Providing consultancy and research in health economics for the NHS, pharmaceutical and health care industries since 1986

DANONE INSTITUTE INTERNATIONAL

Systematic Review of Yoghurt for Weight Management Outcomes

Final Protocol

JULIE GLANVILLE, Associate Director JAQUI EALES,Associate HANNAH WOOD, Information Specialist

26 SEPTEMBER 2014

Contents

Page No.

Acknowledgements

Abbreviations

Section 1: Introduction 2 1.1 Defining Yoghurt 2

Section 2: Objectives 4

Section 3: Methods 5 3.1 Research Question 5 3.2 Search Strategy 8 3.3 Selection of Eligible Studies 11 3.4 Data Extraction 11 3.5 Quality Assessment 12 3.6 Data synthesis 12

Section 4: Report 14 4.1 Draft Report 14 4.2 Final Report 14

Section 5: Timeline 15

References

Appendices:

Appendix A: PRISMA flow diagram Appendix B: PRISMA checklist Appendix C: Protocol changes

All reasonable precautions have been taken by YHEC to verify the information contained in this publication. However, the published material is being distributed without warranty of any kind, either expressed or implied. The responsibility for the interpretation and use of the material lies with the reader. In no event shall YHEC be liable for damages arising from its use.

Abbreviations

BMI Body mass index CI Confidence interval CRD Centre for reviews and dissemination DII Danone Institute International EFSA European food safety authority HRQoL Health-related quality of life OR Odds ratio PRISMA Preferred Reporting Items for Systematic Reviews and Meta-Analyses SR Systematic review RCT Randomized control trial RR Risk ratio WMD Weighted mean difference YHEC York Health Economics Consortium

i

Section 1: Introduction

York Health Economics Consortium (YHEC) has been commissioned by Danone Institute International (DII) to conduct a systematic review (SR) of the effect of yoghurt consumption on weight management outcomes. This document is the protocol for this work, and sets out how YHEC will approach this task and its constituent tasks.

1.1 DEFINING YOGHURT

The Codex Alimentarius international food standards define yoghurt as a form of fermented milk that contains symbiotic cultures of Streptococcus thermophiles and Lactobacillus delbrueckii subsp. Bulgaricus. To be called a yoghurt a fermented milk product must contain milk protein, milk fat, lactic acid, ethanol, microorganisms and yeasts in the proper proportions (Table 1)(1). Probiotic yogurt is differentiated from conventional yoghurt through the addition of further strains of probiotic bacteria (2). This review focuses on the effectiveness of yoghurt containing the symbiotic cultures Streptococcus thermophiles and Lactobacillus delbrueckii subsp. Bulgaricus, as defined by the Codex Alimentarius.

Table 1: The composition of fermented milk products (1)

Fermented Milk Yoghurt, Alternate Kefir Kumys Culture Yoghurt and Acidophilus milk Milk protein Min. 2.7% Min. 2.7% Min. 2.7% Milk fat Less than 10% Less than 15% Less than 10% Less than 10% Titrable acidity, Min. 0.3% Min. 0.6% Min. 0.6% Min. 0.7% expressed as % lactic acid (%m/m) Ethanol(% vol/w) Min. 0.5% Sum of Min. 107 Min. 107 Min. 107 Min. 107 microorganisms constituting the starter culture (cfu/g, In total) Labelled Min. 106 Min. 106 microorganisms (cfu.g, total) Yeasts (cfu/g) Min. 104 Min. 104 Vol. = volume; cfu/g = colony-forming units per gram; Min. = minimum.

The beneficial health effects of yoghurt have been the subject of investigation for over a century. A range of research designs have been employed in the construction of an international evidence base, including observational studies and experimental studies (3, 4). The efficacy of yoghurt has been investigated in relation to a wide range of separate and

Section 1 2 overlapping outcomes including weight management (5), type 2 diabetes (6), cardio-vascular disease risk (7), bone health (8), dental health (9), the risk of various forms of cancer (10), gastro-intestinal health (11), diarrhoea symptoms (12), lactose intolerance (13), malnutrition (14), immunological parameters(15), and overall mortality (16).

Meta-analyses and systematic reviews have been conducted in relation to only a few of these outcomes. Their limited results suggest that consuming yoghurt may reduce the risk of developing type 2 diabetes (17-19), but may have no effect on the risk of developing colorectal cancer (20), hypertension (21) or on overall mortality (22).

