the Methodological quality methodological quality and the credibility of evidence generated by all available meta-analyses evaluating the The methodological quality was evaluated using a modiﬁed association between adherence to a MedDiet and major version of the AMSTAR (A MeaSurement Tool to Assess chronic diseases (T2D, CVD, cancer and cognitive-related systematic Reviews) [23] checklist, which has been disorders) in cohort studies. In a second step, we aimed to recently established to evaluate the methodological quality enumerate and characterize the different deﬁnitions used to of meta-analyses and systematic reviews on the Mediter- assess adherence to the MedDiet in the studies gathered in ranean diet and CVD outcomes and is based on 14 items the meta-analyses, and to emulate the associations on (maximum score of 22) [24]. These are grouped within four chronic diseases with the different dietary MedDiet different domains; (1) ‘‘a priori design’’, which includes adherence indices. two questions, (2) Literatures search and duplicate effort, which includes ﬁve different questions, (3) coding of studies, including two questions, and (4) analysis and 123 Evaluating Mediterranean diet and risk of chronic disease in cohort studies: an umbrella… 911 interpretation, which includes four different questions. The incorporated both within and between study variability original AMSTAR checklist has been previously used to [28]. To evaluate the weighting of each study, the choose high quality systematic reviews and meta-analysis standard error for the logarithm HR/RR/OR of each to build the Dietary Guidelines for Americans 2015–2020 study was calculated and regarded as the estimated [25]. variance of the logarithm HR/RR/OR, using an inverse variance method [28]. Credibility of the evidence To detect discrepancies between the different types of MedDiet adherence scores for an outcome a test for sub- To evaluate credibility of evidence for the association group differences was performed based on a random effects between adherence to MedDiet and risk of the included model (ﬁxed effects model used for the sensitivity outcomes we applied the NutriGrade scoring system (max analysis). 10 points) which comprises the following items for cohort For the summary random effects, we estimated for each studies [26]: (1) risk of bias/study quality/study limitations, meta-analysis the 95% prediction interval (PI), which fur- (2) precision, (3) heterogeneity, (4) directness, (5) publi- ther accounts for the degree of between-study hetero- cation bias, (6) funding bias, (7) effect size, and (8) dose– geneity and gives a range for which we are 95% conﬁdent response. Based on this scoring system we recommend four that the effect in a new study examining the same associ- categories to judge credibility of meta-evidence: high, ation lies within [29]. moderate, low, and very low taking into account the fol- All analyses were conducted using the Review Manager lowing cut-points: C 8 points (high meta-evidence), by the Cochrane Collaboration (version 5.3) and Stata 14.2 6–7.99 points (moderate meta-evidence), 4–5.99 (low (Stata-Corp, College Station, TX. USA). meta-evidence), and 0–3.99 (very low meta-evidence). Identification of different MedDiet scores Results Within the meta-analyses included in this study the dif- The study characteristics of the meta-analyses are sum- ferent scores used in the primary studies were carefully marized in Table 1. A total of 14 publications reporting 27 evaluated. The nine food groups referred to by Tri- meta-analyses on the association of the MedDiet with the chopoulou et al. [27], and usually quoted for the creation of risk of any of the major chronic diseases (T2D, CVD, the MedDiet score were considered as the basis (fruit, cancer, or cognitive-related diseases) were included in the vegetables, legumes, cereals, meat, dairy products, ﬁsh, present umbrella review [16, 17, 19, 30–40]. Among all the alcohol and, healthy fats), and for each primary study we meta-analyses 70 primary studies were included carefully identiﬁed the foods reported to be included within [2, 7, 13, 27, 41–106]. Several different endpoints have the different food groups. Thus, the scores were considered been evaluated: T2D, CVD incidence and/or mortality, to be different when: (1) different food groups were CHD incidence, different types of stroke incidence and/or included, (2) food groups were comprised of different food mortality, MI incidence, MCI incidence, AD incidence, items, and (3) different speciﬁc cut-off values within the and dementia incidence. Four meta-analyses were found food items were applied. This last point was particularly evaluating the association between adherence to the Med- relevant for the different cut-off values used to deﬁne Diet and risk of T2D [16, 30, 31, 40], among which 11 ‘‘moderate alcohol intake’’. primary studies were considered [7, 43, 46, 50, 61, 74, 76, 79, 82, 83, 98]. Comparing the highest versus lowest Statistical analysis adherence category an inverse association between 13% (RR 0.87, 95% CI 0.82, 0.97) and 23% (RR 0.77, 95% CI If at least two cohort studies were included in a meta- 