PERSPECTIVE

Perspective Improving Nutritional Guidelines forSustainable Health Policies CurrentStatus and PerspectivesPaolo Magni1 Dennis M Bier3 Sergio Pecorelli4 Carlo Agostoni2 Arne Astrup5 Furio Brighenti6 Robert Cook7

Emanuela Folco8 Luigi Fontana910 Robert A Gibson11 Ranieri Guerra12 Gordon H Guyatt13 John PA Ioannidis14

Ann S Jackson4 David M Klurfeld15 Maria Makrides16 Basil Mathioudakis17 Alessandro Monaco8 Chirag J Patel18

Giorgio Racagni1 Holger J Schuumlnemann13 Raanan Shamir19 Niv Zmora20 and Andrea Peracino81Department of Pharmacological and Biomolecular Sciences and 2Fondazione IRCCS Cagrave Granda Ospedale Maggiore Policlinico DISCCOUniversitagrave degli Studi di Milano Milan Italy 3Childrenrsquos Nutrition Research Center Baylor College of Medicine Houston TX 4Giovanni LorenziniMedical Science Foundation Houston TX 5Department of Nutrition Exercise and Sports University of Copenhagen Copenhagen Denmark6Department of Food Sciences University of Parma Parma Italy 7Bazian Economist Intelligence Unit Healthcare London United Kingdom8Giovanni Lorenzini Medical Science Foundation Milan Italy 9Department of Clinical and Experimental Sciences University of Brescia BresciaItaly 10Department of Medicine Washington University St Louis MO 11School of Agriculture Food and Wine FOODplus Research CentreUniversity of Adelaide Adelaide Australia 12Department of Preventive Health Ministry of Health Rome Italy 13Department of ClinicalEpidemiology and Biostatistics McMaster University Hamilton Ontario Canada 14Department of Health Policy and Research StanfordUniversity Stanford CA 15Human Nutrition Program USDA Agricultural Research Service Beltsville MD 16Healthy Mothers Babies and ChildrenSouth Australian Health and Medical Research Institute Adelaide Australia 17Consulting sprl Food Legislation and Nutrition Brussels Belgium18Department of Biomedical Informatics Harvard Medical School Boston MA 19Institute of Gastroenterology Nutrition and Liver DiseasesSchneider Childrenrsquos Medical Center of Israel Sackler Faculty of Medicine University of Tel Aviv Tel Aviv Israel and 20Department of ImmunologyWeizmann Institute of Science Rehovot Israel

ABSTRACT

A large body of evidence supports the notion that incorrect or insufficient nutrition contributes to disease development A pivotal goal is thus to

understand what exactly is appropriate and what is inappropriate in food ingestion and the consequent nutritional status and health The

effective application of these concepts requires the translation of scientific information into practical approaches that have a tangible and

measurable impact at both individual and population levels The agenda for the future is expected to support available methodology in nutrition

research to personalize guideline recommendations properly grading the quality of the available evidence promoting adherence to the well-

established evidence hierarchy in nutrition and enhancing strategies for appropriate vetting and transparent reporting that will solidify the

recommendations for health promotion The final goal is to build a constructive coalition among scientists policy makers and communication

professionals for sustainable health and nutritional policies Currently a strong rationale and available data support a personalized dietary

approach according to personal variables including sex and age circulating metabolic biomarkers food quality and intake frequency lifestyle

variables such as physical activity and environmental variables including onersquos microbiome profile There is a strong and urgent need to

develop a successful commitment among all the stakeholders to define novel and sustainable approaches toward the management of the

health value of nutrition at individual and population levels Moving forward requires adherence to well-established principles of evidence

evaluation as well as identification of effective tools to obtain better quality evidence Much remains to be done in the near future Adv Nutr

20178532ndash45

Keywords food genetics microbiome nutritional status personalized nutrition

IntroductionNutritional guidelines a historical perspectiveThe general concept that appropriate nutrition is a verypowerful agent capable of promoting human health isstrongly shared worldwide and has been supported by alarge set of epidemiologic observational and experimental

studies and clinical trials over the last century (1ndash3)Likewise a consistent body of evidence supports the thesisthat incorrect or insufficient nutrition contributes to diseasedevelopment (4) However understanding what exactly isappropriate and what is incorrect or insufficient nutritionhas been a challenge Moreover the effective application of

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these concepts requires the translation of scientific informa-tion into practical approaches that have a tangible measur-able impact at both individual and population levels

Over time translational challenges have brought scien-tists together to try to provide guidance to people throughthe definition of nutritional recommendations and guide-lines that may be successfully implemented in different geo-graphic cultural ethnic and socioeconomic contextsNumerical recommendations for nutrients or foods arenot independent of each other and therefore the review pro-cess in setting guidelines should consider studies that haveused both approaches Moreover some coherence betweenthe different approaches is also expected to be more confi-dent in the trust that can be placed in a guideline The ques-tion about how much of a given nutrient is needed to meetvarious biological requirements was initially answered bysetting reference values for energy and nutrients [dietary ref-erence values (DRVs) RDA] mainly intended to addressmalnutrition due to nutrient deficiency It must be notedthat the early use of terms such as ldquorecommendedrdquo insuch guidance documents (eg Recommended Dietary In-takes) generated the idea of an intrinsic benefit in meetingthese levels of nutrients at the individual level The more ap-propriate term ldquoreferencerdquo is now commonly used as well asthe validity of referring such values mainly to populationsExamples of DRVs exist at international [eg EuropeanFood Safety Authority European Dietary Reference Values(5)] and national levels It must be noted that DRVs gener-alized to a reference average adult represent the basis of nu-trition labeling of foods with evident limits when used toprovide guidance to individuals Conversely with the cur-rent status of the evidence where there is often large residualuncertainty even about big high-level questions in nutri-tion arriving at specific numerical recommendations aboutan exact desirable threshold for specific nutrients (eg nomore than a particular percentage of added sugars) or foods(eg less than a particular amount of red meat weekly) is of-ten an unreliable exercise with outcomes that are debatableIn this perspective it seems meaningless to simply recom-mend reducing saturated fat intake to lt8 energy intakegiven the current knowledge that individual FAs behave bi-ologically very differently and depend on the specific food

matrix Thus in this context recommendations to reducedark chocolate (stearic acid) and cheese intakes may con-ceivably be counterproductive for health