In recent years considerable attention has been paid to understanding the health benefits of probiotic yoghurts, with increasing numbers of systematic reviews having been conducted in this area. DII now wish to conduct a systematic review of the effect of standard yoghurt consumption on outcomes related to weight management. There is particular interest in identifying data for specific subgroups of the general apparently healthy adult population, such as those at risk of diabetes, and for investigating the effects in different ethnic groups.

Section 1 3

Section 2: Objectives

The objective of this project is to produce a systematic review of the effect of standard yoghurt consumption on weight management outcomes.

Section 2 4

Section 3: Methods

A systematic review involves the systematic and transparent identification, selection, extraction and synthesis of studies relevant to the research question (23). The first stage of this protocol is to define the research question and the inclusion and exclusion criteria (Table 3.1).

3.1 RESEARCH QUESTION

To be included in the systematic review, studies must meet all of the following inclusion criteria.

3.1.1 Study types

Relevant comparative studies will be limited to the following study types:

 Randomized controlled trials (RCTs) including quasi-RCTs;  Controlled clinical trials;  Comparative observational studies (including cross sectional studies, cohort studies and case control studies).

Studies with relevant comparative designs published as abstracts, conference presentations or unpublished reports will be included in the review if they report all items from Section 3.1.

Trial protocols, where the study results have not yet been reported, will be noted in a table of forthcoming studies.

We will examine any relevant systematic reviews of evidence on the effects of yoghurt on weight management outcomes to identify any additional studies that might be eligible to be included in the systematic review.

The following non-comparative study designs will not be eligible for inclusion:

 Case reports;  Case series.

Letters, comments and editorials and studies not published in English will not be eligible for inclusion in the systematic review.

3.1.2 Participants

To be included in the review eligible studies will examine the effects of yoghurt on weight management in the apparently healthy adult population (18-65 years). Studies that contain a

Section 3 5 mixed population with a proportion of the population aged over 65 years of age or younger than 18 will be treated as eligible if there are separate results presented for the 18-65 age group.

Studies that contain a mixed population with a proportion of the population aged over 65 years of age will be treated as eligible, if there is a total of 20% or less of the study population who are either aged 65 or younger than 18 years of age.

Studies reporting data for specific subgroups of the general population who are at high risk will also be eligible, for example people with insulin resistance, diabetes or obesity (BMI between 30 and 40).

Studies only examining the effects of yoghurt on weight management in the following populations will be excluded:

 Study populations comprising only people with severe or morbid obesity (BMI ≥40.00)1;  Study populations with a single specific disease or symptom such as anaemia, which are not representative of the apparently healthy general population;  People training for or undertaking physical activity at a professional level (e.g. professional sports people, soldiers or fire service personnel);  Any animal population;  In vitro studies;  Studies using technologies that mimic stomachs.

3.1.3 Interventions

Studies eligible for inclusion in this review will include the following interventions:

 Yoghurt, or any of its synonyms (Yogurt; Yoghourt; Yaourt; Joghurt; Yogourt; Yaghourt; Yahourth; Yoghurd; Joghourt; Jogourt; Maas (Amasi); Dahi; Doi; Perugu; Thayir; Mosaru; Curd; Matsun; Matsoon; Matsoun; Matxoun; Madzoon; Madzoun; Mancun; Matson; Matsoni; Dadiah; Dadih; Stragisto).

Studies will not be eligible for inclusion where yoghurt is featured as an intervention in combination with another substance (e.g. CLA/vitamins/Olibra) which is the main focus of the study. In those studies, yoghurt is being used as a carrier substance for an active ingredient and hence is not the focus of the investigation.

Studies reporting the following interventions will not be eligible for inclusion:

 Probiotic yoghurt;  Fermented milk, kefir and kumys;

1 World Health Organiszation. Global database on body mass index [web page]. Geneva: WHO; 2014. http://apps.who.int/bmi/index.jsp?introPage=intro_3.html

Section 3 6

 Fermented baby formula;  Milk.

For the purposes of this review, yoghurt which is reported to contain any bacteria other than Streptococcus thermophilius and Lactobacillus delbrueckii subsp. Bulgaricus will not be eligible for inclusion.

Only studies reporting oral consumption of yoghurt will be eligible for inclusion in the review. Topical application of yoghurt as an intervention will not be eligible for inclusion.

3.1.4 Comparators

Eligible studies must compare yoghurt with one or more of the following interventions:

 Any non-probiotic yoghurt only (e.g. low fat yoghurt, full fat yoghurt);  Any non-yoghurt substance;  Placebo not including live bacteria;.  Any other non-yoghurt intervention (e.g. yoghurt consumption vs nutritional counselling).