0.66, 0.89) for the risk of T2D was observed. Regarding the analysis for at least two speciﬁc MedDiet adherence different CVD endpoints a total of 12 meta-analyses within scores identiﬁed (e.g. tMedDiet, aMedDiet, sMedDiet) 5 publications were identiﬁed [19, 32–35], and within these a new meta-analysis was carried out to estimate and 31 primary studies were included [2, 13, 41, 44, 47, 49, 51, compare the associations between these scores for the 52, 56, 59, 60, 67, 71, 72, 75, 77, 78, 80, 85–87, 89–93, included outcomes. These new meta-analyses were 96, 100, 103–105]. A 2-point increase in adherence to the performed by combining the multivariable adjusted MedDiet score was associated with a 10% (RR 0.90, 95% RRs, HR of the highest compared with the lowest CI 0.86, 0.94) lower risk of CVD incidence/mortality MedDiet adherence category, or 2-point increase in [19, 34]. Comparing the highest versus lowest category of MedDiet adherence score based on a random effects adherence to the MedDiet the risk of CVD was reduced by model using the DerSimonian–Laird method, which approximately 19% (RR 0.81, 95% CI 0.74, 0.88) to 27% 123 912 C. Galbete et al. (RR 0.73, 95% CI 0.66, 0.80). Similar results were reported (moderate conﬁdence for the effect estimate: further for CHD (RR 0.72, 95% CI 0.60, 0.86), MI (RR 0.67, 95% research could add information on the conﬁdence and may CI 0.54, 0.83), AMI (RR 0.74, 95% CI 0.66, 0.83), and change the effect estimate). stroke (RR 0.77, 95% CI 0.67, 0.90). No association was observed between adherence to the MedDiet and haemor- Description of the different scores rhagic stroke. Regarding overall cancer incidence and/or mortality four meta-analyses were identiﬁed within three A total of 70 primary studies were included within the 27 publications [17, 19, 36], and within these a total of 27 meta-analyses, where 34 different scores meant to reﬂect primary studies were identiﬁed [27, 42, 45, 48, the MedDiet were applied [2, 7, 13, 27, 41–106]. A detailed 53–55, 57–59, 62, 68–70, 72, 73, 75, 78, 80, 84, 94, 96, 97, description of the different deﬁnitions is shown in Table 2. 99–102]. Two meta-analyses considering overall cancer Within the 34 different deﬁnitions gathered from the mortality and one meta-analysis including overall cancer included studies, two main ones could be extracted; the incidence were found [17, 36], whereas in another meta- ﬁrst one made reference to the deﬁnitions derived from the analysis conducted by Soﬁ et al. [19] cancer mortality and one created in 2003 by Trichopoulou et al. [27] (tMedDiet), incidence were combined. Comparing the highest versus which, after the careful evaluation was considered as dif- lowest adherence to MedDiet category a 14% (RR 0.86, ferent from the ﬁrst one used by Trichipoulou et al. [2]. The 95% CI 0.81, 0.91) (4% reduction for cancer incidence) Trichopoulou deﬁnition from 2003 included nine food reduced risk of cancer mortality was reported, whereas a groups, ﬁve were postulated to be in line with it (vegeta- 2-point increase in the MedDiet score was associated with bles, fruits and nuts, cereals, legumes, and ﬁsh), and two a 5% (RR 0.95 95% CI 0.93, 0.97) reduced risk of cancer were in disagreement with it (dairy products and meat). mortality/incidence. Regarding cognitive-related disorders Alcohol intake in moderation was also considered as part three studies meta-analysed the observed effects of Med- of the MedDiet, as well as a higher intake of monounsat- Diet with different outcomes: MCI, AD and dementia urated fats (MUFA) in relation to saturated fats (SFA). [37–39]. A total of 6 meta-analyses were conducted Fourteen studies out of the 70 identiﬁed were using this [37–39]. Comparing highest versus lowest category of deﬁnition to assess adherence to the MedDiet adherence to the MedDiet up to 31% (RR 0.69, 95% CI [7, 27, 41–52]. Nine other deﬁnitions, used in 18 studies, 0.57, 0.84) risk reduction for MCI was observed and 40% were relatively similar to this one (labelled from tMedDiet (RR 0.60, 95% CI 0.48, 0.77) reduction for AD. No asso- 1 to tMedDiet 9) [13, 53–68, 106]. The differences among ciation was observed for incident dementia. these dietary pattern scores were observed in the cut-off Almost all included meta-analyses showed a signiﬁcant values considered to deﬁne moderate alcohol intake as well inverse association between higher adherence to a MedDiet as in how healthy fat intake was reﬂected. Regarding this and risk of chronic diseases. Estimating 95% prediction last point two of these deﬁnitions, tMedDiet 4 and 5 intervals, however, the null value was excluded only in [13, 58–62], considered intake of olive oil instead of the some of the associations (CVD incidence, CVD inci- MUFA: SFA ratio. This modiﬁcation has been commonly dence/mortality, CHD/AMI incidence mortality, unspeci- used in those studies conducted in non-Mediterranean ﬁed stroke incidence/mortality, AD incidence, and MCI countries, where the intake of MUFA could be mainly incidence). This implies that most meta-analyses indicated represented by the fat intake from meat rather than olive high degrees of statistical heterogeneity and/or were based