Nutritional guidelines have been developed over the lastdecades to meet different requirements such as publichealth needs and to promote a healthy lifestyle aimed at re-ducing the prevalence of some noncommunicable diseases(NCDs) (6) Currently nutritional guidelines produced bynational and international institutions and scientific organiza-tions represent a large body of documents including for ex-ample the widely used WHO guidelines on nutrition (7) theDietary Guidelines for Americans 2015ndash2020 Eighth Edi-tion (8 9) the European dietary reference values for nutrientintakes updated by the European Food Safety Authority (5)and the Nordic Nutrition Recommendations (2012) (10) Inparticular WHO guidelines are intended as global evidence-based recommendations directed to a wide audience includ-ing policy makers their expert advisers and technical andprogram staff at organizations involved in the design imple-mentation and scaling-up of nutrition actions for publichealth The Dietary Guidelines for Americans are designedfor professionals to help individuals consume a healthy nu-tritionally adequate diet By US law the information in theseDietary Guidelines forms the foundation for developing fed-eral food nutrition and health policies and programs in theUnited States Beyond the mentioned activities many coun-tries worldwide refer their food policies to national guidelineapproaches Furthermore the UN Development Program ispromoting the Sustainable Development Goals which is auniversal call to action to end poverty protect the planetand ensure that all people enjoy peace and prosperity italso includes gender issues (11 12)

Over the years nutritional guidelines have been devel-oped with the aid of expert panels and systematic reviewsand have been distributed for expert and community com-ment in an effort to link scholarship and policy (13) Al-though the evidence basis in nutrition has increased involume in recent years its robustness is still often uncertainand the derived nutritional guidelines may not have beensignificantly improved This situation leads not only to lim-itations of interpretation that are not always clear-cut in theguidelines themselves but also to criticism of the validity ofthe process by which the guidelines were developed Thusthere is a need to move forward to improve the qualityand efficacy of nutritional guidelines following interna-tional standards (14) and a process that requires valida-tion with regard to various pivotal elements such as fulltransparency in scientific data collection and analysisdocumented evidence-based justification grading and eval-uation of effectiveness Interaction with policy makers andauthoritative communication among all stakeholders in-cluding citizens is desirable (15) but one wants to guardalso against biases that various stakeholders may have Ofparticular relevance to the public is the need to understandthe individual- and sex-related features of proposed nutri-tional recommendations Real-life studies should also be en-couraged to overcome the possible bias between population

Perspective articles allow authors to take a position on a topic of current major importance or

controversy in the field of nutrition As such these articles could include statements based on

author opinions or point of view Opinions expressed in Perspective articles are those of the

author and are not attributable to the funder(s) or the sponsor(s) or the publisher Editor or

Editorial Board of Advances in Nutrition Individuals with different positions on the topic of a

Perspective are invited to submit their comments in the form of a Perspectives article or in a

Letter to the Editor This is a free access article distributed under terms (httpwwwnutrition

orgpublicationsguidelines-and-policieslicense) that permit unrestricted noncommercial use

distribution and reproduction in any medium provided the original work is properly cited

This article emerged from a meeting held in Venice Italy on 1 July 2016 with the participation

of a selected panel of experts and was promoted and organized by the Giovanni Lorenzini

Medical Science Foundation (Houston TX and Milan Italy)

Author disclosures PM DMB SP CA AA FB RC EF LF RAG RG GHG JPAI ASJ DMK MM BM

AM CJP GR HJS RS NZ and AP no conflicts of interest

Address correspondence to PM (e-mail paolomagniunimiit) or AP (e-mail andreaperacino

lorenzinifoundationorg)

Abbreviations used DRV dietary reference value GRADE The Grading of Recommendations Assessment

Development and Evaluation NCD noncommunicable disease RCT randomized clinical trial

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groups selected in trials and actual population compositionand profile

Therefore the agenda for the development of nutritionalguidelines should advance through evaluation of methodol-ogy in nutrition research evidence hierarchy in nutritionand strategies for appropriate vetting and reporting aimedat empowering recommendations including specific impli-cations for the future such as personalized nutrition inhealth promotion (Text Box 1)

Current and Developing Status of KnowledgeMethodology in nutrition researchHistorically nutritional guidelines have been based on allthe evidence available including not only human clinicalstudies but also data available from experimental animalwork and physiological studies This evidence also includesinformation from population-based epidemiologic studiesthat have identified food patterns nutrient intakes and life-styles associated with health promotion or with increasedrisk or progression of NCDs (4 16) Moreover additionalinsights have been generated by some randomized clinicaltrials (RCTs) and innovative new study designs such asMendelian Randomization and environment-wide associa-tion studies

To evaluate the evidence useful for both populationand individual decisions requires that $3 steps be takeninto consideration 1) what are the uncertainty limits ofthe available evidence 2) how can we improve credibilityby reducing uncertainty and variability and 3) does the in-creased evidence credibility lead to improved usefulnessin dietary guidance (17) Interestingly although 96 of the

biomedical literature claims significant positive resultsthe validity of these claims is often questionable (18)The reasons are multiple and generally well known al-though not widely appreciated or acknowledged Amongthese are the problems of nonrandomized designs posthoc data ldquocherry-pickingrdquo and ldquoP hackingrdquo to support de-sired hypotheses lack of a priori data analysis plans orpost hoc transparency in data analyses selective reportingof results lack of study registration on public databaseslack of a replication culture and limited data sharing (19)Moreover in some instances publication quality in thefield of nutrition shows a lack of consistency especiallyfor observational evidence in which analytical approachesto newer data suggest that effects of soft outcomes (eg sur-rogate endpoints) may well be overestimated (20) Conclu-sions drawn from these newer insights support the veryhigh rate of refutation observed in the most-cited claimsof observational studies that were not validated in RCTs(21 22) Nonetheless among the scientific communityan inherent resistance to refutation is frequently observedso that unreliable and contradictory papers often have longlives as supporting references (23) Interestingly it has re-cently been demonstrated that 685 of studies reportingroutinely collected data did so for research questions al-ready addressed by RCTs (24) suggesting that observa-tional data may not be as informative as often claimedMost likely some inherent obstacles must be overcomein making sure that expert committees review draft guide-lines and evidence provided in the format of a consensusconference with the participation of all stakeholdersMoreover because a substantial part of the evidence in nu-trition is based on observational data credibility on thecausal pathway is often questionable (25) which is a prob-lem compounded by weak conclusions drawn from diversesubgroups stratified analyses and data dredging in theabsence of any preregistration Conclusions drawn fromnutrition research studies are sometimes based on statis-tically significant but small or tiny effect sizes (26) Tinyeffects may still be credible but they are highly susceptibleto even minimal bias Although larger-scale data and newmeasurement platforms offer novel opportunities theyalso provide the potential for even higher error and mis-leading claims

RCTs are an important pillar in evidence-based medicineand require improvement when done in the nutrition fieldThere is a need for improved transparency and improvedquality evidence of nonregulated interventions especiallycompared with the rate of registration and publication ofnondrug trials (27) because a large number of nutritionaltrials have never been registered (19)

Additionally RCT designs in nutrition require attentionto pragmatic issues to reduce the user burden of dietary as-sessment and long-term compliance personnel and fundingmechanisms to accommodate large sample sizes and focuson important patient-relevant outcomes (28) Additionalstrategies to improve nutritional research include the analy-sis of subgroups with stratified effects pooling studies and