Studies that compare yoghurt with the following only will not be eligible for inclusion in the systematic review:

 Yoghurt containing any other active substance, where the active substance is the main focus of the study;2  Probiotic yoghurt;  Fermented buffalo milk.

3.1.5 Outcomes

To be included in this review studies will assess the interventions featured in section 3.1.3 in relation to at least one of the following weight management outcomes:

 Percent body fat (fat body mass or fat mass expressed as a proportion, ratio or percentage);  Percent lean body mass (lean fat expressed as a proportion, ratio or percentage);  Body weight;  Body Mass Index (BMI);3  Waist Circumference;  Composite measures related to weight management (for example measures combining body weight, BMI and/or waist circumference).

2 For example yoghurt with CLA/vitamins/Olibra vs yoghurt without CLA/vitamins/Olibra would be excluded from the systematic review.. 3 Body Mass Index (BMI) is defined as (weight/height2)(24)

Section 3 7

Table 3.1: Summary of inclusion/exclusion criteria

PICOS Inclusion criteria Exclusion criteria Participants The healthy adult population (18-65  Human populations with specific years) diseases or studies only in the morbidly obese;  People training for or undertaking high level physical performances;  Any animal population;  In vitro studies;  Studies using technologies that mimic stomachs. Interventions Yoghurt (consumed orally)  Probiotic yoghurt;  Non-probiotic yoghurt used as the carrier base for other active substances;  Fermented milk, kefir and kumys;  Fermented baby formula;  Milk;  Yoghurt with bacteria other than Streptococcus thermophilius and Lactobacillus delbrueckii subsp. Bulgaricus;  Topical application of yoghurt. Comparators  Any non-probiotic yoghurt;  Probiotic yoghurt;  Any non-yoghurt intervention;  Fermented buffalo milk;  Any placebo or control product that  Non-probiotic yoghurt used as the does not contain other active carrier base for other active probiotics and/or prebiotics. substances. Outcomes  Body weight  Body Mass Index (BMI)  Waist Circumference  Fat body mass  Lean body mass  Composite measures Study types  RCTs;  Case reports  Controlled clinical trials  Case series  Comparative observational studies  Letters (Cross sectional studies, cohort  Comments studies, case-control studies).  Editorials

Full papers, abstracts and conference presentations, trial reports and unpublished reports will be eligible.

3.2 SEARCH STRATEGY

The systematic review involves a search for relevant studies. The search will be very sensitive since it involves only the search concept for yoghurt and uses many synonyms to capture that concept. The strategy explicitly excludes records which are letters, editorials, comments or case reports, where the databases offer such options. Where databases offer the facility, animal studies will be excluded using a well-established search approach. The Medline strategy is shown in Figure 3.1.

Section 3 8

Figure 3.1 Medline search strategies to identify studies reporting the health benefits of yoghurt

1 yogurt/ 2 streptococcus thermophilus/ 3 lactobacillus delbrueckii/ 4 (yogurt$ or yoghurt$ or yoghourt$ or yaourt$ or joghurt$ or yogourt$ or yaghourt$ or yahourth$ or yoghurd$ or joghourt$ or jogourt$).ti,ab. 5 (maas or amasi$1 or dahi$1 or da-hi$1 or dohi$1 or meesti$1 or perugu$1 or thayir$1 or thayiru$1 or mosaru$1 or curd$1 or matsun$1 or matsoon$1 or matsoun$1 or matzoun$1 or madzoon$1 or madzoun$1 or matson$1 or matsoni$1 or dadiah$1 or dadih$1 or stragisto$1 or q?zana$1 or dhahi$1 or dhaunro$1 or juju dhau$1 or rahmjoghurt$ or jameed$1 or zabadi$1 or labni$1 or lebni$1 or labneh$1 or m?st chekide$1).ti,ab. 6 (streptococcus adj3 thermophilus).ti,ab. 7 s thermophilus.ti,ab. 8 (lactococcus adj3 thermophilus).ti,ab. 9 l thermophilus.ti,ab. 10 (lactobacillus adj3 delbruecki$).ti,ab. 11 l delbruecki$.ti,ab. 12 bulgaricus.ti,ab. 13 or/1-12 14 (letter or editorial or comment or case reports).pt. 15 case report.ti. 16 animals/ not (animals/ and humans/) 17 13 not (14 or 15 or 16)

The searches will not be limited by date or language, so that if required studies in languages other than English can be identified for consideration in any future updates.

3.2.1 Resources Searched

The literature search will be conducted in a range of relevant databases to identify studies investigating the health benefits of yoghurt (Table 3.3). Grey literature will be identified via OAISTER, OpenGrey and NTIS. Unpublished studies will be identified from, clinical trial registries and conference proceedings.