oil. Another variation of this deﬁnition, tMedDiet 1 on a limited number of studies. [53–55], included the intake of polyunsaturated fatty acids (PUFA) together with MUFA. Methodological quality The second main deﬁnition observed referred to the one created by Fung et al. [71], the alternative MedDiet index In total, the overall methodological quality of the included (aMedDiet). The authors modiﬁed the original score cre- meta-analyses was rated as moderate (Table 1). On aver- ated by Trichopoulou et al. by considering some eating age, the meta-analyses achieved a mean of 16.5 points behaviours that were associated with lower risk of chronic (75% of the maximum score). disease. Thus, the authors separated into two different groups fruits and nuts, eliminated the dairy group, included Credibility of the evidence whole grain products only, as well as only red and pro- cessed meat. Nine studies used this deﬁnition and ﬁve other The NutriGrade credibility of evidence judgement varied studies used a deﬁnition relatively similar to this one between low (low conﬁdence for the effect estimate: fur- [69–77]. The main difference was observed in how alcohol ther research provides important information on the con- intake in moderation was deﬁned, and also one of these ﬁdence and likely change the effect estimate) and moderate 123 Evaluating Mediterranean diet and risk of chronic disease in cohort studies: an umbrella… 913 Table 1 General and speciﬁc characteristics of the included meta-analysis References Outcome and No. Sample Follow- Predictive NutriGrade Modiﬁed Included Results re-analyses RR (95% Results re-analyses RR (95% summary of the studies size, up Interval grading AMSTAR MedDiet- CI) and test for subgroup CI) and test for subgroup estimates RR included cases (years) (95% CI) [26] rating [24] scores* (ref.) differences (random effects differences (ﬁxed effects (95% CI) model) model) Jannasch et al. T2D incidence 6 cohort 183,392, 10–20 (0.77, Low 18/22 tMedDiet: High versus low adherence High versus low adherence [16] studies 17,561 1.00) [7, 50] RR: 0.87 (0.82, RR (tMedDiet): 0.87 (0.81, RR (tMedDiet): 0.87 (0.81, 0.97) tMedDiet 4: 0.93) 0.93) [61] I = 26% RR (aMedDiet): 0.88 (0.75, RR (aMedDiet): 0.89 (0.84, aMedDiet: 1.04) 0.98) [74] Test for subgroup differences Test for subgroup aMedDiet 2: (tMedDiet vs aMedDiet): differences (tMedDiet vs [79] aMedDiet): p = 0.83 aMedDiet 4: p = 0.51 [82] Schwingshackl T2D incidence 8 cohort 129,647, 3.2–20 (0.61, Moderate 17/22 tMedDiet: High versus low adherence High versus low adherence et al. [40] studies 19,463 1.11) [46, 50] RR: 0.83 RR (tMedDiet): 0.86 (0.74, RR (tMedDiet): 0.88 (0.81, tMedDiet 4: 1.01) 0.95) (0.74, 0.92) [61] RR (aMedDiet): 0.82 (0.68, RR (aMedDiet): 0.79 (0.71, I = 56% aMedDiet: 1.00) 0.87) [76] Test for subgroup differences Test for subgroup aMedDiet 2: (tMedDiet vs aMedDiet): differences (tMedDiet vs [79] aMedDiet): p = 0.70 aMedDiet 4: p = 0.11 [82] CA: [98] MedDiet 1: [83] Koloverou T2D incidence 9 cohort 135,168, 3.2–20 (0.62, Low 16/22 tMedDiet: High versus low adherence High versus low adherence et al. [30] studies 19,609 1.15) [43, 46, 50] RR: 0.77 RR (tMedDiet): 0.88 (0.76, RR (tMedDiet): 0.88 (0.81, tMedDiet 4: 1.02) 0.95) (0.66, 0.89) [61] RR (aMedDiet): 0.83 (0.67, RR (aMedDiet): 0.79 (0.71, I = 58% aMedDiet: 1.04) 0.89) [76] Test for subgroup differences Test for subgroup aMedDiet 2: (tMedDiet vs aMedDiet): differences (tMedDiet vs [79] aMedDiet): p = 0.66 aMedDiet 4: p = 0.12 [82] CA: [98] MedDiet 1: [83] 914 C. Galbete et al. Table 1 continued References Outcome and No. Sample Follow- Predictive NutriGrade Modiﬁed Included Results re-analyses RR (95% Results re-analyses RR summary of the studies size, up Interval grading AMSTAR MedDiet- CI) and test for subgroup (95% CI) and test for estimates RR (95% included cases (years) (95% CI) [26] rating [24] scores* (ref.) differences (random effects subgroup differences (ﬁxed CI) model) effects model) Esposito T2D incidence 6 cohort 95,384, 3.2–20 (0.50, Low 17/22 MedDiet 1: High versus low adherence High versus low adherence et al. studies 7129 1.26) [83] RR: 0.80 (0.68, 0.93) RR (tMedDiet): 0.46 (0.09, RR (tMedDiet): 0.87 (0.77, [31] tMedDiet: 2.21) 0.98) I = 64% [46, 50] RR (aMedDiet): 0.82 (0.68, RR (aMedDiet): 0.79 (0.71, 0.87) aMedDiet 2: 1.00) [79] Test for subgroup differences Test for subgroup aMedDiet: (tMedDiet vs aMedDiet): differences (tMedDiet vs [76] aMedDiet): p = 0.47 aMedDiet 4: p = 0.21 [82] Rosato CHD/AMI 9 cohort 392,283, 4.9–20 (0.50, Moderate 14/22 MedDiet 6: NA NA et al. incidence/mortality studies 4256 0.99) [90] [32] RR: 0.74 (0.66, tMedDiet 4: 0.83) [60] I = 27% tMedDiet: [44, 47] tMedDiet 2: [56] MedDiet 3: [85] mMedDiet: [96] aMedDiet: [77] MedDiet 7: [91] Unspeciﬁed stroke 5 cohort 107,074, No (0.61, Low tMedDiet: NA NA incidence/mortality studies 1210 follow- 0.98) [41, 49, 51] RR: 0.77 (0.67, up to aMedDiet: 0.90) 20 [77] I =0% MedDiet 3: [85] MedDiet 8: [93] Evaluating Mediterranean diet and risk of chronic disease in cohort studies: an umbrella… 915 Table 1 continued References Outcome and No. Sample Follow- Predictive NutriGrade Modiﬁed Included