TEXT BOX 1 NUTRITIONAL GUIDELINES AHISTORICAL PERSPECTIVEAppropriate nutrition is a powerful factor prevent-ing multiple age-related chronic diseases and pro-moting human healthExcessive unbalancedmdashbut also insufficientmdashnutrition contributes to disease developmentCurrent nutritional guidelines based on observa-tional epidemiological studies and some clinicaltrials have provided guidance to health profes-sionals policy makers and the public for decadesNutritional recommendations and guidelines aremost effective when implemented within appropri-ate geographic cultural ethnic and socioeconomiccontexts without forgetting age and sex differencesNutritional guidelines should evolve through theincorporation of insights into the methodology ofguideline methods better evidence adherence tograding data within established hierarchy of avail-able evidence avoiding conflicts of interest andaiming at a constructive coalition among allstakeholders

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the use of biomarkers when available although the effectcould be diluted in the case of large RCTs (19 29 30)

A relevant observation when evaluating the health im-pact of nutrition is that people actually eat intact foodsand not isolated nutrients Most generalized nutritionalguidelines are couched in terms of daily nutrient intakesAlthough this is clearly important it appears obvious thatbioavailability of nutrients incorporated into a food matrixmay be affected by their effects on digestion and absorp-tion which are also modulated by the matrix effect or bythe actions of the gut microbiota Moreover the composi-tion of many foods is not completely known food compo-sition tables are often incomplete or out of date and somecompounds are impossible to measure or are unknownNot surprisingly even for the most extensively studied ques-tions discrepancies may occur when nutrients or foods areevaluated (eg substitution of saturated fat with polyunsat-urated fat in substitution studies compared with assessingthe association between saturated fat intake in dairy pro-ducts and health outcomes) These factors add to the uncer-tainty of conclusions about nutrients drawn from studiesusing foods (Text Box 2)

Taking advantage of big data In recent decades majorimprovements in measurement capacity and computerizeddata analysis have led to fast high-throughput analysesat much lower costs These have allowed different andheterogeneous sources of data to be integrated in novelways that provide reliable new insights Big data maybe derived from epidemiological cohorts or relatedbiorepositories with the power to elucidate millions ofgenetic variants and thousands of environmental andnutritional factors in their study participants Althoughthis is crucial it is rather difficult to study and understandbecause it is inherently individual with several variables

based on genome and the individual interaction with thesurrounding environment (starting from parentsrsquoexperience and fetal interferences) Electronic medicalrecords of millions of patients containing clinicalpharmacological and laboratory data are currently beingrepurposed for research and discovery These researchpractices generate new concepts for discovery which inturn raise new questions concerning what to measure andhow in health research whether and how to use andinterpret these big data for discovery and what roles theywill eventually play in developing guidelines (31) Humanhealth recommendations may benefit from large-scale datawhen noise is minimized because false alarms due toconfounding variables or other biases are possible evenwith very-large-scale studies (32ndash34)

Enhancement of the validity of guideline precision mayemerge from big data analysis if accompanied by systematictesting addressing multiplicity (29 35ndash38) and replicatingexperiments as well as considering the vibration of effects(shifts in the effect-size distribution due to selected adjust-ments or other analytical choices) in shaping the empiricaldistribution of effect sizes due to model choice (20) Further-more nutritional exposures and behavior are highly corre-lated with one another (33 34 39 40) posing challenges inevaluating possible associations Therefore it is an imperativealong with systematically testing associations with clinicaloutcomes to estimate how large (or small) an association iswith respect to all other possible correlations (33)

There is also a need to assess associations between notjust single nutritional factors and outcomes but an entiresystem of correlated nutritional factors and outcomes to ac-curately capture the complex and correlated dietary behav-ior of humans There is the further need to documentanalytical approaches and provide both accessible analyticaltools and computer infrastructure to enable reproducible re-search There are various aspects of reproducible researchranging from the ability to recompute data analytic resultsgiven an observed dataset and knowledge of the pipeline(41) to reproducibility across different datasets (reproduci-bility of results) and reproducibility of inferences from thesame datasets and analyses (42) (Text Box 3)

Toward personalized nutrition When approaching novelmethodologies in nutrition research it is important to focuson the associations among individual genotypes and pheno-types aiming at personalized nutritional strategies that willeffectively promote the health of individuals Ideally thecomplex gene-gene and gene-environment interactions andepigenetic modulation should be taken into considerationwhen assessing nutritional and other environmental linkswith NCDs such as obesity dyslipidemia cardiovasculardiseases and cancer (43ndash46)

In the context of the current population epidemics ofmetabolic diseases related to the interaction between the ge-nome and nutritional changes and environmental factorsthere are well-appreciated differences in how individualswithin the population respond to the same environmental

TEXT BOX 2 METHODOLOGY IN NUTRITIONRESEARCHMost evidence on nutrition is based on observa-tional dataClinical outcomes with nominally statistically sig-nificant results are often arguable and of debatableclinical significanceRandomized trials can confirm causality but haveinherent design constraints for nutritional inter-ventionsMost secondary subgroup analyses and stratified ef-fects are weak at bestLarge-scale data and new measurement platformsoffer improved opportunities but have the potentialfor even higher error ratesClinical nutrition research designs and implementa-tion studies require reforms focused on improvedcredibility and utility

Nutritional guidelines for sustainable health policies 535

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stimuli For example people have largely different glucoseresponses to the same food (47) and recent data suggestthat integrating individual information into a multidimen-sional algorithm that predicts specific responses to foodmay allow definition of personalized diets (48) It has beenproposed that one should individualize the diet accordingto personal variables including sex age and microbiomeprofile (49) Major determinants of the variability in an in-dividualrsquos glucose response to food may include food qualityintake frequency and lifestyle including physical activitycirculating metabolic biomarkers and the gut microbiotaData based on continuous postprandial glucose measure-ments have demonstrated that whether a food is nominallygood or bad regarding its effect on the postprandial glyce-mic response is largely dependent on the individual con-suming the specific food in relation to his or her personalizedvariables (48) Thus individual people can have very differ-ent responses to the same food (Fig 1) For instance in re-sponse to white bread consumption some people have theexpected postprandial glucose spikes whereas others donot (47 50) (Fig 2) Moreover dietary interventions target-ing postmeal glucose responses induce consistent changesin the gut microbiota with relevant variations accordingto the type of diet (high-glucose response compared with low-glucose response diets) (51) Therefore diets designed to

maintain normal postprandial blood glucose concentrationsmust be personally tailored If so population-basedguidelines may have limited generalizability when theprevalence of specific genetic lifestyle and other factorsable to have a large impact in modifying the effect ofthe diet consumed is large in the population addressedIn any case predictive diets for individuals are quite com-plex and population-based clinical trials that test thevalue of the intervention of personalized recommenda-tions on health outcomes including time to cardiovascu-lar disease cancer and death must occur To date fewobservational investigations have shown the utility ofintegration of high-dimension information including(prevalent) genetic variants microbiome and environ-mental exposures These studies already partially ongo-ing will hopefully demonstrate feasibility for large-scaleclinical trials for personalized interventions Thereforeat this stage such predictors can assist in devising a dietaryplan but cannot replace the general nutrition recommenda-tions (Text Box 4)