Table 3.3: Databases and resources to be searched

Database Interface MEDLINE and MEDLINE In-Process OvidSP EMBASE OvidSP Cochrane Database of Systematic Reviews (CDSR) Cochrane Library/Wiley Interscience Cochrane Central Register of Controlled Trials Cochrane Library/Wiley Interscience (CENTRAL) DARE Database of Abstracts of Reviews of Effects CRD interface (DARE) Health Technology Assessment Database (HTA) CRD interface Science Citation Index (SCI) Web of Knowledge Conference Proceedings Citation Index – Science Web of Knowledge (CPCI-S)

Section 3 9

Database Interface African Index Medicus http://indexmedicus.afro.who.int/ LILACS http://search.bvsalud.org/portal/ OAISTER http://oaister.worldcat.org/ OpenGrey http://www.opengrey.eu/ NTIS Proquest Dialog Biosis Proquest Dialog CAB Abstracts Proquest Dialog Food Science and Technology Abstracts Proquest Dialog ClinicalTrials.gov www.clinicaltrials.gov ICTRP (trials) http://www.who.int/ictrp/en/

Information on ongoing or recently completed studies, unpublished research, and research reported in the grey literature will be identified by searching selected major conference proceedings from the last four years:

 ESPEN congress;  The International Scientific Conference on Nutraceuticals and Functional Foods (Food and function);  European Nutrition Conference (FENS);  Federation of American Societies for Experimental Biology (FASEB);  American Dietetics Association;  Federation of European Microbiological Societies (FEMS);  American Society of Microbiology (ASM);  American College of Gastroenterology (ACG) Annual Scientific Meetings;  Digestive Disease Week;  British Society of Gastroenterology meetings;  United European Gastroenterology Week;  American Dairy Products Institute (ADPI)  International Dairy Federation (IDF)  International Functional Food Conference  American Society for Nutrition (ASN)  European Society for Paediatric Gastroenterology Hepatology and Nutrition (ESPGHAN)  North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition (NASPGHAN)  International Scientific Association for Probiotics and Prebiotics ISAPP)  Obesity Society Annual Scientific Meeting  European Congress on Obesity (European Association for the Study of Obesity)  American Diabetes Association’s Scientific Sessions  (American) Endocrine Society Annual meeting and ENDO

The reference lists of relevant reviews, trials and studies will be searched to identify any further studies.

The results will be loaded into EndNote bibliographic software and deduplicated using several algorithms.

Section 3 10

3.3 SELECTION OF ELIGIBLE STUDIES

Record selection will be undertaken using several passes.

The first pass will be undertaken by two reviewers independently to rapidly remove obviously irrelevant records including those records which report animal studies, address probiotic yoghurts,, include ineligible study design features, or report outcomes that are not of interest.

Then initial record selection from the title and abstract will be undertaken by two reviewers independently (second pass). The reviewers will be seeking to identify the studies most likely to contain evidence of the effects of yoghurt on weight management outcomes. If there is uncertainty about whether a record is relevant it will be selected for further checking. At this stage advice on inclusion criteria refinement may be sought from DII.

The full text of potentially relevant studies will then be obtained, if it has not been already. The full papers will be assessed for relevance by two reviewers independently (third pass). Discrepancies will be resolved through discussion or by consulting a third reviewer. Studies that are considered ineligible at this stage will be listed in an ‘Excluded Studies’ table with reasons for exclusion (EFSA 2010: section 4.1.1.5). This table will be included in the final report. Studies that we are unable to obtain will be listed in another table.

Where questions about study eligibility remain, we will contact the study’s primary investigator.

The number of studies identified by the search and excluded at various stages will be recorded and reported in a PRISMA study flow diagram (see Appendix A) following the PRISMA checklist (Appendix B)(25).

3.4 DATA EXTRACTION

At the data extraction stage some studies, on close inspection, may prove ineligible. These studies will be described in an ‘excluded studies’ table with the reasons for exclusion reported. The number of records lost at this stage of the review process will be documented in the flow diagram (see Appendix A).

We will develop a data extraction template in Excel. Data likely to be extracted from each study include:

 Description of the study design (for example, duration, participant selection), interventions/actions investigated and details of how the interventions were delivered and by whom;  Country of study and ethnicity of participants;  Inclusion and exclusion criteria and their characteristics at baseline, along with any differences between study groups, where applicable;

Section 3 11

 Details of any “at risk”4 subgroups of the population;  Numbers of participants in the study and details of numbers lost to follow up or who withdrew;  Details of the primary and secondary outcomes investigated and the measures used to investigate those outcomes, and the results;  Method of randomisation (if applicable) or sample selection.

