Evidence-Based Research in Pediatric Nutrition
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Description

Recognition of evidence-based medicine is not only increasing rapidly, but it has become essential to pediatric nutrition. Starting with some methodological issues - discussing systemic reviews, meta-analyses and clinical trials - this publication then concisely summarizes current knowledge as well as ignorance and uncertainty regarding selected aspects of childhood nutrition. These aspects include functional gastrointestinal disorders, issues concerning various kinds of milk, complementary foods, enteral nutrition, celiac disease or obesity. Contents are based on evidence and summarize current guidelines; moreover, when there is no clear evidence, they provide some food for thought.

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Date de parution 12 septembre 2013
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EAN13 9783318024579
Langue English
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Evidence-Based Research in Pediatric Nutrition
World Review of Nutrition and Dietetics
Vol. 108
Series Editor
Berthold Koletzko Munich
Evidence-Based Research in Pediatric Nutrition
Volume Editors
Hania Szajewska Warsaw
Raanan Shamir Petach-Tikva
4 figures, and 8 tables, 2013
_______________________ Prof. Hania Szajewska The Medical University of Warsaw Department of Paediatrics Warsaw, Poland
_______________________ Prof. Raanan Shamir Institute of Gastroenterology, Nutrition and Liver Diseases Schneider Children's Medical Center Sackler Faculty of Medicine, Petach-Tikva Sackler Faculty of Medicine, Tel-Aviv University Tel-Aviv, Israel
Library of Congress Cataloging-in-Publication Data
Evidence-based research in pediatric nutrition / volume editors, Hania Szajewska, Raanan Shamir.
p.; cm. –– (World review of nutrition and dietetics, ISSN 0084-2230 ; vol. 108)
Includes bibliographical references and indexes.
ISBN 978-3-318-02456-2 (hard cover: alk. paper) –– ISBN 978-3-318-02457-9 (electronic version)
I. Szajewska, Hania, editor of compilation. II. Shamir, Raanan editor of compilation. III. Series: World review of nutrition and dietetics; v. 108. 0084-2230
[DNLM: 1. Child Nutritional Physiological Phenomena. 2. Diet Therapy. 3. Evidence-Based Medicine. 4. Food. W1 WO898 v.108 2013 / WS 130]
RJ53.P37
615.8'548083––dc23
2013025761
Bibliographic Indices. This publication is listed in bibliographic services, including Current Contents ® and PubMed/MEDLINE.
Disclaimer. The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publisher and the editor(s). The appearance of advertisements in the book is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
Drug Dosage. The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any change in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
© Copyright 2013 by S. Karger AG, P.O. Box, CH-4009 Basel (Switzerland)
www.karger.com
Printed in Germany on acid-free and non-aging paper (ISO 9706) by Stückle Druck, Ettenheim
ISSN 0084-2230
e-ISSN 1662-3975
ISBN 978-3-318-02456-2
e-ISBN 978-3-318-02457-9
Contents
List of Contributors
Preface
Szajewska, H. (Warsaw); Shamir, R. (Petach-Tikva)
Methodological Considerations
Importance of Systematic Reviews and Meta-Analyses in Pediatric Nutrition
Szajewska, H. (Warsaw)
Strengths and Weaknesses of Observational Nutritional Studies
Patro-Gołąb, B.; Szajewska, H. (Warsaw)
Scientific Standards for Human Intervention Trials Evaluating Health Benefits of Foods, and Their Application to Infants, Children and Adolescents
Woodside, J.V. (Belfast); Koletzko, B.V. (Munich); Patterson, C.C. (Belfast); Welch, R.W. (Coleraine)
Impact of Early Nutrition on Later Outcomes
Early Nutrition and Health: Short- and Long-Term Outcomes
Gruszfeld, D.; Socha, P. (Warsaw)
Issues in Infant Feeding
Probiotics, Prebiotics, and Dietary Fiber in the Management of Functional Gastrointestinal Disorders
Horvath, A.; Szajewska, H. (Warsaw)
Growing-Up Milk: A Necessity or Marketing?