Results re-analyses RR (95% Results re-analyses RR (95% summary of the studies size, up Interval grading AMSTAR MedDiet- CI) and test for subgroup CI) and test for subgroup estimates RR (95% included cases (years) (95% CI) [26] rating [24] scores* (ref.) differences (random effects differences (ﬁxed effects CI) model) model) Ischemic stroke 5 cohort 181,295, 6.5–20 (0.67, Low tMedDiet: NA NA studies 2997 1.00) [41] RR: 0.82 (0.73, 0.92) tMedDiet 2: I =0% [56] tMedDiet 8: [67] aMedDiet: [71] MedDiet 7: [91] Haemorrhagic stroke 4 cohort 178,727, 6.5–20 (0.36, Low tMedDiet: NA NA RR: 1.01 (0.74, studies 737 2.82) [41] 1.37) tMedDiet 8: I = 36% [67] aMedDiet: [71] MedDiet 7: [91] Unspeciﬁed CVD 11 831,642, 4.9–20 (0.62, Moderate tMedDiet: High versus low adherence High versus low adherence incidence/mortality cohort 56 695 1.06) [47, 52] RR (tMedDiet): 0.69 (0.54, RR (tMedDiet): 0.70 (0.58, RR: 0.81 (0.74, studies tMedDiet 2: 0.89) 0.86) 0.88) [56] RR (aMedDiet): 0.83 (0.74, RR (aMedDiet): 0.81 (0.79, I = 80% tMedDiet 4: 0.94) 0.84) [59] Test for subgroup differences Test for subgroup differences aMedDiet: (tMedDiet vs aMedDiet): (tMedDiet vs aMedDiet): [72, 75, 77] p = 0.18 p = 0.17 MedDiet 3: [85] MedDiet 4: [87] MedDiet 7: [92] mMedDiet: [96] 916 C. Galbete et al. Table 1 continued References Outcome and No. Sample Follow- Predictive NutriGrade Modiﬁed Included Results re-analyses RR (95% Results re-analyses RR (95% summary of the studies size, up Interval grading AMSTAR MedDiet- CI) and test for subgroup CI) and test for subgroup estimates RR included cases (years) (95% CI) [26] rating [24] scores* (ref.) differences (random effects differences (ﬁxed effects (95% CI) model) model) Grosso CVD incidence 13 274,023, 2–20 (0.57, Moderate 16/22 tMedDiet: High versus low adherence High versus low adherence et al. cohort 11,688 0.92) [44, 47, 49] RR: 0.73 (0.66, RR (tMedDiet): 0.71 (0.60, RR (tMedDiet): 0.72 (0.63, [33] studies 0.80) tMedDiet 2: 0.85) 0.82) [56] I = 36% RR (MedDiet 3): 0.80 (0.66, RR (MedDiet 3): 0.83 (0.74, tMedDiet 4: 0.97) 0.92) [60] RR (sMedDiet): 0.22 (0.06, RR (sMedDiet): 0.21 (0.12, aMedDiet: 0.82) 0.37) [71] Test for subgroup differences Test for subgroup differences iMedDiet: (tMedDiet vs MedDiet 3 vs (tMedDiet vs MedDiet 3 vs [41] sMedDiet): sMedDiet): MedDiet 5: p = 0.13 p \ 0.01 [89] MedDiet 3: [85, 86] MAI: [105] sMedDiet: [103, 104] Evaluating Mediterranean diet and risk of chronic disease in cohort studies: an umbrella… 917 Table 1 continued References Outcome and No. Sample Follow- Predictive NutriGrade Modiﬁed Included Results re-analyses RR (95% Results re-analyses RR (95% summary of the studies size, up Interval grading AMSTAR MedDiet- CI) and test for subgroup CI) and test for subgroup estimates RR included cases (years) (95% CI) [26] rating [24] scores* (ref.) differences (random effects differences (ﬁxed effects (95% CI) model) model) CVD mortality 14 786,279, 5.8–40 (0.53, Low tMedDiet: RR (tMedDiet): 0.76 (0.68, RR (tMedDiet): 0.76 (0.68, cohort 9563 1.06) [44, 49] 0.85) 0.85) RR: 0.75 studies tMedDiet 4: RR (aMedDiet): 0.77 (0.68, RR (aMedDiet): 0.77 (0.71, (0.68, 0.83) [13, 59] 0.86) 0.84) I = 75% aMedDiet: Test for subgroup differences Test for subgroup differences [71] (tMedDiet vs aMedDiet): (tMedDiet vs aMedDiet): aMedDiet 1: p = 0.93 p = 0.93 [78] aMedDiet 3: [80] MAI: [105] MedDiet 3: [85] MedDiet 5: [89] rmMedDiet: [100] MedDiet 6: [90] mMedDiet: [96] CHD incidence 4 cohort 153,502, 4.9–20 (0.38, Low tMedDiet: NA NA studies 2910 1.36) [44, 47] RR: 0.72 tMedDiet 4: (0.60, 0.86) [60] I =NA aMedDiet: [71] MI incidence 3 cohort 44,428, 9–14 (0.17, Low tMedDiet 2: NA NA studies 1364 2.70) [56] RR: 0.67 (0.54, 0.83) MedDiet 3: [85] I =NA MedDiet 5: [89] 918 C. Galbete et al. Table 1 continued References Outcome and No. Sample Follow- Predictive NutriGrade Modiﬁed Included Results re-analyses RR (95% Results re-analyses RR summary of the studies size, up Interval grading AMSTAR MedDiet- CI) and test for subgroup (95% CI) and test for estimates RR (95% included cases (years) (95% CI) [26] rating [24] scores* (ref.) differences (random effects subgroup differences (ﬁxed CI) model) effects model) Stroke incidence 5 cohort 159,995, 7.9–20 (0.37, Low tMedDiet 2: NA NA studies 2444 1.56) [56] RR: 0.76 (0.60, 0.96) aMedDiet: I = 52% [71] MedDiet 3: [85] MedDiet 5: [89] iMedDiet: [41] Martinez- CVD 12 671,005, 4.9–40 (0.79, Low 11/22 tMedDiet: Per 2-point increase Per 2-point increase Gonzalez incidence/mortality cohort 15,909 1.03) [44, 47, 49] RR(tMedDiet): 0.87 (0.81, RR(tMedDiet): 0.87 (0.82, and Bes- studies RR: 0.90 (0.86, 0.94) tMedDiet 2: 0.93) 0.92) Rastrollo [56] I = 78% RR(aMedDiet): 0.91 (0.88, RR(aMedDiet): 0.91 (0.89, [34] tMedDiet 4: 0.95) 0.94) [60] Test for subgroup differences Test for subgroup aMedDiet: (tMedDiet vs aMedDiet): differences (tMedDiet vs [71] aMedDiet): p = 0.22 aMedDiet 1: p = 0.14 [78] mMedDiet: [96] rmMedDiet: [100] MAI: [105] MedDiet 5: [89] MedDiet 3: [85] Evaluating Mediterranean diet and risk of chronic disease in cohort studies: an umbrella… 919 Table 1 continued References Outcome and No. Sample Follow- Predictive NutriGrade