Design of Clinical Trials Evaluating Dietary Interventions in Patients with Functional Gastrointestinal Disorders

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Design of Clinical Trials Evaluating Dietary Interventions in Patients With Functional Gastrointestinal Disorders

Chu K. Yao , BND (Hons)1 , P e t e r R . G i b s o n , M D , F R A C P1 a n d S u s a n J . S h e p h e r d , P h D , M N D , B A p p S c i2

Clear guiding principles for the design and conduct of dietary intervention trials in functional gastrointestinal disorders (FGID) are lacking. This narrative review examines the specifi c challenges associated with the design and reporting in dietary intervention trials. Dietary intervention trials need to address the collinearity between food, nutrients, and bioactive components that obscure the relationship between food and their effects in the gut. Randomized, double-blinded, placebo-controlled studies remain the gold standard for dietary trials, but are limited by diffi culties in adequate masking of study food or inappropriate choice of placebo food/ diets. Provision of study diets as the preferred delivery method can somewhat address these limitations, although allowing good adherence compared with education-based dietary interventions. Issues associated with participant expectancies and dietary behaviors can alter the true effectiveness of a diet. In addition, failure to adjust for or report baseline intake of nutrients of interest can reduce their magnitude of benefi t. Bias in subjective reports and choice of measurement tools can preclude accurate assessment of food-intake data. In the design of elimination and rechallenge studies, suffi cient time period and adequate exclusion of dietary triggers are essential to ensure symptoms are well-controlled before rechallenging. The route and frequency of challenging, design of test food, and/ or placebo should match the aims of the rechallenge phase. Long-term effi cacy data of such therapeutic diets has been poorly documented in most studies. Standardized guidelines that address many of the challenges outlined above are suggested to strengthen the quality of evidence for dietary therapies in FGID.

Am J Gastroenterol 2013; 108:748–758; doi: 10.1038/ajg.2013.77; published online 23 April 2013

INTRODUCTION METHODS Th e process of designing a pharmacological intervention trial A literature search was performed through Medline, CINAHL, is clearly established. Th ere have been numerous publications and PubMed, using the keywords “ diet, ” “ dietary intervention / and guidelines by the Food and Drug Administration and other therapy / management, ” “ feeding studies, ” “ food challenge, ” as well national regulatory bodies made available to improve standards as “ placebo, ” “ blinded, ” “ compliance ” and “ adherence. ” Th e search of design and reporting of these pharmacological trials. For included observational studies, randomized or nonrandomized example, the STROBE Statement provides a structural guide clinical trial designs in both FGID and other clinical areas. Stud- for observational studies, the CONSORT Statement for rand- ies were assessed for their design and administration of dietary omized controlled trials, and the TREND Statement for non- intervention, use of placebo, strategies for blinding, measurement randomized comparative trials ( 1 – 3 ). Although these guiding of compliance, nutritional end-points, if any, and potential risks principles are also applicable to nonpharmacological trials, there for reporting bias. Review papers on pharmacological therapeutic are several concepts that can be diffi cult to implement in dietary trial conducted in FGID were also examined and compared with ROLE OF FOOD IN FUNCTIONAL GASTROINTESTINAL DISORDERS ROLE OF FOOD IN FUNCTIONAL GASTROINTESTINAL DISORDERS studies. Furthermore, no comprehensive reporting guidelines dietary trials for similarities and diff erences. are available for dietary interventions, in general, or specifi - cally for studies in functional gastrointestinal disorders (FGID). Hence, this narrative review aims to discuss methodological COMPARISON OF THE DESIGN OF DIETARY AND challenges and quality of reporting specifi c to dietary interven- DRUG TRIALS tion trials and, subsequently, recommend standardized guide- Th ere are many aspects of clinical trials that are shared by pharma- lines to enhance the quality and acceptability of future trials and ceutical and dietary studies. For example, the success of both inter- their outcomes. ventions are dependent on many factors, including interactions

1 Alfred Hospital, Monash University, Melbourne , Victoria , Australia ; 2 Department of Dietetics and Human Nutrition, La Trobe University, Bundoora, Victoria, Australia . Correspondence: Susan J. Shepherd, PhD, MND, BAppSci, Department of Dietetics and Human Nutrition, La Trobe University, Bundoora, Victoria 3086 , Australia . E-mail [email protected] or [email protected] Received 17 December 2012; accepted 26 February 2013

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between individual dietary components is diffi cult, because of Table 1 . Comparison of methodological considerations between several factors. First, studies that focus on the role of individual drug and dietary trials nutrients in the form of pure supplements may not capture their Drugs Food true eff ects on health as when they are consumed within a diet Chemical effect on Specifi c Multicollinearity ( 7 ). For example, in studies of cardiovascular risk factors, high targets intake of saturated fat is associated with increased low-density Composition Isolated substances with Heterogeneous mixture lipoprotein levels, but this eff ect was not seen with the consump- similar chemical and of nutrients and tion of high-fat dairy products ( 9). When attempting to identify physical characteristics bioactive components food culprits that contribute to adverse symptoms in patients Administration Small dose taken whole Consumed throughout with FGID, it is important to note that other dietary components at defi ned times the day that could be candidates for symptom induction may coexist Baseline exposure Can be absent before Continuous exposure in food. Hence, the attribution of an eff ect in an observational intervention and varying between study may be hazardous. An example is the dilemma regard- persons ing symptom improvement on a gluten-free diet, as gluten and Access No / limited access to Readily accessible fructans coexist in wheat and rye (10,11 ). In addition, informa- study drugs tion obtained in, e.g., case – control surveys of dietary patterns, Placebo Easy to make Diffi cult to design may not adequately capture fl uctuations in dietary intake over Infl uence of Small-to-moderate effect Powerful effect the longer term ( 12 ). Th ese factors alone and in combination can pre-conceived ideas weaken fi ndings of studies that rely upon identifying diff erences Blinding Double-blinding easy Diffi cult and often not in dietary patterns of healthy compared with FGID populations, with placebo pills feasible to double-blind to understand the role of food components in the pathogenesis of FGID.