The implementation of such novel approaches (eg big-data analysis personalized nutrition algorithms) needs to beevaluated against conclusions based on traditional methodsMoreover although the inclusion of these methods intonew guidelines will surely improve the knowledge base

TEXT BOX 3 TAKING ADVANTAGE OF BIG DATABig data analysis may provide answers based on a multitude of new ways to interrogate datasets and uncover insightsinto generating improved guidelinesBig data may be derived from large epidemiological cohorts andor related biorepositories and have the potentialpower to elucidate relations among millions of genetic variants and thousands of environmental and nutritionalfactors but their utility is still to be provenThe huge number of analytic scenarios can multiply the analytical challenges and magnify potential biasesTo enhance the validity of conclusions from big data there is a need for

middot systematic testing procedures to address multiple hypotheses testing and results replication to enhance the validityof the results

middot consideration of the dense correlative nature of both clinical outcomes and nutritional factors

middot modeling scenarios that are fully detailed and explicitly transparent

middot increased education for literacy in understanding and interpreting information at the big-data levelHuman health could benefit from large-scale data only if large-scale bias is likewise minimized

FIGURE 1 PPGRs to identicalstandardized meals can be highly variableamong different people (A) Populationresponses to standardized meals Kerneldensity estimation histogram of PPGRs ofhealthy individuals (n = 800) to 4 selectedmeals (B) Four individual responses to breadshowing the high interpersonal variability inPPGRs to bread across participants iAUCincremental AUC PPGR postprandial glucoseresponse Reprinted from reference 48 withpermission from Elsevier

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it remains to be shown whether the problems these methodscreate in more complex interpretations will lead to de-monstrable improvements in better health and diseaseoutcome in the long-term and in various sociocultural andeconomic conditions

Evidence hierarchy in science with a focus on nutritionThe evidence hierarchy built on the principles of the scien-tific method is a construct widely shared among all sciencesNutrition as a science must comply with and be judged bythe same scientific principles as far as the grading the qualityof its evidence is concerned In practice difficulties associ-ated with designing and conducting human studies usingreal foods may limit compliance with these principles atthe highest levels of the evidence hierarchy Nonethelesslimitations of this kind do not serve as reasons to elevatethe level of evidence obtained but rather to limit the cer-tainty of conclusions drawn from the evidence availableMoreover within this context properly grading the caliberof available evidence is pivotal because trustworthy guide-lines must systematically weigh both the amount of evidenceand its quality The Grading of Recommendations Assess-ment Development and Evaluation (GRADE) approachadopted by gt100 organizations worldwide has become thestandard for rating the quality of evidence (52) The GRADE

Working Group (53) has provided tools that indicate thereasons for a recommendation (direction strength and cer-tainty) and allow adoption adaptation and new develop-ment of recommendations globally Key criteria includethe following how big is the problem locally how directis the evidence how does it impact on resources equity ac-ceptability and feasibility (54 55)

In the GRADE system randomized trials are initiallygraded as high-quality evidence but their grade can be rateddown to moderate or lowvery low based on limitations in 5categories risk of bias inconsistency indirectness impreci-sion and publication bias (54 56) On the other hand ob-servational studies are initially graded as low-qualityevidence but can be rated up to a higher grade primarilyon the basis of large effect sizes GRADE also provides guid-ance for grading recommendations as strong or weak Apanel makes strong recommendations when the net benefitsclearly favor one option A panel makes weak recommenda-tions in the face of uncertainty either because the evidenceis of low or very-low quality or because the desirable andundesirable consequences (54 57) are closely balanced Inmaking decisions regarding direction and strength of recom-mendations guideline panels should always consider themagnitude of the desirable and undesirable consequencesthe certainty of the evidence regarding those consequences

TEXT BOX 4 TOWARD PERSONALIZED NUTRITIONPeople have highly variable postmeal glucose responses to identical mealsFollowing current dietary guidelines may result in high glycemic responses in some subjects accelerating metabolicdisease development which the guidelines were intended to preventAn individualrsquos microbiome is a driver of interpersonal variability in postmeal responsesIntegrating personal parameters and microbiome features into an algorithmmay allow more accurate predictions ofpersonalized postmeal glucose response to defined mealsPersonalized diets normalize postmeal glucose responses and increase complianceA personalized nutritional approach based on validated algorithms may be relevant for effectively promoting indi-vidual health

FIGURE 2 PPGRs to real-life meals canbe highly variable among differentpeople (A) IQRs (10thndash90th percentiles)of the PPGRs of healthy individuals(n = 800) to different meals along withthe amounts of carbohydrates consumed(green means 6 SDs) (B) An example ofinverse PPGRs to a set of 2 isocaloric real-life meals iAUC incremental AUC PPGRpostprandial glucose response Reprintedfrom reference 48 with permission fromElsevier

Nutritional guidelines for sustainable health policies 537

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and the values and preferences of the population towhom the recommendation applies the last being crucialin ensuring compliance Panels may also consider re-source use acceptability feasibility and equity in makingtheir recommendations If guidelines are not adapted toreal life it is unlikely they will be used

Evidence in nutrition strategies for appropriatevetting and reporting aimed at empoweringrecommendationsTo produce trustworthy and optimal guidelines mandates awell-constructed panel of discussants including scientificexperts in the specific nutritional areas methodologists in-cluding statisticians practicing clinicians and patients andpolicy makers needs to become involved when necessaryif medical and clinical care guidelines are under consider-ation Expert translators are also of paramount importancewhen considering the wide practical use of these guidelinesand the subsequent impact on clinical practice as well as onthe population

Standards for trustworthy guidelines are well established(eg Institute of Medicine recommendations) (58) Severalauthoritative international organizations (WHO Instituteof Medicine the Guideline International Network and theGRADE Working Group) agree on the key principles forthe development of high-quality guidelines (59) Interna-tional standards exist that will also ensure trustworthinessfor nutritional guidelines based on progression to higherlevels as bias in the quality of evidence declines (60)

Recommendations should be based on an explicit and trans-parent process that maximizes the use of the highest-qualitygraded evidence minimizes distortions biases and conflictsof interest provides a clear explanation of the logical relationsbetween alternative care options and health outcomes and pro-vides ratings of both the quality of evidence and the strength ofrecommendations (61) More realistically to provide high-quality systematic reviews of todayrsquos expansive literature will re-quire more than the voluntary spare time of already-pressedscientists Governments should be obliged to appropriatethe funds necessary for producing timely high-quality andevidence-based dietary reference intakes (62)

Because foods are so intimately related to lifestyles andfood cultures in humans instruments to assess the qualityof life in relation to nutrition and nutrition-related lifestylechanges are also needed (63) Moreover there is a need toassess sustainability (eg environmental impact or eco-nomic impact) with regard to future recommendations Asit is obviously appropriate trustworthy guidelines shouldbe reconsidered and revised when important new evidencewarrants modifications of recommendations