The methods of analysis will be collected along with details of subgroup analyses and their rationale. Information about whether analyses were pre-planned or post-hoc can also be collected.

Inadequately reported or missing data will be explicitly noted in the Excel spreadsheet.

Data will be extracted by two reviewers independently. Any discrepancies will be resolved through discussion or by consulting a third reviewer.

Where the information that we need is not presented in the paper we will contact the study authors to ask for the data.

3.5 QUALITY ASSESSMENT

We will undertake quality assessment of the eligible studies using appropriate quality appraisal checklists, as well as conducting detailed extraction of study methods and outcomes. The internal and external validity of all eligible studies will be quality assessed. RCTs will be assessed using the Cochrane risk of bias tool and cohort studies will be assessed using the CRD cohort studies checklist (26) (Appendix C).

Quality assessment will be conducted by two researchers independently. The two data sets will then be consolidated and any disagreements will be discussed between the reviewers.

3.6 DATA SYNTHESIS

The studies will be summarised in tables providing data on their methods and results. We will assess the similarity of studies and availability of data, and where studies are similar enough and data are available we may be able to undertake statistical pooling, in the form of a meta-analysis. If appropriate, the results will be statistically pooled for the outcomes of interest using a fixed-effect model where results are homogeneous and random-effects models where results are heterogeneous. The methods of pooling will be described. For dichotomous outcomes, the results will be presented as relative risks (RR) with 95% confidence intervals (CIs). Hazard ratios (HR) will be presented for any time-to-event analyses. For continuous outcomes, results will be presented as a weighted mean difference (WMD), with 95% confidence intervals (CIs). Heterogeneity will be assessed

4 “At risk” may include people with diabetes, or with risk factors for chronic disease such as hypertension, high LDL or who are obese.

Section 3 12 using the chi-squared and I-squared statistics where an I2 of 0-25% represents no heterogeneity, 25-50% represents moderate heterogeneity, 50-75% represents substantial heterogeneity and 75-100% represents considerable heterogeneity. The results from any meta-analyses will be graphically presented as forest plots. All analyses will be conducted using the Review Manager (RevMan) software. The strengths and weaknesses of the synthesis will also be discussed.

Sensitivity analysis will be undertaken, if data permit, by the ethnic origin of study populations.

We will provide a narrative summary, irrespective of the feasibility of pooling. This will provide an exploration of the relationship between studies and will discuss patterns (if appropriate) in the data. An overall assessment of the strength of the research evidence in relation to the research questions will be provided.

Section 3 13

Section 4: Report

4.1 DRAFT REPORT

Although the final style and format of the report is to be agreed, we anticipate that we will present the report according to the PRISMA reporting guidelines (25).

The report will be structured as follows and content will be detailed (as far as possible):  Executive summary;  List of tables and figures;  Introduction and background to the research question;  Objectives of the review;  Description of the research methods; o Eligibility criteria; o Search strategy; o Record selection o Quality assessment; o Study data extraction; o Analyses of the results.  Results; o Study selection; o Study characteristics; o Quality assessment; o Syntheses of results; o Any additional analyses (e.g. subgroup analysis).  Discussion; o Summary of the evidence; o Limitations; o Conclusions.  References;  Included studies tables;  Excluded studies tables;  Forthcoming studies table;  PRISMA checklist;  Search strategies.

4.2 FINAL REPORT

Following comments from DII, we will amend the draft report as necessary. These amendments, once agreed, will form the final report.

Section 4 14

Section 5: Timeline

The timescale for this project is shown in Table 5.1. The timeline is based on an estimate of the numbers of studies likely to be included at each stage of review. The timelines may be impacted by waiting for responses to queries from authors and the client. We have taken account of staff summer holidays, in the timelines.