Przyrembel, H. (Berlin); Agostoni, C. (Milan)
Cow's Milk and Goat's Milk
Turck, D. (Lille)
The Timing of Introduction of Complementary Foods and Later Health
Agostoni, C. (Milan); Przyrembel, H. (Berlin)
Dietary Interventions for Primary Allergy Prevention – What Is the Evidence?
von Berg, A. (Wesel)
Vitamin and Mineral Supplementation of Term Infants: Are They Necessary?
Lubetzky, R.; Mandel, D.; Mimouni, F.B. (Tel-Aviv)
Issues in Nutrition of Children
Enteral Nutrition
Kolaček, S. (Zagreb)
Celiac Disease- Prevention Strategies through Early Infant Nutrition
Chmielewska, A.; Szajewska, H. (Warsaw); Shamir, R. (Petach-Tikva)
Interventions for Treating Obesity in Children
De Miguel-Etayo, P.; Bueno, G.; Garagorri, J.M.; Moreno, L.A. (Zaragoza)

Author Index
Subject Index
List of Contributors
Carlo Agostoni
Pediatric Clinic 2
Department of Clinical Sciences and Community Health
University of Milan
Fondazione IRCCS Cà Granda-Ospedale
Maggiore Policlinico
Via della Commenda, 9
IT-20122 Milan (Italy)
Gloria Bueno
GENUD (Growth, Exercise, NUtrition and
Development) Research Group
Department of Paediatrics
Faculty of Medicine
University of Zaragoza, Zaragoza (Spain)
C/Domingo Miral s/n
ES-50.009 Zaragoza (Spain)
Anna Chmielewska
Department of Paediatrics
The Medical University of Warsaw
Dzialdowska 1
PL-01-184 Warsaw (Poland)
Pilar De Miguel-Etayo
GENUD (Growth, Exercise, NUtrition and
Development) Research Group
Department of Physiatry and Nursing
Faculty of Health Sciences
Department of Paediatrics
Faculty of Medicine
University of Zaragoza, Zaragoza (Spain)
C/Domingo Miral s/n
ES-50.009 Zaragoza (Spain)
Jesús M. Garagorri
GENUD (Growth, Exercise, NUtrition and
Development) Research Group
Department of Paediatrics
Faculty of Medicine
University of Zaragoza, Zaragoza (Spain)
C/Domingo Miral s/n
ES-50.009 Zaragoza (Spain)
Dariusz Gruszfeld
Neonatal Intensive Care Unit
Children's Memorial Health Institute in Warsaw
Al. Dzieci Polskich 20
PL-04-730 Warsaw (Poland)
Andrea Horvath
Department of Paediatrics
The Medical University of Warsaw
Dzialdowska 1
PL-01-184 Warsaw (Poland)
Sanja Kolaček
University Department of Paediatrics
Referral Center for Paed. Gastro & Nutrition
Children's Hospital Zagreb
Klaiceva 16
HR-10000 Zagreb (Croatia)
Berthold V. Koletzko
Division of Metabolic and Nutritional Medicine
Dr von Hauner Children's Hospital
University of Munich Medical Centre
Lindwurm Strasse 4
DE-80337 Munich (Germany)
Ronit Lubetzky
Department of Pediatrics
Tel Aviv-Sourasky Medical Center
6 Weizman Street
IL-64239 Tel-Aviv (Israel)
Dror Mandel
Department of Neonatology
Tel Aviv-Sourasky Medical Center
6 Weizman Street
IL-64239 Tel-Aviv (Israel)
Francis B. Mimouni
Department of Pediatrics
Tel Aviv-Sourasky Medical Center
6 Weizman Street
IL-64239 Tel-Aviv (Israel)
Luis A. Moreno
GENUD (Growth, Exercise, NUtrition and
Development) Research Group
Department of Physiatry and Nursing
Faculty of Health Sciences
C/Domingo Miral s/n
ES-50.009 Zaragoza (Spain)
Bernadeta Patro-Gołąb
Department of Paediatrics
The Medical University of Warsaw
Dzialdowska 1
PL-01-184 Warsaw (Poland)
Chris C. Patterson
Centre for Public Health
Queen's University Belfast
Institute of Clinical Sciences B
Grosvenor Road
Belfast BT12 6BJ (UK)
Hildegard Przyrembel
Bolchener Str. 10
DE-14167 Berlin (Germany)