The presence of conflicts of interest can lead to biasedand potentially incorrect recommendations (64) Interna-tional principles for disclosure of interests and managementof conflicts in guidelines have been developed to address thisissue However declaration of conflict alone seems a poorstrategy overall More acceptable options for managing con-flicts are to exclude altogether those with major conflicts or

to allow input by conflicted individuals to participate in thediscussion but excluding them from the decision-makingprocess Several tools for the development of trustworthyguidelines are available In particular a comprehensive check-list of items and related resources can help guideline de-velopers in their enterprise (14) (Fig 3) Additional toolsinclude the Essential Reporting Items for Practice Guidelinesin Healthcare (65) statement which helps those producingguidelines report them properly and in a certain formatfor the lay audience (Text Box 5)

Implications for the futureBased on the concepts developed above one might envisiona series of implications for the future aimed at improvingnutritional guidelines and effectively applying them to peo-ple worldwide These could also consider personalized nu-trition ethnic and geographic preferences more effectivetranslation of nutrition guidelines for the public and pro-motion of sustainability and cooperation among all nutrit-ion stakeholders

Among them the food industry plays a central role whenfood industry interventions in industrial food productionare taken into consideration Very rarely it is possible to ac-cess foods that have not been treated industrially or have notundergone a treatment (ie pesticide treatment or geneticmanipulation) at any level of the production chain Howis it possible to manage this artificial input into the foodchain What is the impact on individuals

Ethnic and geographic issues Lessons learned from em-ploying the experimental principles discussed immediatelyabove might also be extended to individualizing guidelinesbased on ethnic and national food preferences The selectionof specific local foods included in a diet represents a criticalissue in the translation of guidelines as well as likely healthpromotion outcomes because dietary compliance is inti-mately related to local and ethnic food preferences It is nowalso well appreciated that nutrient-based recommendationsshould be focused on foods as the source of nutrientsMoreover recommendations should not be based on indirectevidence such as a prediction from nutrient compositionlisted in the label but on solid scientific evidence accumu-lated from actual subject responses to the particular foodsthemselves (48) These refinements can lead to improvementin dietary approaches based on traditional or regional habitsthat have already been validated and translated intorecommendations for health promotion eg starting withthe Mediterranean Diet (66) and translating it intocorresponding regional geographic variants including therecently developed New Nordic Diet in Denmark (67 68)

Effectively translating nutritional guidelines for thepublic A particularly relevant issue in effective guideline de-velopment is how to properly communicate the informationto the general public in the current era of widespread largelyuncontrolled dissemination of information via an almostlimitless variety of media outlets The revolution in online

538 Magni et al

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media has drastically altered the pressure on journalists toreach readers changing the ways that complicated storiessuch as nutritional topics are written and presented Indeednutritional issues which are often intrinsically complexare difficult to report comprehensively and even when trulybalanced frequently fail online Because ambiguity does notsell there is pressure to oversimplify

The traditional fact-checking stringency of legitimateprint media outlets has largely been bypassed by many ofthe newer electronic ldquoinformationrdquo sites online The resulthas been an abundance of often-conflicting informationthat both generates public confusion and produces issuesof credibility (69 70) Problems often begin with the reli-ability of the media translation of the original research

reports Recently 18 kinds of media spin were identifiedand $1 spin was found in 88 of media research reports25 failed to report adverse events mentioned in the scien-tific article 49 claimed a causal effect despite a non-randomized study design and 21 extrapolated abeneficial effect from an animal study to humans (71) Formany people the media are the main provider of the infor-mation that individuals use to make decisions about theirhealth Thus inaccurate incomplete or imprecise reportingof the research reports themselves is a major impediment inconveying solid nutrition evidence from scientists to citi-zens However the scientists themselves are not blamelessin this context Lazarus et al (72) reported finding$1 exam-ple of spin in 84 of scientific reports studied most

TEXT BOX 5 EVIDENCE IN NUTRITION STRATEGIES FOR APPROPRIATE VETTING ANDREPORTING AIMED AT EMPOWERING RECOMMENDATIONS

Trustworthy guidelines should

middot be based on a systematic review of the existing evidence

middot be developed by a knowledgeable multidisciplinary panel of experts and representatives from key affected groups

middot consider important patient subgroups and patient preferences as appropriate

middot be based on an explicit and transparent process that minimizes distortions biases and conflicts of interest

middot provide a clear explanation of the logical relations between alternative care options and health outcomes

middot provide ratings of the quality of the evidence and strength of the recommendations

middot be reconsidered and revised as appropriate when important new evidence arises

FIGURE 3 Diagram of the guideline development process The steps and involvement of various members of the guidelinedevelopment group are interrelated and not necessarily sequential The guideline panel and supporting groups work collaborativelyinformed through consumer and stakeholder involvement and report to an oversight committee or board overseeing the processConsiderations for organization planning and training encompass the entire guideline development project and steps such asdocumenting the methodology used the decisions made and considering conflicts of interest occur throughout the process PICOpatientproblem intervention comparison outcome Reprinted from reference 14 with permission from Access Copyright

Nutritional guidelines for sustainable health policies 539

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commonly the improper implication of causality and a highdegree of overselling the research findings in approximatelyhalf of the publication abstracts Furthermore although peerreviewers identified an example of spin in about half of theresearch manuscripts they reviewed resulting in author re-moval of two-thirds of these items the peer reviewers failedto identify spin in three-quarters of the abstracts of the man-uscripts reviewed (73) Surprisingly for 15 of the reviewedarticles the referees themselves suggested adding some spinand in 9 of the reviewed articles the authors themselvesadded additional spin (73)

Promoting sustainability and cooperation among allnutrition stakeholders For guidelines to be maximally ef-fective there is a need for cooperation among all nutritionstakeholders (individuals citizens of any age and sex scien-tists clinicians policy makers the food industry the com-munications industry etc)

Furthermore reshaping food systems around sustainablediets is one of the worldrsquos biggest challenges for the 21st cen-tury Sustainability is a complex concept and sustainable de-velopment was first introduced in Europe in the 1980s Inthe ensuing years there has been a growing concern for sus-tainability including the food and nutrition field which hasgained the attention of researchers academics and practi-tioners and has become a focus for governments private or-ganizations and other stakeholders (74) Countries vary intheir conceptual understanding of sustainability and in itspractical implementation determined by their own healthagencies in the complex local policy environment Neverthe-less the nature of global interconnectivity today posessustainability problems that must be solved at the interna-tional level Different approaches (evidence briefs policydialogues and benchmarking) mandate international infor-mation and debate on policymaking

ConclusionsIn this article the most important issues relevant to improv-ing nutritional guidelines are discussed and the proposedconcepts and actions are the result of the merged effortsof a qualified panel of experts in the related areas The fol-lowing conclusions of such joint work are proposed