Table 5.1: Timelines for the systematic review

Activity Completion date

Project initiation meeting held TBC Production of draft protocol 29/08/14 Protocol finalised 23/09/14 Database searches completed 07/10/14 Record selection / ordering / further selection 21/10/14 completed Full text assessment for relevance completed 27/10/14 (approx. 85 studies) Record extraction and quality assessment completed 17/11/14 (approx. 40 studies) Synthesis and prepare draft report 15/12/14 Revised report (in light of DII comments) December 2014/January 2015

R:\Projects\JMG\JMG355 - Danone Yoghurt and Weight Management\Admin\Yoghurt and Weight management Final protocol 26 Sept 2014.docx JMG 26/09/14

Section 5 15

References

1. Codex Committee on Milk and Milk Products. Codex Standard for Fermented Milks (2nd Ed). In. New Zealand: Codex Alimentarius 2010. p. 11. 2. Meyer AL, Elmadfa I, Herbacek I, Micksche M. Probiotic, as well as conventional yogurt, can enhance the stimulated production of proinflammatory cytokines. Journal of Human Nutrition and Dietetics. 2007;20(6):590-98. DOI: 10.1111/j.1365-277X.2007.00807.x. 3. Bonjour JP, Benoit V, Payen F, Kraenzlin M. Consumption of yogurts fortified in vitamin D and calcium reduces serum parathyroid hormone and markers of bone resorption: a double- blind randomized controlled trial in institutionalized elderly women. J Clin Endocrinol Metab. 2013;98(7):2915-21. DOI: http://dx.doi.org/10.1210/jc.2013-1274. 4. Douglas SM, Ortinau LC, Hoertel HA, Leidy HJ. Low, moderate, or high protein yogurt snacks on appetite control and subsequent eating in healthy women. Appetite. 2013;60(1):117-22. DOI: http://dx.doi.org/10.1016/j.appet.2012.09.012. 5. Burns AA, Lindmark L, Livingstone MBE, Mullaney U, Rowland I, Welch RW. Consumption of yoghurt containing modified fat increases satiety and reduces subsequent food intake. Proceedings of the Nutritional Society. [serial on the internet]. 1998; 57: 121a. Available from: URL. [cited Date Accessed]; 6. O'Connor LM, Lentjes MA, Luben RN, Khaw KT, Wareham NJ, Forouhi NG. Dietary dairy product intake and incident type 2 diabetes: a prospective study using dietary data from a 7- day food diary. Diabetologia. 2014. DOI: 10.1007/s00125-014-3176-1. 7. Buyuktuncer Z, Fisunoglu M, Guven GS, Unal S, Besler HT. The cholesterol lowering efficacy of plant stanol ester yoghurt in a Turkish population: A double-blind, placebo- controlled trial. Lipids in Health and Disease. 2013;12(1). DOI: http://dx.doi.org/10.1186/1476-511X-12-91. 8. Heaney RP, Rafferty K, Dowell MS. Effect of yogurt on a urinary marker of bone resorption in postmenopausal women. Journal of the American Dietetic Association. 2002;102(11):1672-74. 9. Telgi RL, Yadav V, Telgi CR, Boppana N. In vivo dental plaque pH after consumption of dairy products. Gen Dent. 2013;61(3):56-9. 10. Kurahashi N, Inoue M, Iwasaki M, Sasazuki S, Tsugane AS. Dairy product, saturated fatty acid, and calcium intake and prostate cancer in a prospective cohort of Japanese men. Cancer Epidemiol Biomarkers Prev. 2008;17(4):930-7. DOI: http://dx.doi.org/10.1158/1055- 9965.EPI-07-2681. 11. Ballesta S, Velasco C, Borobio MV, Arguelles F, Perea EJ. [Fresh versus pasteurized yogurt: comparative study of the effects on microbiological and immunological parameters, and gastrointestinal comfort]. Enferm Infecc Microbiol Clin. 2008;26(9):552-7. 12. Pashapour N, Iou SG. Evaluation of yogurt effect on acute diarrhea in 6-24-month-old hospitalized infants. Turk J Pediatr. 2006;48(2):115-8. 13. Adibi P, Mirshahzadeh P, Sadeghizadeh A. Dairy intolerance syndrome in Iranian young adult. J. 2009;14(6):357-66. 14. Sazawal S, Habib A, Dhingra U, Dutta A, Dhingra P, Sarkar A, et al. Impact of micronutrient fortification of yoghurt on micronutrient status markers and growth - a randomized double blind controlled trial among school children in Bangladesh. BMC Public Health. 2013;13:514. DOI: http://dx.doi.org/10.1186/1471-2458-13-514. 15. Olivares M, Paz Diaz-Ropero M, Gomez N, Sierra S, Lara-Villoslada F, Martin R, et al. Dietary deprivation of fermented foods causes a fall in innate immune response. Lactic acid bacteria can counteract the immunological effect of this deprivation. J Dairy Res. 2006;73(4):492-8. 16. Goldbohm RA, Chorus AMJ, Garre FG, Schouten LJ, Brandt PA. Dairy consumption and 10-y total and cardiovascular mortality: a prospective cohort study in the Netherlands. Am J Clin Nutr. 2011;93(3):615-27.