Raanan Shamir
Institute of Gastroenterology, Nutrition and
Liver Diseases
Schneider Children's Medical Center of Israel
Professor of Pediatrics, Sackler Faculty of
Medicine, Tel-Aviv University
14 Kaplan St.
IL-49202 Petach-Tikva (Israel)
Piotr Socha
Department of Gastroenterology, Hepatology
and Immunology
Children's Memorial Health Institute in Warsaw
Al. Dzieci Polskich 20
PL-04-730 Warsaw (Poland)
Hania Szajewska
Department of Paediatrics
The Medical University of Warsaw
Dzialdowska 1
PL-01-184 Warsaw (Poland)
Dominique Turck
Division of Gastroenterology, Hepatology and
Nutrition
Department of Pediatrics
Jeanne de Flandre Children's Hospital
Lille University Faculty of Medicine
INSERM U995
Avenue Eugène Avinée
FR-59037 Lille cedex (France)
Andrea von Berg
Department of Pediatrics
Marien-Hospital Wesel
Pastor-Janssen-Str. 8-38
DE-46483 Wesel (Germany)
Robert W. Welch
Northern Ireland Centre for Food and Health
School of Biomedical Sciences
University of Ulster
Cromore Road
Coleraine BT52 1SA (UK)
Jayne V. Woodside
Centre for Public Health
Queen's University Belfast
Institute of Clinical Sciences B
Grosvenor Road
Belfast BT12 6BJ (UK)
Preface
'All animals are equal but some animals are more equal than others'. This famous quote from George Orwell is relevant to medical research: all studies are equal but some studies are more equal than others. This reflects the hierarchy of evidence, one of the fundamental principles of evidence-based medicine (EBM), which is the topic of this book.
What exactly is EBM? The term ‘EBM’ first appeared in medical journals 21 years ago, i.e. in 1992. David Sackett, one of the pioneers in this field, defined EBM as 'the conscientious, explicit, and judicious use of current best evidence in making decisions about the care of individual patients'.
Since the beginning, EBM has received criticism. Terms such as ‘cookbook medicine’, as well as accusations that EBM denigrates clinical expertise and ignores patient's views, were (and still are) commonly used and voiced by critics. Still, only 15 years after the term appeared, in 2007 the British Medical Journal considered EBM as one of the most important milestones of the last 160 years, along with such achievements as anesthesia, antibiotics, discovery of DNA structure, the pill, sanitation, or vaccines.
Thus, despite the skepticism, recognition of EBM is increasing rapidly, and it is unlikely to disappear. EBM has become essential to pediatric nutrition, hence the decision to dedicate this book to it.
The book starts with some methodological issues. It then summarizes, in a concise manner, current knowledge, but also ignorance and uncertainty, regarding some aspects of childhood nutrition. It does not intend to cover all topics, but it definitely covers the main items. It is based on evidence, summarizes current guidelines, but often, when there is no clear evidence, gives some food for thought.
Evidence, even if of the highest quality, is never enough, which is another fundamental principle of EBM. It will not apply to everyone. The evidence should not be applied blindly. Instead, the clinical decision should be an individual one and should take into account the patient context, including the patient's values regarding specific benefits and harms.
Being up to date with current medical research in order to deliver the best possible care to patients has never been easy, and it is not getting easier. We hope this book will provide a framework from which decisions about pediatric nutrition can be made.
As editors, we would like to thank all contributing authors for their hard work. Without their commitment, this book would not have been possible.
Hania Szajewska , Warsaw Raanan Shamir , Petach-Tikva
Methodological Considerations
Szajewska H, Shamir R (eds): Evidence-Based Research in Pediatric Nutrition. World Rev Nutr Diet. Basel, Karger, 2013, vol 108, pp 1-10 (DOI: 10.1159/000351479)
______________________
Importance of Systematic Reviews and Meta-Analyses in Pediatric Nutrition
Hania Szajewska
Department of Paediatrics, The Medical University of Warsaw, Warsaw, Poland
______________________
Abstract
To address information overload, systematic methods have been developed to identify, assess, and synthesize information. This chapter provides an overview of the basic principles of systematic review and meta-analysis of randomized controlled trials, which are considered to be the best study design for answering questions about the effectiveness of an intervention. It also discusses the problems and limitations of using a meta-analytical approach. As the number of systematic reviews and meta-analyses is increasing rapidly, also in the field of pediatric nutrition, it is essential that the strengths as well as the limitations and caveats of this approach are well understood.