Modiﬁed Included Results re-analyses RR (95% Results re-analyses RR (95% summary of the studies size, up Interval grading AMSTAR MedDiet- CI) and test for subgroup CI) and test for subgroup estimates RR (95% included cases (years) (95% CI) [26] rating [24] scores* (ref.) differences (random effects differences (ﬁxed effects CI) model) model) Soﬁ et al. CVD 14 752,293, 4.5–20 (0.83, Moderate 14/22 MedDiet: [2] Per 2-point increase Per 2-point increase [19] incidence/mortality cohort 16,631 0.97) tMedDiet: RR (tMedDiet): 0.87 (0.83, RR (tMedDiet): 0.87 (0.83, studies RR: 0.90 (0.87, 0.92) [44, 47, 49] 0.91) 0.91) I = 38% tMedDiet 2: RR (aMedDiet): 0.92 (0.89, RR (aMedDiet): 0.92 (0.89, 0.94) [56] 0.94) tMedDiet 4: Test for subgroup differences Test for subgroup differences [59, 60] (tMedDiet vs aMedDiet): (tMedDiet vs aMedDiet): aMedDiet: p = 0.08 p = 0.06 [71] aMedDiet 1: [78] MedDiet 3: [85] MedDiet 4: [87] iMedDiet: [41] mMedDiet: [96] rmMedDiet: [100] 920 C. Galbete et al. Table 1 continued References Outcome and No. Sample Follow- Predictive NutriGrade Modiﬁed Included Results re-analyses RR Results re-analyses RR summary of the studies size, cases up Interval grading AMSTAR MedDiet- (95% CI) and test for (95% CI) and test for estimates RR (95% included (years) (95% CI) [26] rating [24] scores* (ref.) subgroup differences subgroup differences (ﬁxed CI) (random effects model) effects model) Cancer 14 2,720,221, 7.9–16 (0.88, Moderate tMedDiet: Per 2-point increase RR Per 2-point increase RR incidence/mortality cohort 83,111 1.02) [42, 45] (tMedDiet): 0.96 (0.94, (tMedDiet): 0.96 (0.96, studies 0.99) 0.97) RR: 0.95 (0.93, 0.97) tMedDiet 1: [53–55] RR (aMedDiet): 0.93 (0.93, RR (aMedDiet): 0.95 (0.93, I = 65% 0.98) 0.98) tMedDiet 4: [58, 59] Test for subgroup Test for subgroup differences (tMedDiet vs differences (tMedDiet vs tMedDiet 5: aMedDiet): aMedDiet): [62] p = 0.76 p = 0.42 aMedDiet: [69, 70] aMedDiet 1: [78] mMedDiet: [96] rmMedDiet: [100] iMedDiet: [97] Psaltopoulou Stroke 4 cohort 152,843, 7.9–20 (0.68, Low 19/22 tMedDiet: NA NA et al. [35] studies 2560 1.03) [41] RR: 0.84 (0.74, 0.95) tMedDiet 2: I =0% [56] aMedDiet: [71] MedDiet 3: [85] Evaluating Mediterranean diet and risk of chronic disease in cohort studies: an umbrella… 921 Table 1 continued References Outcome and No. Sample Follow- Predictive NutriGrade Modiﬁed Included Results re-analyses RR (95% Results re-analyses RR summary of the studies size, cases up Interval grading AMSTAR MedDiet- CI) and test for subgroup (95% CI) and test for estimates RR included (years) (95% CI) [26] rating [24] scores* (ref.) differences (random effects subgroup differences (ﬁxed (95% CI) model) effects model) Schwingshackl Cancer mortality 14 1,363,136, 6.3–40 (0.70, Moderate 18/22 tMedDiet: High versus low adherence High versus low adherence et al. [17] cohort 54,569 1.05) [45, 48] RR: 0.86 RR (tMedDiet): 0.92 (0.74, RR (tMedDiet): 0.83 (0.78, studies (0.81–0.91) tMedDiet 3: 1.15) 0.88) [57] I = 82% RR (aMedDiet): 0.80 (0.78, RR (aMedDiet): 0.80 (0.78, tMedDiet 9: 0.83) 0.83) [68] Test for subgroup Test for subgroup aMedDiet: differences (tMedDiet vs differences (tMedDiet vs [72, 73, 75] aMedDiet): aMedDiet): aMedDiet 3: p = 0.22 p = 0.31 [80] mMedDiet: [96] rmMedDiet: [100] MedDiet 2: [84] MedDiet 9: [94] FA: [99] Bloomﬁeld Cancer mortality 13 991,306, 5.8–40 (0.72, Low 15/22 tMedDiet: High versus low adherence High versus low adherence et al. [36] cohort 49,819 1.04) [27, 45] RR: 0.86 RR (tMedDiet): 0.92 (0.64, RR (tMedDiet): 0.84 (0.69, studies tMedDiet 3: 1.31) 1.02) (0.82, 0.91) [57] RR (aMedDiet): 0.81 (0.78, RR (aMedDiet): 0.81 (0.78, I = 77% aMedDiet: 0.85) 0.83) [72, 73, 75] Test for subgroup Test for subgroup aMedDiet 3: differences (tMedDiet vs differences (tMedDiet vs [80] aMedDiet): aMedDiet): mMedDiet: p = 0.48 p = 0.68 [96] FA: [99] rmMedDiet: [100] MedDiet 2: [84] AHEI: [102] 922 C. Galbete et al. Table 1 continued References Outcome and No. Sample Follow- Predictive NutriGrade Modiﬁed Included Results re-analyses RR (95% CI) Results re-analyses RR (95% summary of the studies size, up Interval grading AMSTAR MedDiet- and test for subgroup differences CI) and test for subgroup estimates RR (95% included cases (years) (95% CI) [26] rating [24] scores* (random effects model) differences (ﬁxed effects CI) (ref.) model) Cancer incidence 3 cohort 591, 8.7–24 (0.87, Low tMedDiet NA NA studies 002, 1.05) 1: [53] RR: 0.96 (0.95, 48,683 0.97) AHEI: [101] I =0% Wu and MCI incidence RR: 5 cohort 27,667, 2.2–12 (0.70, Moderate 18/22 tMedDiet NA NA Sun [37] 0.83 (0.75, 0.93) studies 2376 1.00) 6: [63, 64] I =0% tMedDiet 8: [106] aMedDiet 3: [81] MedDiet 4: [88] AD incidence RR: 5 cohort 7609, 4–12 (0.41, Moderate tMedDiet NA NA 0.60 (0.48, 0.77) studies 838 0.89) 6: [64, 65] I =0% tMedDiet 7: [66] MedDiet4: [88] MedDiet 10: [95] Dementia RR: 1.07 3 cohort 9811, 5–12 (0.17, Low tMedDiet NA NA (0.81,1.42) studies 632 6.61) 7: [66] I =0% aMedDiet 3: [81] MedDiet 4: [88] Cao et al. MCI incidence 4 cohort 766, 2.2–5 (0.49, Low 10/22 tMedDiet NA NA [38] studies 6294 0.96) 6: RR: 0.69 (0.57, [63–65] 0.84) tMedDiet I =1% 7: [66] Singh MCI incidence RR: 2 