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17. Aune D, Norat T, Romundstad P, Vatten LJ. Dairy products and the risk of type 2 diabetes: a systematic review and dose-response meta-analysis of cohort studies. Am J Clin Nutr. 2013;98(4):1066-83. DOI: http://dx.doi.org/10.3945/ajcn.113.059030. 18. Gao D, Ning N, Wang C, Wang Y, Li Q, Meng Z, et al. Dairy products consumption and risk of type 2 diabetes: systematic review and dose-response meta-analysis. PLoS ONE. 2013;8(9):e73965. DOI: http://dx.doi.org/10.1371/journal.pone.0073965. 19. Tong X, Dong JY, Wu ZW, Li W, Qin LQ. Dairy consumption and risk of type 2 diabetes mellitus: a meta-analysis of cohort studies. Eur J Clin Nutr. 2011;65(9):1027-31. DOI: http://dx.doi.org/10.1038/ejcn.2011.62. 20. Aune D, Lau R, Chan DSM, Vieira R, Greenwood DC, Kampman E, et al. Dairy products and colorectal cancer risk: A systematic review and meta-analysis of cohort studies. Annals of Oncology. 2012;23(1):37-45. DOI: http://dx.doi.org/10.1093/annonc/mdr269. 21. Soedamah-Muthu SS, Verberne LD, Ding EL, Engberink MF, Geleijnse JM. Dairy consumption and incidence of hypertension: a dose-response meta-analysis of prospective cohort studies. Hypertension. 2012;60(5):1131-7. DOI: http://dx.doi.org/10.1161/HYPERTENSIONAHA.112.195206. 22. O'Sullivan TA, Hafekost K, Mitrou F, Lawrence D. Food sources of saturated fat and the association with mortality: a meta-analysis. Am J Public Health. 2013;103(9):e31-42. DOI: http://dx.doi.org/10.2105/AJPH.2013.301492. 23. European Food Safety Authority. Application of systematic review methodology to food and feed safety assessments to support decision making. EFSA Journal. 2010;8(6):1637. 24. Cole TJ, Bellizzi MC, Flegal KM, Dietz WH. Establishing a standard definition for child overweight and obesity worldwide: international survey; 2000. 25. Liberati A, Altman D, Tezlaff J, Mulrow C, Gotzsche P, Ioannidis J, et al. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate healthcare interventions: explanation and elaboration. BMJ. 2009;339:b2700. 26. Higgins J, Green S, (editors). Cochrane Handbook for Systematic Reviews of Interventions: The Cochrane Collaboration; 2011.

References 17

APPENDIX A

PRISMA flow diagram

PRISMA 2009 Flow Diagram

Records identified through Additional records identified

database searching through other sources

(n = ) (n = )

Identification

Records after duplicates removed (n = )

Records screened Records excluded (n = ) (n = )

Screening

Full-text articles Full-text articles assessed for eligibility excluded, with reasons (n = ) (n = )

Eligibility Studies included in qualitative synthesis (n = )

Studies included in

quantitative synthesis

(meta-analysis)

Included (n = )

Appendix A i

APPENDIX B

PRISMA checklist

Reported on page Section/topic # Checklist item # TITLE Title 1 Identify the report as a systematic review, meta-analysis, or both. Title page ABSTRACT Structured summary 2 Provide a structured summary including, as applicable: background; objectives; data sources; study eligibility criteria, participants, and interventions; study appraisal and synthesis methods; results; limitations; conclusions and implications of key findings; systematic review registration number. INTRODUCTION Rationale 3 Describe the rationale for the review in the context of what is already known. Objectives 4 Provide an explicit statement of questions being addressed with reference to participants, interventions, comparisons, outcomes, and study design (PICOS). METHODS Protocol and 5 Indicate if a review protocol exists, if and where it can be accessed (e.g., Web address), registration and, if available, provide registration information including registration number. Eligibility criteria 6 Specify study characteristics (e.g., PICOS, length of follow-up) and report characteristics (e.g., years considered, language, publication status) used as criteria for eligibility, giving rationale. Information sources 7 Describe all information sources (e.g., databases with dates of coverage, contact with study authors to identify additional studies) in the search and date last searched. Search 8 Present full electronic search strategy for at least one database, including any limits used, such that it could be repeated. Study selection 9 State the process for selecting studies (i.e., screening, eligibility, included in systematic review, and, if applicable, included in the meta-analysis). Data collection process 10 Describe method of data extraction from reports (e.g., piloted forms, independently, in duplicate) and any processes for obtaining and confirming data from investigators.