Copyright © 2013 S. Karger AG, Basel
To address information overload, systematic methods have been developed to identify, assess, and synthesize information. Consequently, the number of systematic reviews, with or without a meta-analysis, is increasing rapidly, and they are unlikely to disappear. To the contrary, they continue to gain popularity, also in the field of pediatric nutrition. Currently, they are essential for reliable and accurate summarizing of the evidence on the efficacy and safety of healthcare interventions. Considering this, it is crucial that the strengths as well as the limitations and caveats of this approach are well understood. This chapter provides an overview of the basic principles of systematic review and meta-analysis of randomized controlled trials (RCTs), which are considered to be the best study design for answering questions about the effectiveness of an intervention. It also discusses the problems and limitations of using a meta-analytical approach. Considerations linked to the field of nutrition are briefly discussed.
Narrative Review, Systematic Review, and Meta-Analysis – What Is the Difference?
Traditional narrative reviews, which are still common, usually summarize evidence on a specific topic. However, they do not routinely use systematic methods to identify, assess, and synthesize information, thus, they are prone to bias and error [ 1 ].
Similarly, experts' opinions are not free of potential biases. Experts often disagree with each other, are not explicit, and have strong opinions and little time. In addition, experts frequently do not use systematic methods, and they often disagree with the evidence. All of the systematic and random errors in the assessment of current evidence may be overcome by a systematic approach. Thus, to address the problems with the traditional narrative reviews and experts' opinions, systematic reviews (with or without a meta-analysis) have been developed.
While the two terms, i.e. ‘a systematic review’ and ‘a meta-analysis’, are commonly used interchangeably, there is a distinction between them. A systematic review is 'a review of a clearly formulated question that uses systematic and explicit methods to identify, select and critically appraise relevant research, and to collect and analyze data from studies that are included in the review. Statistical methods may or may not be used to analyze and summarize the results of the included trials' [ 2 ]. A meta-analysis is a name that is given to any review article when statistical techniques are used in a systematic review to combine the results of included trials to produce a single estimate of the effect of a particular intervention [ 2 ].
Why Perform a Systematic Review?
In 2004, Clarke [ 3 ] stated that 'nobody should do a trial without reviewing what is known’. A few years later, he reconfirmed his position by stating that 'clinical trials should begin and end with systematic reviews of relevant evidence’ [ 4 ]. In addition to these clear messages, the main formal objectives of performing a meta-analysis include the following [ 2 ]:
• to increase power, i.e. the chance to reliably detect a clinically important difference if one actually exists,
• to increase precision in estimating effects, i.e. narrow the confidence interval around the effects,
• to answer questions not raised by individual studies,
• to resolve controversies arising from studies with conflicting results, and
• to generate new hypotheses for future studies.
How to Conduct a Systematic Review
Key components needed to conduct a systematic review include: (1) Formulation of the review question (the problem). The use of the acronym PICO is helpful, as the key components of a research question about the effectiveness of an intervention should address the types of participants (P), intervention(s) (I), comparison(s) (C), and outcome(s) (O) of interest. (2) Searching for studies based on predefined inclusion and exclusion criteria. (3) Selecting studies, collecting data, and creating evidence-based tables. (4) Assessing the risk of bias in the included trials. Usually the following criteria generally associated with good-quality studies are evaluated: adequacy of sequence generation, allocation concealment, and blinding of investigators, participants, outcome assessors, and data analysts; intention-to-treat analysis, and comprehensive follow-up (≥80%). (5) Synthesizing data from included studies and meta-analysis, if appropriate. To ensure transparency and reproducibility, each step must be carefully documented. See the Cochrane Collaboration ( www.cochrane.org ) [ 2 ], which developed guidance on conducting a systematic review, for further reading.
Is It Always Appropriate to Pool the Results?
The take-home message is that it is always appropriate to perform a systematic review, and every meta-analysis should be preceded by a systematic review. However, not every systematic review should be finalized with a meta-analysis, in fact it is sometimes erroneous and even misleading to perform a meta-analysis [ 2 ]. While it is unrealistic to expect absolute similarity of all the studies, comparability is needed. In principle, data should only be pooled if they are homogeneous, i.e. the participants, intervention, comparison, and outcome(s) must be similar (homogeneous) or at least comparable [ 2 ].