Nutritional guidelines a historical perspectiveThere is a need to move forward to improve the quality andefficacy of nutritional guidelines starting from an unbiasedassessment of the currently consolidated information Thefuture agenda should advance through evaluation of newlyavailable methodology in nutrition research to personalizeguideline recommendations properly grade the evidencequality adhere to evidence hierarchy in nutrition and en-hance strategies for appropriate vetting and transparentreporting to solidify the recommendations for health pro-motion The final goal is to build a constructive coalitionamong scientists policy makers and communications pro-fessionals to develop and implement sustainable health andnutritional policies Constructive integration that facilitates

harmonization among institutions is necessary for the for-mulation of nutritional recommendations guidelines andpolicies because they must be implemented in different geo-graphical cultural ethnic and socioeconomic contexts toproduce a relevant public health impact

Methodology in nutrition researchNutritional trials require an improvement in the design col-lection analysis transparency and quality of evidence at alllevels of research To improve nutritional research it is im-portant to increase study registration in public databases andto include predeclaration of endpoints and analytical ap-proaches and open access for data Nutritional guidelinesneed to be periodically reexamined and revised accordinglyas new data become available Moreover there is a need toensure that dietary essential nutrient and food recommen-dations apply to all subjects present in the society Inno-vative scientific research generates new concepts fordiscovery raising new questions concerning what and howto use the novel findings The pervasive expansion of bigdata in the health research field has opened new horizonsfor their use for discovery or to develop guidelines (31) gen-erating many challenges especially in the context of causalpathway interpretation Human health could benefit fromlarge-scale data analysis if large-scale noise is minimizedand confounding variables or other biases are evaluated(32ndash34) Proper use of big data may help in designing nutri-tional guidelines for individual intervention and improvetheir effectiveness and relevance over the limitations of thegeneralized approach available today (48)

Evidence hierarchy in science with a focus onnutritionThe principles of the scientific method apply to nutrition asthey do to all disciplines classified as scientific Trustworthyguidelines should be based on systematic summaries of thebest available properly graded evidence addressing each rec-ommendation that is part of the guidelines In making deci-sions regarding direction and strength of recommendationsguideline panels should consider the totality of evidence andthe magnitude of the desirable and undesirable healtheffects the domains of evidence certainty or uncertaintyboth with respect to the desired goals and potential undesir-able effects To support sustainability guideline panelsshould also consider all desirable and undesirable conse-quences including resource use environmental and ecolog-ical consequences acceptability feasibility and equity inmaking their recommendations (54ndash57 75 76)

Evidence in nutrition strategies for appropriatevetting and reporting aimed at empoweringrecommendationsTo produce trustworthy and optimal guidelines it is manda-tory to have a well-constructed well-balanced panel of discus-sants including experts in specific areas methodologistsand practicing clinicians and patients if medical and clini-cal care guidelines are under consideration (77) Guidelines

540 Magni et al

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TEXT BOX 6 COMMON ACCEPTABLE DEFINITIONSBiomarkers

middot A biomarker is a natural molecule gene or functional characteristic by which a specific physiological or patho-logical process can be identified They are commonly used to diagnose conditions and to assess how advanced anindividualrsquos illness is

Conflict of interest

middot An interest that may affect an individualrsquos ability to impartially assess the evidence or provide a perspective on aparticular topic Conflicts can be financial where the person is in direct or indirect receipt of financial support orintellectual where the person may have a reputation built on a particular stance on an issue

Diet

middot Diet is the sum of food and drink consumed by an individual and often implies its quality composition and ef-fects on health

Dietary guidelines

middot Dietary guidelines translate nutritional guidelines into food intake recommendations by using nontechnical lan-guage enabling individual consumers to compose their daily diet in a way that provides the appropriate nutrition

Feasibilityimplementation

middot Feasibility and implementation consider how health policy will be implemented including assessing and mitigat-ing any individual social cultural economic and practical barriers to implementation for example not recom-mending food sources of nutrition that the majority of the population may not be able to access because offinancial constraints or availability

Food

middot Food consists of essential body nutrients such as carbohydrates fats proteins vitamins or minerals which areingested and assimilated by an individual to produce energy stimulate growth and maintain life

Guidelines

middot Guidelines are a series of recommendations on a particular topic (eg health condition or aspect of health suchas nutrition) developed by a multidisciplinary panel based on an independent systematic review of the best avail-able evidence Guideline panels can include health professionals and academics specializing in that area as well asrepresentatives of other groups such as the general public the policy makers and the industry

Nutrition

middot Nutrition interprets the interaction of nutrients and other substances in food in relation to the linked metaboliceffects within the body It includes food intake absorption assimilation metabolism and excretion

Nutritional guidelines

middot Nutritional guidelines focus on the quantities of individual nutrients and quality and quantity of whole foods thatpeople should consume to achieve a healthy nutritional state Nutritional guidelines may include estimates such asDRVs reference intake and daily intake These guidelines usually apply to the entire healthy population by usingbroad groups such as different age ranges but can also be tailored to more focused population groups The gen-eral public often come into contact with these when examining food packaging which may have DRVs on thefront etc

Nutritional status

middot Nutritional status includes the condition of the body influenced by the actions and interactions generated fromthe food intake through metabolism and absorption in the gut (exercised by microbiome genetic and food com-ponent interactions) and the consequent metabolism and handling within the body (due to genetic and organmdashnot only liver and kidneymdashfunctions) toward to the nutritional status differences on health effects

Policy makers

middot Policy makers are professionals working within local and national government who are responsible for translatingresearch findings into actionable health policy to promote health in their population for example creating food-based guidelines based on nutritional guidelines the best available evidence and stakeholder input

RCT

middot An RCT is a clinical study with a specific design aimed to reduce bias when testing a new treatment Subjects par-ticipating in the trial are randomly allocated to either the group receiving the treatment under investigation or to agroup receiving standard treatment (or placebo treatment) as the control

Substitution effect

middot When advised to eat less of one nutrient (eg carbohydrate) or individual food the public will substitute that itemwithanother Substitution advice should be provided to ensure healthy substitutions that do not have unintended harms

continued

Nutritional guidelines for sustainable health policies 541

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should be based on an explicit and transparent processthat minimizes distortions biases and conflicts of interestprovides a clear explanation of the logical relations betweenalternative care options and health outcomes and providesratings of the quality of the evidence and the strength ofthe recommendations (61) The GRADE recommendationclassifies systematic reviews of RCTs with an initial scoreof high and classifies systematic reviews of cohort studieswith a score of low As the studies are evaluated the indi-vidual RCTs can be rated lower and the individual cohortstudies can be rated higher depending on prespecified lim-itations of the former and the effect sizes of the latter Tocomplement this methodologic gap improved measuresand tools that also take into account nutrition researchndashspecific requirements (eg dietary assessment methodsand their validation or funding bias) for assessing the meta-evidence (quality of the evidence of the meta-analyses) needto be developed Recently an attempt to adapt the GRADEapproach to specifically address peculiarities of nutrition re-search has been proposed [NutriGRADE from Schwingshacklet al (78)] For optimal implementation this approach is bestconducted with interaction with the GRADE working groupwhich we encourage and welcome strongly