Appendix B i

Reported on page Section/topic # Checklist item # Data items 11 List and define all variables for which data were sought (e.g., PICOS, funding sources) and any assumptions and simplifications made. Risk of bias in 12 Describe methods used for assessing risk of bias of individual studies (including individual studies specification of whether this was done at the study or outcome level), and how this information is to be used in any data synthesis. Summary measures 13 State the principal summary measures (e.g., risk ratio, difference in means). Synthesis of results 14 Describe the methods of handling data and combining results of studies, if done, including measures of consistency (e.g., I2) for each meta-analysis. Risk of bias across 15 Specify any assessment of risk of bias that may affect the cumulative evidence (e.g., studies publication bias, selective reporting within studies). Additional analyses 16 Describe methods of additional analyses (e.g., sensitivity or subgroup analyses, meta- regression), if done, indicating which were pre-specified. RESULTS Study selection 17 Give numbers of studies screened, assessed for eligibility, and included in the review, with reasons for exclusions at each stage, ideally with a flow diagram. Study characteristics 18 For each study, present characteristics for which data were extracted (e.g., study size, PICOS, follow-up period) and provide the citations. Risk of bias within 19 Present data on risk of bias of each study and, if available, any outcome level studies assessment (see item 12). Results of individual 20 For all outcomes considered (benefits or harms), present, for each study: (a) simple studies summary data for each intervention group (b) effect estimates and confidence intervals, ideally with a forest plot. Synthesis of results 21 Present results of each meta-analysis done, including confidence intervals and measures of consistency. Risk of bias across 22 Present results of any assessment of risk of bias across studies (see Item 15). studies Additional analysis 23 Give results of additional analyses, if done (e.g., sensitivity or subgroup analyses, meta- regression [see Item 16]). DISCUSSION

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Reported on page Section/topic # Checklist item # Summary of evidence 24 Summarize the main findings including the strength of evidence for each main outcome; consider their relevance to key groups (e.g., healthcare providers, users, and policy makers). Limitations 25 Discuss limitations at study and outcome level (e.g., risk of bias), and at review-level (e.g., incomplete retrieval of identified research, reporting bias). Conclusions 26 Provide a general interpretation of the results in the context of other evidence, and implications for future research. FUNDING Funding 27 Describe sources of funding for the systematic review and other support (e.g., supply of This project was data); role of funders for the systematic review. funded by Danone Institute International

Appendix B iii

APPENDIX C

Quality Assessment Tools

Cochrane Risk of Bias Tool

STUDY DETAILS (citation): 5.1.1 Domain Description (provide evidence from text and any further comments) Judgement

Adequate sequence generation Was the allocation sequence Yes Unclear No adequately generated?

Allocation concealment Was allocation adequately Yes Unclear No concealed?

Blinding Was knowledge of the allocated interventions Yes Unclear No adequately prevented during the study?

Incomplete outcome data addressed Were incomplete outcome Yes Unclear No data adequately addressed?

Free of selective reporting Are reports of the study free Yes Unclear No of suggestion of selective outcome reporting?

Free of other bias Was the study apparently free of other problems that could Yes Unclear No put it at a high risk of bias?

Adapted from Higgins JPT, Green S (editors). Cochrane Handbook for Systematic Reviews of Interventions Version 5.0.2 [updated September 2009]. The Cochrane Collaboration, 2009. Available from www.cochrane-handbook.org.

Appendix C i

Cohort Studies

Trial ID: Details Is there sufficient description of the groups and the distribution of prognostic factors? Are the groups assembled at a similar point in their disease progression? As the intervention/treatment reliable ascertained? Were the groups comparable on all important confounding variables? Was there adequate adjustment for the effect of these confounding variables? Was a dose response relationship between intervention and outcome demonstrated? Was outcome assessment blind to exposure status? Was follow-up long enough for the outcomes to occur? What proportion of the cohort was followed up? Were drop-out rates and reasons for dropout similar across intervention and unexposed groups?

Case Control studies

Trial ID: Details Is the case definition explicit? Has the disease state of the cases been reliably assessed and validated? Were the controls randomly selected from the source of population of the cases? How comparable are the cases and controls with respect to potential confounding factors? Were interventions and other exposures assessed in the same way for case and controls? How was the response rate defined? Were the non response rates and reasons for non response the same in both groups?

Is it possible that over matching has occurred in that cases and controls were matched on factors relating to exposure?

Was an appropriate statistical analysis used (matched or unmatched)?

Appendix C ii