What Is Heterogeneity?
For a meta-analysis, heterogeneity refers to any kind of variability (diversity) among the studies. It is called ‘clinical heterogeneity’ if it is due to clinical differences, such as differences in the participants, interventions, comparisons, and/or outcomes. Heterogeneity due to variability in study designs is referred to as 'methodological heterogeneity.' One tool to display heterogeneity is the forest plot, the interpretation of which is described below. If significant heterogeneity exists, the reviewers should attempt to identify and explain its potential sources.
How to Interpret a Forest Plot
A forest plot is a graphic display of the results from individual studies together with the combined result. Figure 1 shows an interpretation of a forest plot from a hypothetical meta-analysis comparing the effect of a new infant formula supplemented with a novel ingredient with a standard infant formula for the prevention of the outcome.

Fig. 1. Forest plot from a hypothetical meta-analysis comparing the effect of a new infant formula with a standard infant formula on the risk of an outcome. The relative risk of 0.36 suggests that, compared to use of the standard formula, the use of the new infant formula reduces the risk of the outcome in an infant (64% reduction). CI indicates confidence interval.
Possible Flaws of a Meta-Analysis
Failure to Identify All Relevant Studies
Searching one database is never enough. It is advisable to search at least Medline, EMBASE, and the Cochrane Library. If possible, no restrictions on language should be applied, although a recent study found no evidence of a systematic bias from the use of language restrictions [ 5 ]. At least two reviewers should be involved in order to minimize bias and error during the study searching and selection. The set of key words used for searching should be as complete as possible.
Risk of Bias in Included Trials
Any meta-analysis is only as good as the constituent studies (‘garbage in – garbage out’) [ 6 ]. Often, some of the trials included in the analysis have a number of methodological limitations (i.e. unclear or inadequate allocation concealment, no blinding, no intention-to-treat analysis). Within the nutritional field, one of the hot topics is what is an acceptable loss to follow-up in long-term RCTs. In the context of evidence-based medicine, only a loss of ≤20% is considered acceptable. In the field of nutritional research, the latter has been questioned as unnecessary and unhelpful [ 7 ].
Unpublished Data
Inclusion of unpublished data in a systematic review is a controversial issue [ 8 ]. Evidence exists that studies demonstrating high treatment effects are more likely to be published than studies yielding negative results, and that unpublished studies differ systematically from those that have been published [ 9 , 10 ]. Thus, inclusion of unpublished data reduces the risk of publication bias, defined as the failure to report results of a negative trial. However, it is not without challenges and drawbacks fully reviewed elsewhere [ 2 ].
Inconclusiveness
Inconclusive results, with frustrating statements such as ‘no clear evidence’, ‘some evidence of a trend’, etc., are a frequent problem with systematic reviews or meta-analyses. However, the demonstration of clinical uncertainty about any therapeutic or preventive issue is an important finding [ 11 ]. Clinical uncertainty is a prerequisite for the large-scale RCTs needed to evaluate the influence of such interventions. It also helps to clarify available treatment options and stimulate new and better research. In addition, it allows a more accurate calculation of the sample sizes required in future trials.
Opposite Conclusions
A number of factors may contribute to discordance among systematic reviews addressing the same clinical question and performed at almost the same time by reviewers with the same access to relevant databases, which have been reviewed in detail elsewhere [ 12 ]. In brief, these include differences in the review question (e.g. participants being adults and children or adults only), search strategy (e.g. inclusion or exclusion of unpublished data), data extraction, assessment of study quality (e.g. inclusion of both high- and low-quality studies), and statistical methods used for data synthesis.
Meta-Analysis versus Large RCT
Differences in the results of meta-analyses as compared with the results of large RCTs occur in approximately one third of cases. Currently, it is unclear what should be done when the result of a meta-analysis of many small trials is later contraindicated by the findings of a large RCT [ 13 ]. It seems reasonable that one of the major factors to be considered is the methodological quality of the both the original RCT and the meta-analysis [ 14 ]. If both the small trials and large RCT are of high methodological quality, the results of the small trials are more reliable. Still, the types of participants, interventions, outcomes, and settings, as well as the time when the study was conducted, should be considered among other factors [ 13 ].