cohort 2626, 2.2–4.5 NA Low 17/22 tMedDiet NA NA et al. 0.73 (0.56, 0.96) studies 438 6: [39] [63, 64] I =0% Evaluating Mediterranean diet and risk of chronic disease in cohort studies: an umbrella… 923 deﬁnitions, aMedDiet 4 [82], included the food group high fat-dairy products as not being in line with the MedDiet. Apart from these two main groups of deﬁnitions we identiﬁed 16 other scores used to assess MedDiet adher- ence in 24 reports [41, 83–105]. A great variability was observed among these different deﬁnitions (see Table 2). In addition, some of the meta-analyses here evaluated included also studies in which MedDiet adherence specif- ically was not intended to be assessed. This is for example the case of the meta-analyses from Bloomﬁeld et al. [36] evaluating the effects of the MedDiet on cancer mortality and incidence. There, the authors also included two reports in which the Alternative Healthy Eating Index (AHEI) was assessed and not the MedDiet [101, 102]. In their meta- analysis on cancer mortality Bloomﬁeld et al. also included the study of Menotti et al. [99], in which two dietary pat- terns were identiﬁed by means of factor analysis. Particu- larly, the authors observed a dietary pattern characterized by high consumption of bread, pasta, potatoes, vegetables, ﬁsh, and oil and by lower consumption of milk, sugar, fruit, and alcoholic beverages and argued this was similar to the MedDiet dietary pattern. Similarly, two of the meta-anal- yses here identiﬁed evaluating the effects of MedDiet on the onset of T2D [30, 40] included the study of Brunner et al. [98], in which dietary patterns were obtained by cluster analysis. In this study one of the clusters identiﬁed was strong and positively correlated with the intake of fruit, vegetables, rice, pasta, and wine, and thus named Mediterranean-like cluster. Test for subgroup differences comparing different types of MedDiet adherence scores Several of the included meta-analyses reported moderate to high statistical heterogeneity, which could be related to the different indices applied. Once we identiﬁed the different scores used in the primary studies and considered these as similar enough, if at least two cohort studies were included in a meta-analysis for at least two different MedDiet scores, we combined the studies applying similar scores in a new meta-analysis and tested for possible subgroup dif- ferences in between the different scores. Comparing the tMedDiet versus the aMedDiet score suggested no evidence for subgroup differences (p [ 0.10) for T2D as outcome in the random effects model (Table 1). In the meta-analysis by Bloomﬁeld et al. on cancer mor- tality, an inverse association was observed with aMedDiet (RR 0.81, 95% CI 0.78, 0.85), while no association with the tMedDiet was found (RR 0.92, 95% CI 0.64, 1.31). However, as in the re-analysis of the work from Soﬁ et al. for cancer mortality/incidence, no evidence for subgroup differences were observed in the study from Bloomﬁeld et al. Regarding CVD, a marginal difference in the Table 1 continued References Outcome and No. Sample Follow- Predictive NutriGrade Modiﬁed Included Results re-analyses RR (95% CI) Results re-analyses RR (95% summary of the studies size, up Interval grading AMSTAR MedDiet- and test for subgroup differences CI) and test for subgroup estimates RR (95% included cases (years) (95% CI) [26] rating [24] scores* (random effects model) differences (ﬁxed effects CI) (ref.) model) AD incidence RR: 2 cohort 3668, 4–5 NA Low tMedDiet NA NA 0.64 (0.46, 0.89) studies 328 7: [66] I =0% tMedDiet 6: [65] T2D type 2 diabetes, CVD cardiovascular disease, CHD coronary heart disease, MI myocardial infarction, AMI acute myocardial infarction, MCI mild cognitive impairment, AD Alzheimer’s disease, FA factor analysis, AHEI Alternative Healthy Eating Index, MAI Mediterranean Adequacy Index, CA cluster analysis *This makes reference to the indices identiﬁed in Table 2 924 C. Galbete et al. subgrouping (test for subgroup difference p = 0.06) was exploratory methods [98, 99] to other scores not explicitly observed when reanalysing the meta-analysis by Soﬁ et al. created to assess MedDiet, such as the Alternative Healthy [19], where the tMedDiet showed a stronger inverse asso- Eating Index [101, 102]. ciation (RR 0.87, 95% CI 0.83, 0.91) compared to studies The tMedDiet score was used for the ﬁrst time by Tri- using the aMedDiet score (RR 0.92, 95% CI 0.89, 0.94). chopoulou et al. [27] in the EPIC-Greece cohort in 2003, Nevertheless, no statistically signiﬁcant subgroup differ- while the aMedDiet score was created and used for the ﬁrst ences were observed in any of the other meta-analyses. The time by Fung et al. [70] in the Nurses’ Health Study. This ﬁxed effects sensitivity analyses conﬁrmed mainly the second one was a literature-updated version according to results of the random effects meta-analysis. published evidence. As stated before, for most of the Unfortunately, in the case of the meta-analyses on analyses here conducted, similar associations were cognitive-related diseases it was not possible to test for observed when applying one or the other score. In the sub-group differences