Implications for the futureNovel approaches may lead to the development of nutri-tional exercise and pharmacological interventions targetingthe metabolic and molecular causes of human ageing andhealth promotion inhibiting pro-aging pathways that con-trol the accumulation of molecular damage in multiple tis-sues or minimizing the risks of diseases that contribute toor accelerate those pathways (48 79) Accurate predictionsof the individual metabolic response integrating differentapproaches may lead to personalized nutrition able to com-bine health promotion and the possible use of locally avail-able foods (48) The transfer of this information to novelnutritional guidelines to improve the effectiveness of currentgeneralized guidelines however still appears complex

Although most guidelines have historically focused onthe essential nutrient components of foods future nu-tritional recommendations must evaluate evidence derivedfrom ingestion of whole foods or diets

A crucial issue is the communication of the fundamentalnutritional information in the current electronic media

environment where traditional factual evidence verificationis often lacking Improved communications and effectivenessrequire cooperation among all nutrition stakeholders (the laypublic basic scientists practicing clinicians policy makers in-dustry education communication etc) The specific issue ofsustainability requires the additional communication amonggovernments nations and international regulatory agencies

In conclusion there is a strong and urgent need todevelop a successful commitment among all the stakeholdersto define novel approaches to the management of the healthvalue of nutrition at the individual and population levelsMoving forward requires adherence to well-established prin-ciples of evidence evaluation and the identification of effectivetools to obtain better-quality evidence Much remains to bedone in the near future A starting step is to identify commonacceptable definitions (Text Box 6)

AcknowledgmentsPanel of experts invited to the meeting in Venice ItalymdashCarlo Agostoni Pediatric Medium Intensity Care Unit De-partment of Clinical Sciences and Community Health Uni-versitagrave degli Studi di Milano Fondazione IRCCS Carsquo GrandaOspedale Maggiore Policlinico Milan Italy Arne AstrupDepartment of Nutrition Exercise and Sports Universityof Copenhagen Denmark Dennis M Bier Childrenrsquos Nu-trition Research Center Baylor College ofMedicine HoustonTX Furio Brighenti Department of Food Sciences Universityof Parma Italy Paolo Cavallo Perin Department of MedicalSciences University of Turin Italy Elena Colombo GiovanniLorenzini Medical Science Foundation Milan Italy RobCook Bazian Economist Intelligence Unit HealthcareLondon United Kingdom Lorenzo Maria Donini Food Sci-ence and Human Nutrition Research Unit Sapienza Univer-sity Rome Italy Christopher Emsden Policy Sonar RomeItaly Emanuela Folco Giovanni Lorenzini Medical ScienceFoundation Milan Italy and Houston TX Luigi FontanaDepartment of Clinical and Experimental Sciences Universityof Brescia Italy and Department of Medicine WashingtonUniversity St Louis MO Robert A Gibson School ofAgriculture Food and Wine FOODplus Research CentreUniversity of Adelaide Australia Maria Giovanna GrazianiGastroenterology and Digestive Endoscopy Unit SanGiovanni Addolorata Hospital Rome Italy Ranieri GuerraDepartment of Preventive Health Ministry of Health

continued from previous pageSurrogate disease biomarker

middot In some research areas it may be challenging to conduct studies that are sufficiently long term to wait for diseaseoutcomes (such as heart attack) or answers that may be required in the meantime In such cases biomarkers ofthat disease (eg blood pressure) can be measured to predict the likely risk of later developing the disease How-ever these results indicate a possible risk rather than providing direct causal proof

Weakqualifiedconditional recommendations

middot Where evidence is limited in terms of its quality or quantity this affects the level of certainty in any conclusionsbased on that evidence Describing recommendations as weak qualified or conditional communicates this levelof uncertainty

542 Magni et al

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Rome Italy Gordon H Guyatt Department of ClinicalEpidemiology and Biostatistics McMaster UniversityHamilton ON Canada John PA Ioannidis CF RehnborgChair in Disease Prevention Department of Health Policyand Research Stanford University Stanford CA AnnS Jackson Giovanni Lorenzini Medical Foundation HoustonTX David M Klurfeld Human Nutrition Program USDAAgricultural Research Service Beltsville MD Paolo MagniDepartment of Pharmacological and Biomolecular SciencesUniversitagrave degli Studi di Milano Milan Italy Carlos DanielMagnoni Department of Nutrition and Nutritional TherapyHCor Heart Hospital (SP) Department of Clinical NutritionDante Pazzanese Cardiovascular Institute Sao Paulo BrazilMaria Makrides Healthy Mothers Babies and ChildrenSouth Australian Health and Medical Research InstituteAdelaide Australia Basil Mathioudakis Consulting sprlFood Legislation and Nutrition Brussels Belgium AlessandroMonaco Giovanni Lorenzini Medical Science FoundationMilan Italy Elvira Naselli La Repubblica Rome ItalyElly OrsquoBrien Bazian Economist Intelligence Unit LondonUnited Kingdom Chirag J Patel Department of Biomed-ical Informatics Harvard Medical School Boston MASergio Pecorelli Giovanni Lorenzini Medical FoundationHouston TX Andrea Peracino Giovanni Lorenzini Med-ical Science Foundation Milan Italy Giorgio RacagniDepartment of Pharmacology and Biomolecular SciencesFaculty of Pharmaceutical Sciences Universitagrave di MilanoMilan Italy Holger J Schuumlnemann Department of Clin-ical Epidemiology and Biostatistics McMaster UniversityHamilton ON Canada Raanan Shamir Institute Gas-troenterology Nutrition and Liver Diseases SchneiderChildrenrsquos Medical Center of Israel - Sackler Facultyof Medicine University of Tel Aviv Israel Katherine LTucker Department of Clinical Laboratory and Nutri-tional Sciences University of Massachusetts LowellMA Peter Whoriskey The Washington Post WashingtonDC Niv Zmora Department of Immunology WeizmannInstitute of Science Rehovot Israel All authors read andapproved the final version of the paper

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28 Heacutebert JR Frongillo EA Adams SA Turner-McGrievy GM Hurley TGMiller DR Ockene IS Perspective randomized controlled trialsare not a panacea for diet-related research Adv Nutr 20167423ndash32

29 Tzoulaki I Patel CJ Okamura T Chan Q Brown IJ Miura KUeshima H Zhao L Van Horn L Daviglus ML et al A nutrient-wide association study on blood pressure Circulation 20121262456ndash64

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31 Khoury MJ Ioannidis JP Medicine Big data meets public healthScience 20143461054ndash5

32 Patel CJ Chen R Kodama K Ioannidis JP Butte AJ Systematic identi-fication of interaction effects between genome- and environment-wideassociations in type 2 diabetes mellitus Hum Genet 2013132495ndash508

33 Patel CJ Ioannidis JP Placing epidemiological results in the context ofmultiplicity and typical correlations of exposures J Epidemiol Com-munity Health 2014681096ndash100