Systematic Review of RCTs versus Non-RCTs
The availability of only a small number of RCTs and/or important limitations of RCTs may raise the question of including non-RCTs in analyses. The main reasons to consider including non-RCTs in analyses are as follows: to examine the necessity for undertaking an RCT by summarizing the results of non-RCTs and providing an explicit evaluation of the weaknesses of available non-RCTs; to assess evidence when an RCT design would be unethical (e.g. breastfeeding compared to formula feeding), and to obtain evidence regarding long-term and/or rare outcomes [ 15 ]. If non-RCTs are included, the results should be always interpreted with caution as potential biases, particularly selection bias, are more likely to occur.
Safety Assessment
In general, the methodology for conducting systematic reviews of benefits and safety/ harms overlaps. However, whereas systematic reviews of RCTs are sufficient for providing information regarding the efficacy and short-term safety aspects of these trials, they may be insufficient for providing adequate information about long-term safety and long-term consequences. To adequately address harms, systematic reviews should include evidence from both RCTs and non-RCTs. The inclusion of the latter is to be considered particularly for addressing rare adverse effects, long-term adverse effects, or outcomes unknown when the RCTs were performed [ 16 ].
Overviews of Reviews
The increasing number of individual reviews has led to the development of systematic reviews (or overviews) of reviews. Methods used to systematically identify and critically appraise published and unpublished systematic reviews have been developed [ 17 ]. In principle, the methodology is similar to that used for systematic reviews of interventions; however, overviews include reviews rather than primary RCTs. One of the strengths of these overviews is that they allow the comparison of the findings of separate reviews, thus, provide healthcare professionals a better background for decision-making. One recent example of such a review is the document on the prevention of eczema in infants and children summarizing evidence from Cochrane and non-Cochrane reviews [ 18 ].
Are Systematic Reviews Original Research?
Critics frequently consider systematic reviews as secondary research. A recent survey of editors of core clinical journals found that most of them regarded systematic reviews as original research (although the conclusions might be hampered by a 45% non-responder rate) [ 19 ].
How to Report
Poor reporting of any research may diminish its potential usefulness. Thus, efforts have been made to improve the quality of reporting, and formal requirements for reporting systematic reviews and meta-analyses have been developed. The editors now require that authors follow the PRISMA (Preferred Reporting Items for Systematic reviews and Meta-Analyses) guidelines. The PRISMA statement consists of a 27-item checklist and a four-phase flow diagram (for details, see Liberati et al. [ 20 ] and the associated website ( www.prisma-statement.org/ )), and it is an evolution of the original QUOROM guideline.
Assessing the Validity of a Systematic Review
Critical appraisal of systematic reviews and meta-analyses involves answering a number of questions. Three principal questions are as follows: (i) Is the review valid? (ii) What are the results? (iii) What is the applicability of the results to your patients or setting? See table 1 for ten detailed questions for critical appraisal of a systematic review.
Issues Related to Systematic Reviews in the Field of Nutrition
Lichtenstein et al. [ 21 ] summarized, on behalf of the US Agency for Healthcare Research and Quality, issues related to conducting nutrition-related systematic reviews. Whereas not all of these issues are applicable to pediatric nutrition, especially to infant nutrition, they are important for consideration. In brief, these issues include: (1) baseline exposure to the nutrients of interest, either from food and/or supplement intake, or, in certain cases, endogenous synthesis (e.g. vitamin D, vitamin K); (2) nutrient status of an individual or population; (3) bioequivalence of different chemical forms of nutrients; (4) bioavailability of different chemical forms of nutrients; (5) bioavailability of nutrients; (6) multiple and interrelated biological functions of a nutrient; (7) undefined nature of the nutrient intervention, and (8) uncertainties in assessing doseresponse relationships.
Table 1. Questions for rapid critical appraisal of a systematic review [data taken from 22 ]

Conclusion
In the hierarchy of research designs, the results of a systematic review, with or without a meta-analysis, are considered to be the evidence of the highest grade. If available, systematic reviews and meta-analyses should be used in support of clinical decision-making. However, similar to all others types of research, systematic reviews and meta-analyses have both strengths and limitations. It is essential that both are well understood.