due to the small number of studies meta-analysis by Bloomﬁeld et al. differences in the esti- included. mates were observed but the test for subgroup differences was not signiﬁcant. These observed differences could be due to the selection of healthier items included in the Discussion aMedDiet score compared to the tMedDiet. This is the case, for example, of whole grains; the most recent meta- In this umbrella review of meta-analyses, we summarized analyses observed an inverse dose–response association of the ﬁndings from prospective cohort studies and investi- whole grains with cancer mortality [107, 108]. The evi- gated the different scores used to assess MedDiet and their dence regarding the health implications of dairy products is implications on the risk of major chronic diseases (T2D, controversial. A recent meta-analysis observed in a non- CVD, cancer and cognitive-related diseases). We observed linear dose–response model that low intake of total dairy that a higher adherence to the MedDiet was associated with products could be protective against cancer-related deaths lower incidence of T2D, lower incidence/mortality of [109]. Concerning meat and processed meat, the World CVD, and lower incidence/mortality of cancer; the credi- Cancer Research Fund International recommends an aver- bility of this evidence ranged from low to moderate. Low age consumption under 300 g a week, and to limit as much credibility of the evidence implies that the conﬁdence in as possible the intake of processed meat [110]. The same the effect estimate was low and that further research will report stated that processed meat has been particularly provide important evidence on the conﬁdence and likely associated with an increased risk of colorectal and stomach change the effect estimate, while moderate credibility non-cardia cancers. Finally, the inclusion of two food means that further research could add evidence on the groups for fruits and nuts instead of combining them into conﬁdence and may change the effect estimate [26]. Two one attributes a higher weight of these food items presumed scores assessing adherence to the MedDiet were manly to have a beneﬁcial effect on health. These two food applied in cohort studies (tMedDiet and aMedDiet). groups, as well as whole grains, are rich in ﬁbre, nutrient Overall, we observed little difference in risk associations particularly associated with lower risk of colorectal cancer comparing tMedDiet versus aMedDiet indices in the sub- [111]. In any case, our analyses are restricted to overall group meta-analysis. In the meta-analysis by Soﬁ et al. cancer mortality; the broad consideration of overall cancer [19], which assessed the effect of the MedDiet on the risk and this approach could complicate possible conclusions of CVD incidence/mortality, some differences were and interpretations due to the different nature and aetiology observed; in this case, both MedDiet scores associated with of the different cancer sites. Still, no difference has been lower risk, but the effects observed for the tMedDiet score observed for T2D and CVD even though foods like whole were stronger. grains and red meat have been also shown to be associated with these diseases [112–116]. Mediterranean diet scores and health Some other limitations should be mentioned. In the ﬁrst associations place, our analyses have been restricted to the ones already performed by the authors and this could complicate the Within the large variety of indices attempting to reﬂect comparisons. For example, some of the authors combined adherence to the MedDiet two scores could be identiﬁed incidence and mortality in one outcome while other pre- which were applied more frequently; the tMedDiet used in ferred to assess these separately. Moreover, the deﬁnitions 32 studies [7, 13, 27, 41–68, 106], and the aMedDiet used for the scores here identiﬁed were restricted to the ones in 14 studies [69–82]. Nineteen other deﬁnitions were previously identiﬁed by the authors conducting the meta- found within the remaining 24 studies [41, 83–105]. These analyses we have here evaluated. Thus, other scores used to were very disperse; from dietary patterns derived by assess adherence to the MedDiet could not have been 123 Evaluating Mediterranean diet and risk of chronic disease in cohort studies: an umbrella… 925 Table 2 Description of the different scores identiﬁed representing MedDiet Vegetables Legumes Fruits/nuts Cereals Fish Meat Dairy products Alcohol Fat intake Extras Cited MedDiet 1 1 2 3 – 1 1 n.d. 1 – [2] tMedDiet 1 1 1 1 1 1 1 1 1 – [7, 27, 41–52] tMedDiet 1 1 1 1 1 1 1 1 1 4 – [53–55] tMedDiet 2 1 1 2 1 1 1 1 3 1 – [56] tMedDiet 3 1 1 1 1 1 1 1 4 1 – [57] tMedDiet 4 1 1 1 1 1 1 1 1 2 – [13, 58–61] tMedDiet 5 1 1 1 1 1 1 1 – 2 – [62] tMedDiet 6 1 1 2 1 1 1 1 16 1 – [63–65] tMedDiet 7 1 1 2 1 1 1 1 14 1 – [66] tMedDiet 8 1 1 2 1 1 1 1 17 1 – [67, 106] tMedDiet 9 1 1 2 1 1 1 1 1 1 [68] aMedDiet 1 1 2, 3 2 1 2 – 5 1 – [69–77] aMedDiet 1 1 1 2, 3 2 1 2 – 15 1 – [78] aMedDiet 2 1 1 2, 3 2 1 2 – 6 1 – [79] aMedDiet 3 1 1 2, 3 2 1 2 – 7 1 – [80, 81] aMedDiet 4 1 1 2, 3 2 1 2 2 6 1 – [82] MedDiet 1 2, 3 – 2 2 1 – – – 2 – [83] MedDiet 2 