34 Patel CJ Ioannidis JP Studying the elusive environment in large scaleJAMA 20143112173ndash4

35 Patel CJ Cullen MR Ioannidis JP Butte AJ Systematic evaluation ofenvironmental factors persistent pollutants and nutrients correlatedwith serum lipid levels Int J Epidemiol 201241828ndash43

36 Patel CJ Rehkopf DH Leppert JT Bortz WM Cullen MRChertow GM Ioannidis JP Systematic evaluation of environmental andbehavioural factors associated with all-cause mortality in the UnitedStates National Health and Nutrition Examination Survey Int J Epide-miol 2013421795ndash810

37 Merritt MA Tzoulaki I Tworoger SS De Vivo I Hankinson SEFernandes J Tsilidis KK Weiderpass E Tjoslashnneland A Petersen KE et alInvestigation of dietary factors and endometrial cancer risk using anutrient-wide association study approach in the EPIC and Nursesrsquo HealthStudy (NHS) and NHSII Cancer Epidemiol Biomarkers Prev 201524466ndash71

38 Merritt MA Tzoulaki I van den Brandt PA Schouten LJ Tsilidis KKWeiderpass E Patel CJ Tjoslashnneland A Hansen L Overvad K et alNutrient-wide association study of 57 foodsnutrients and epithelialovarian cancer in the European Prospective Investigation into Cancerand Nutrition study and the Netherlands Cohort Study Am J ClinNutr 2016103161ndash7

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40 Ioannidis JP Loy EY Poulton R Chia KS Researching genetic versusnongenetic determinants of disease a comparison and proposed uni-fication Sci Transl Med 200917ps8

41 Leek JT Peng RD Opinion reproducible research can still be wrongadopting a prevention approach Proc Natl Acad Sci USA 20151121645ndash6

42 Goodman SN Fanelli D Ioannidis JP What does research reproduci-bility mean Sci Transl Med 20161341ps12

43 Parnell LD Lee YC Lai CQ Adaptive genetic variation and heart dis-ease risk Curr Opin Lipidol 201021116ndash22

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45 Pigeyre M Yazdi FT Kaur Y Meyre D Recent progress in geneticsepigenetics and metagenomics unveils the pathophysiology of humanobesity Clin Sci (Lond) 2016130943ndash86

46 Reddon H Gueant JL Meyre D The importance of gene-environmentinteractions in human obesity Clin Sci (Lond) 20161301571ndash97

47 Vega-Loacutepez S Ausman LM Griffith JL Lichtenstein AH Interindi-vidual variability and intra-individual reproducibility of glycemic indexvalues for commercial white bread Diabetes Care 2007301412ndash7

48 Zeevi D Korem T Zmora N Israeli D Rothschild D Weinberger ABen-Yacov O Lador D Avnit-Sagi T Lotan-Pompan M et al Person-alized nutrition by prediction of glycemic responses Cell 20151631079ndash94

49 Zmora N Zeevi D Korem T Segal E Elinav E Taking it personallypersonalized utilization of the human microbiome in health and dis-ease Cell Host Microbe 20161912ndash20

50 Vrolix R Mensink RP Variability of the glycemic response to singlefood products in healthy subjects Contemp Clin Trials 2010315ndash11

51 Thaiss CA Zmora N Levy M Elinav E The microbiome and innateimmunity Nature 201653565ndash74

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54 Alonso-Coello P Schunemann HJ Moberg J Brignardello-Petersen R Akl EA Davoli M Treweek S Mustafa RA Rada GRosenbaum S et al GRADE Working Group GRADE Evidence toDecision (EtD) frameworks a systematic and transparent approachto making well informed healthcare choices 1 introduction BMJ2016353i2016

55 Schuumlnemann HJ Mustafa R Brozek J Santesso N Alonso-Coello PGuyatt G Scholten R Langendam M Leeflang MM Akl EA et alGRADE Working Group GRADE Guidelines 16 GRADE evidence todecision frameworks for tests in clinical practice and public healthJ Clin Epidemiol 20167689ndash98

56 Guyatt GH Alonso-Coello P Schunemann HJ Djulbegovic BNothacker M Lange S Murad MH Akl EA Guideline panels shouldseldom make good practice statements guidance from the GRADEWorking Group J Clin Epidemiol 2016803ndash7

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61 Fretheim A Schunemann HJ Oxman AD Improving the use of re-search evidence in guideline development 3 Group composition andconsultation process Health Res Policy Syst 2006415

62 Bier DM Willett WC Dietary Reference Intakes resuscitate or let dieAm J Clin Nutr 20161041195ndash6

63 Schuumlnemann HJ Sperati F Barba M Santesso N Melegari C Akl EAGuyatt G Muti P An instrument to assess quality of life in relation tonutrition item generation item reduction and initial validation HealthQual Life Outcomes 2010826

64 Schuumlnemann HJ Al-Ansary LA Forland F Kersten S Komulainen JKopp IB Macbeth F Phillips SM Robbins C van der Wees P et alBoard of Trustees of the Guidelines International Network GuidelinesInternational Network principles for disclosure of interests andmanagement of conflicts in guidelines Ann Intern Med 2015163548ndash53

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67 Mithril C Dragsted LO Meyer C Blauert E Holt MK Astrup AGuidelines for the New Nordic diet Public Health Nutr 2012151941ndash7

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68 Mithril C Dragsted LO Meyer C Tetens I Biltoft-Jensen A Astrup A

Dietary composition and nutrient content of the New Nordic Diet

Public Health Nutr 201316777ndash8569 Yavchitz A Boutron I Bafeta A Marroun I Charles P Mantz J

Ravaud P Misrepresentation of randomized controlled trials in

press releases and news coverage a cohort study PLoS Med 20129

e100130870 Vinkers CH Tijdink JK Otte WM Use of positive and negative words

in scientific PubMed abstracts between 1974 and 2014 retrospective

analysis BMJ 2015351h646771 Haneef R Lazarus C Ravaud P Yavchitz A Boutron I Interpretation of

results of studies evaluating an intervention highlighted in Google

health news a cross-sectional study of news PLoS One 201510

e014088972 Lazarus C Haneef R Ravaud P Boutron I Classification and preva-

lence of spin in abstracts of non-randomized studies evaluating an in-

tervention BMC Med Res Methodol 2015158573 Lazarus C Haneef R Ravaud P Hopewell S Altman DG Boutron I

Peer reviewers identified spin in manuscripts of nonrandomized

studies assessing therapeutic interventions but their impact on spin in

abstract conclusions was limited J Clin Epidemiol 20167744ndash51

74 Johnston JL Fanzo JC Cogill B Understanding sustainable diets adescriptive analysis of the determinants and processes that influencediets and their impact on health food security and environmentalsustainability Adv Nutr 20145418ndash29

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79 Fontana L Kennedy BK Longo VD Seals D Melov S Medical researchtreat ageing Nature 2014511405ndash7

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