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Prof. Hania Szajewska, MD Department of Paediatrics The Medical University of Warsaw Dzialdowska 1, PL-01-184 Warsaw (Poland) E- Mail hania@ipgate.pl
Methodological Considerations
Szajewska H, Shamir R (eds): Evidence-Based Research in Pediatric Nutrition. World Rev Nutr Diet. Basel, Karger, 2013, vol 108, pp 11-17 (DOI: 10.1159/000351480)
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Strengths and Weaknesses of Observational Nutritional Studies
Bernadeta Patro-Gołąb Hania Szajewska
Department of Paediatrics, The Medical University of Warsaw, Warsaw, Poland
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Abstract
Observational studies, which are often performed, play a meaningful role in nutritional research. They provide the best answers to questions regarding prevalence, prognosis, diagnosis, and treatment harms. Moreover, they generate hypotheses and prompt further, adequately designed research. However, despite their many advantages, observational nutritional studies have important limitations. These are factors that are strictly bound to the specific study design, nutrition-related, or performance-quality dependent. Potential advantages and disadvantages determine each study's strengths and weaknesses. Thus, knowledge of these advantages and disadvantages is crucial for proper planning, satisfactory study performance, and reasonable interpretation of the results.
Copyright © 2013 S. Karger AG, Basel
The term ‘observational study’ itself suggests the character of the research applied. By passive observation, without interference from a participant's exposure, the investigator draws final conclusions. Historically, some careful observations in the area of nutrition have led to scientific findings of great importance. One such example is the identification of wheat as a possible trigger of celiac disease made by the Dutch pediatrician, Willem-Karel Dicke. He started to consider wheat as a trigger after a single case report of a mother who observed improvement in the health of her child suffering from celiac disease following removal of bread from the diet. Later, again based on observations, he reported that a shortage of bread in the Netherlands during World War II led to a significant improvement among patients affected by celiac disease, which was followed by deterioration after the war, when bread became easily available [ 1 ].
This paper briefly reviews methodological issues associated with observational studies, including their strengths and limitations. Considerations linked to the field of nutrition are briefly discussed.
When Do You Perform Observational Studies?
The place for observational studies in general research, including that related to the nutritional field, is clearly dependent on the scientific question being asked. According to the Oxford Centre for Evidence-Based Medicine [ 2 ], undertaking an observational study is the method of choice for answering questions regarding prevalence ('How common is the problem?') , diagnosis ('Is this diagnostic or monitoring test accurate?') , prognosis ('What will happen if we do not add a therapy?') , and treatment harms ('What are the common harms?') [ 2 ]. High-quality systematic reviews of these types of studies obviously override a single study [ 2 ].
Observational studies (as lower-level evidence) also play a role in hypothesis generating and prompting further, adequately designed research. There are also some circumstances when a theoretically experimental study/randomized controlled trial is the optimal study design (such as for questions about the effectiveness of an intervention); however, in practice, an observational study turns out to be superior or even the only possible solution in some cases [ 3 ]. For example, randomization to formula feeding versus breastfeeding is unfeasible and unethical. Other reasons to consider performing observational studies include the analysis of long-term outcomes, the need for a large sample size to evaluate interventions for the prevention of rare events, and the dramatic effect of an intervention that, therefore, is unlikely to be biased by confounding factors [ 2 , 3 ].
A recent paper by Ortiz-Moncada et al. [ 4 ] provides an idea of how far observational studies permeate nutritional research. The authors analyzed original articles published in five journals dedicated to nutrition (i.e. American Journal of Clinical Nutrition, European Journal of Clinical Nutrition, Journal of Nutrition, European Journal of Nutrition , and Public Health Nutrition) between January and June 2007. The analysis showed that 68.2% of the papers presented the results of observational studies compared to 31.8% of the papers that presented the results of experimental trials. The cross-sectional study was the most frequent design among all types of observational studies. A lack of descriptive studies was observed.
Classification of Observational Studies
Although different classifications of study designs exist, in general there are two major types of observational studies. These are descriptive and analytical studies ( fig. 1 ). Some of the observational study designs can combine elements from different study designs and, therefore, no label can be applied to them. Each study design has its strengths and limitations, mainly in relation to the potential to establish causality. Generally, the strengths and weaknesses of observational studies related to nutrition can be (a) design-specific, (b) nutrition-related, and (c) performance-quality dependent (based on how they are conducted and even reported).