1, 4 – 2 2 1 3 3 8 3 – [84] MedDiet 3 1 2 2 1 1 1 1 13 4 – [85, 86] MedDiet 4 5* * 2 3 1 1 1 1 6 – [87, 88] MedDiet 5 1 – 2 1 1 4 1 2 4 – [89] MedDiet 6 1 2 2 2 1 2, 5 2 14 5 – [90] MedDiet 7 8** 2 ** 2 1 2 11 5 11 – [91, 92] MedDiet 8 1, 8 2, 3 1 2 1 3, 6, 9, 10 3 – 2 2, 5-10 [93] MedDiet 9 1 – 2, 3 9 1 2, 3 12 5 1 4 [94] MedDiet 10 1 1 2 2 1 2, 5 2 18 2 3 [95] mMedDiet 6 3 – 1 1 1 1 – 1 – [96] iMedDiet 7 1 2 4 1 6 4 9 2 1, 2 [41, 97] CA 1 – 2 5, 6 – – 5, 6 8, 10 – – [98] FA 1 – – 4, 7 1 – – – 7 3 [99] rmMedDiet 6 – 4 2 1 1 1 2 4 – [100] AHEI 1 2 5 2 – 2 – 11 8–10 2, 4 [101, 102] 926 C. Galbete et al. Table 2 (continued) Vegetables Legumes Fruits/nuts Cereals Fish Meat Dairy products Alcohol Fat intake Extras Cited sMedDiet 1 1 1 2 1 2, 5, 7 2, 7 12 2 3 [103, 104] MAI 1 1 2 1 1 1, 7 8–10 8 2 2, 3, 5 [105] Vegetables (?); 1: vegetables; 2: raw vegetables; 3: cooked vegetables; 4; salad; 5: vegetables ? legumes; 6: vegetables ? potatoes; 7: Mediterranean vegetables (raw tomatoes, leafy vegetables, onion and garlic, salad, fruiting vegetables); 8: vegetables ? fruits (excl. potatoes and fruit juices) Legumes (?); 1: legumes; 2; legumes ? nuts; 3: legumes ? nuts ? seeds Fruits/nuts (?); 1: fruits ? nuts; 2: fruits; 3: nuts; 4; fruits ? juices; 5: fresh fruit only Cereals (?); 1: cereals; 2: whole grain cereals; 3; cereals ? potatoes; 4: pasta; 5: whole grain bread; 6: pasta ? rice; 7: bread; 8: reﬁned cereals (-); 9: max score = 3rd quintile of intake (bread, rice and white potatoes) Fish (?); 1: ﬁsh (and seafood) Meat; 1: meat and meat products (-); 2: red and processed meat (-); 3: white meat (?); 4: meat, meat products and egg (-); 5: poultry (-); 6: red meat (-); 7: eggs (-); 8: preferred white meat over red meat and processed meat; 9: organ meat (-); 10: egg (?) Dairy products; 1: dairy products (-); 2: high-fat dairy products (-); 3: dairy products (?); 4: butter (-); 5: full-cream milk (-); 6: butter (?); 7: low-fat dairy products (?); 8: Butter, margarine or cream; 9: milk; 10: cheese; 11: fermented dairy products (?); 12: max. score 3rd quintile of intake Alcohol; 1: max. score = women 5–25 g/d, men 10–50 g/d; 2: max. score C sex-speciﬁc median; 3: max. score [ 0 drinks/wk B 2 drinks/d; 4: max. score = women B 1 drink/d, men B 2 drinks/d; 5: max. score = women 5–15 g/d, men 10–25 g/d; 6: max score = 5–15 g/d; 7: max. score = women 5–15 g/d, men 10–15 g/d; 8: wine; 9: max. score C 0–12 g/d; 10: beer (CA); 11: max. score = women 0.5–1.5 drinks/d, men 0.5–2.0 drinks/d; 12: max. socre \ 3 glasses/d = 5 points and min. score [ 7 glasses/d or none = 0 points; 13: max. score C 1 drink/month; 14: max. score to those in the second quintile of alcohol intake; 15: max. score = 5–25 g/day for everybody; 16: max. sore = [ 0–30 g/d; 17: max. score = women 1–7 drinks/wk, men 1–14 drinks/ wk; 18: max. score 1–300 ml/d Fats; 1: MUFA:SFA ratio; 2: Olive oil; 3: MUFA; 4: (MUFA ? PUFA):SFA ratio; 5: PUFA ? MUFA; 6: PUFA:SFA ratio; 7: Oils; 8: trans fatty acids; 9: EPA ? DHA fatty acids; 10: PUFA; 11: olive oil and/or rapeseed oil as main sources of fat Extras; 1: potatoes (-); 2; sugar-sweetened beverages (-); 3: potatoes (?); 4: Sodium (-); 5: confectionary; 6: fruit juices and drinks; 7: pickled food; 8: deep fried food; 9; salty snacks; 10: pizza CA, cluster analysis; FA, factor analysis; AHEI, Alternative Healthy Eating Index; MAI, Mediterranean Adequacy Index; (-), not in line with the MedD; (?), in line with the MedD; MUFA, monosaturated fatty acids; SFA, saturated fatty acids; PUFA, polyunsaturated fatty acids; EPA, eicosapentaenoic acid; DHA, docosahexaenoic acid; n.d., not deﬁned Evaluating Mediterranean diet and risk of chronic disease in cohort studies: an umbrella… 927 identiﬁed. This is the case, for example of the Mediter- Compliance with ethical standards ranean diet pyramid [117]. On the other hand, other sources Conflict of interest The authors declare that they have no conflict of of heterogeneity due to the construction of the scores have interest. not been evaluated here. Moreover, umbrella reviews are limited by their primary objective. In our case we targeted Open Access This article is distributed under the terms of the Creative meta-analyses on prospective observational studies and Commons Attribution 4.0 International License (http://creative commons.org/licenses/by/4.0/), which permits unrestricted use, dis- thus, no randomized controlled trials were included. Also, tribution, and reproduction in any medium, provided you give only studies included within the identiﬁed meta-analyses appropriate credit to the original author(s) and the source, provide a have been here evaluated; any other potentially relevant link to the Creative Commons license, and indicate if changes were study could not have been included. 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Evaluating Mediterranean diet and risk of chronic disease in cohort studies: an umbrella review of meta-analyses

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Evaluating Mediterranean diet and risk of chronic disease in cohort studies: an umbrella review of meta-analyses

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