Fig. 1. Types of observational studies adapted from Oxford CEMB [ 6 ] and the algorithm by Grimes and Schulz [ 9 ].
Design-Specific Advantages and Disadvantages of Observational Studies
Descriptive Observational Studies
The role of descriptive studies (i.e. case report, case series report, cross-sectional study, surveillance, ecological correlational studies) is to report the occurrence of a condition in a population/individual, however without quantifying the relationship between variables [ 5 , 6 ]. The lack of a control group is a characteristic feature of these types of studies. In general, their advantages include low cost, relative ease to perform, and usually no ethical problems to address [ 3 , 5 ]. In addition, descriptive studies allow one to analyze the trend and plan healthcare interventions, and they are useful in hypothesis generating [ 5 ]. The main disadvantage of descriptive studies is that the observed associations usually do not allow one to establish causality [ 5 ].
Analytical Observational Studies
These studies aim to quantify the relationship between an exposure and an outcome by comparison of groups (exposed and unexposed) [ 6 ]. Based on the time point when the outcome is determined, this group includes three main types of studies: cohort studies, case-control studies, and cross-sectional studies.
Cohort Studies
Regardless of the type of cohort study (prospective or retrospective), it always begins with exposure of one group (cohort) and moves on to the outcome, which is assessed in comparison to another, unexposed group. One advantage of cohort studies is that they can provide information not only about the incidence of a disorder but also about the process of the disorder over time [ 7 ]. Cohort studies also allow one to investigate multiple outcomes related to one exposure and do not raise concerns about the temporal sequence between exposure (as a cause of an outcome) and outcome [ 7 ]. This study design is a useful tool when rare exposure is the case [ 7 ]. It also has the ability to reduce survivor bias (important when fatal diseases are considered) and does not raise ethical concerns [ 7 ]. Some important disadvantages include a relatively high risk of selection bias, an often very long duration and the associated problem of loss to follow-up, and high costs (due to the long follow-up) [ 3 , 6 , 7 ]. Cohort studies are also not optimal for evaluating rare diseases (problem of the large sample size) and very distant outcomes (very long study duration) [ 7 ]. Another disadvantage is that it is not possible to establish causality.
Case-Control Studies
A specific outcome and its absence is the starting point for this type of study. By retrospective analysis, the investigator collects information regarding exposure from two groups of participants – those who experienced the outcome in comparison to controls who are outcome-free [ 6 , 8 ]. Case-control studies require relatively moderate financial efforts, less time, and a smaller sample size compared to cohort studies [ 3 , 8 ]. Completeness of follow-up is easy to achieve. These studies might be the method of choice when very rare and/or distant outcomes are the subject of the research question [ 6 ]. However, their results are often affected by recall bias or are dependent on records regarding exposure obtained in the past. They are prone to confounding factors and require a lot of investigator effort to minimize selection bias [ 6 , 8 ]. Casecontrol studies are troublesome when exposure is not frequent. This study design often leaves the question about the sequence of events (exposure and outcome occurrence) unanswered [ 3 , 8 ].
Cross-Sectional Studies
Although a cross-sectional study is often purely descriptive (a simple survey assessing prevalence), it may also be a study that quantifies the relationship between exposure and outcome and, therefore, has an analytical character [ 6 ]. The main feature of a cross-sectional study is that the relationship between a particular condition and some variables in a defined population is assessed at one point in time [ 9 ]. This model, although useful for prevalence assessment, cannot describe the incidence of a disease [ 3 , 10 ]. This type of study is relatively cheap, ethically sound, and not so time-consuming; however, these studies often leave uncertainty about the temporal sequence, making it hard to decide what the cause is and what the effect is [ 3 , 6 , 10 ].
Nutrition-Related Issues
There are some aspects of nutritional (observational and experimental) studies that are strictly associated with nutrition, and they are not necessary with the study design. In general, the major strength of these studies is the importance and great impact of nutritional research on individuals' lives and on the general population, as we all are exposed to nutrition for a lifetime. Nutritional research has been even more significant since we realized the role of diet in the etiologies of many relevant diseases such as cardiovascular disease and cancer. Nutritional studies are also influential because of the modifiable character of our diets.

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