Dietary intervention trials between the food / drug tested and the patient, the physician and In clinical trials, issues with designing the diet of interest, the physical setting, appropriate selection of the patient cohort, participant expectancies and characteristics, controlling for and and the choice of delivery method or form of intervention ( 4 ). minimizing noncompliance to dietary changes, and measur- However, dietary trials tend to be more reactive to external varia- ing adherence can limit the validity of a research trial. Although bles and design diffi culties in comparison with drug trials. Table 1 randomized, double-blinded, placebo-controlled studies are the summarizes the key diff erences in methodological concepts gold standard for accurate evaluation of successful interventions between drug and dietary trials. in FGID ( 13 ), they are not always achievable in dietary therapies. One of the core complexities of dietary studies is that food com- Th ese design challenges and recommendations for managing prises a diverse mix of nutrients and bioactive components. As these challenges are described below. a combination of whole food and diets are normally consumed, intakes are highly correlated (5 ). Food consumption is further Challenges with participant expectancies and eating behaviors . complicated by dietary behaviors and determinants of these Participants enrolled in a dietary trial can alter trial outcomes behaviors. signifi cantly via the strong infl uence of preconceived ideas. For Furthermore, a dietary component can have functional roles in example, food taboos or, conversely, the perception of comfort several physiological pathways. If dietary eff ects exerted on another or curative properties of a food can stimulate a physiological re- pathway are not captured, an inaccurate picture of its true eff ects sponse despite the absence of a biological basis ( 4,14,15 ). In ad- can be shown (6 ). In addition, comprehensive knowledge regard- dition, if subjects have a preconception of perceived intolerance, ing the composition of food is necessary (7 ) to achieve a better it may lead to an incorrect assumption of an inability to tolerate understanding of food and its physiological eff ects. Yet, there are component(s) of a diet. Examples of these are patients with irri- still gaps in our knowledge of food composition, such as the resist- table bowel syndrome and lactose intolerance, who oft en believe ROLE OF FOOD IN FUNCTIONAL GASTROINTESTINAL DISORDERS ant starch content in food (8 ). they are intolerant of all dairy food ( 16 ). Other behavioral determinants of food intake include the setting and style of food. For example, usual eating behaviors may DESIGN OF DIETARY TRIALS AND METHODOLOGICAL be altered if one is observed while eating or if eating in a hospital ISSUES setting ( 17 ). Th e size of meals or portions can also aff ect intake Observational studies ( 18 ). Study participants can be infl uenced by mass media, friends, Th e majority of data regarding the associations between nutri- and health professionals regarding food choices. For example, food ent intake or dietary patterns and the genesis of gastrointestinal high in omega-3 fatty acids may be favored if individuals value symptoms in patients with FGID are derived from observational their anti-infl ammatory properties, and this may subsequently studies. However, the interpretation of evidence for a relationship aff ect study outcomes.

Recommendations food components may have familiar smell, color, or taste, the blinding can be compromised by opening of the capsules by the • Where possible, ensure the setting for collecting data regarding food intake is similar to the patient’s normal environment participant. • Record any food aversions and other food beliefs the • Placebo food: Th ere are diffi culties with using whole food in participant may have, including reasons, to identify any their natural form because of the potential for inherent chemi- response bias cal diversity within the food; e.g., even two of the same variety of apple will vary in their chemical composition owing to several factors, such as variations in ripeness. Some studies have Challenges with the control of background food intake . unsuitably matched test food with a diff erent placebo; e.g., a When performing dietary intervention trials, particularly where whole kiwifruit has been compared with a glucose pill (22 ). In food supplements or food challenges are being evaluated, it is rechallenge studies, the confounding infl uence of other proper- essential to obtain data on the baseline intake of the food or ties within the placebo food may be an issue in triggering gut food component being challenged. A number of studies have symptoms. To overcome this, both test and placebo food can be not eliminated or quantifi ed the nutrient or dietary component manufactured to be identical for taste, texture, and appearance, of interest in the background diet before and / or during the in- but to diff er only in one component. For example, the use of tervention. Th e consequence of this omission may lead to un- muffi ns in evaluating the specifi c eff ects of gluten was achieved certainties regarding amount of food or nutrient (in the absence by using carbohydrate-depleted gluten that had lost function- of any nutritional defi ciencies) required to derive health benefi ts ality — the muffi ns were of similar texture and taste, and the (19 ). Likewise, the background intake of the food component potential confounding eff ects of FODMAPs on triggering gut may infl uence endpoints in the placebo group, especially if the symptoms were avoided ( 10). supplement is being used in amounts that can be obtained from • Placebo diet: Th e design of an appropriate “ sham ” diet is com- food rather than in pharmacological quantities. An example of plicated by the need to counterbalance the removal of a dietary this is the evaluation of the bifi dogenic eff ects of supplemen- component with another constituent to ensure that a similar tation with fructo-oligosaccharides. As prebiotic eff ects are nutritional profi le is kept for both test and placebo diets ( 7 ). observed at amounts readily obtained in the diet, a specifi c eff ect It is important to ensure that the number and groups of food of the supplement may well be lost if the background fructan changed between the two diets should be as closely matched as intake is not considered. Th is may have been responsible for possible ( 23 ), particularly in evaluating the effi cacy of elimina- the absence of eff ect in a study in Crohn’ s disease (20 ). In addition diets. It is also oft en impossible to blind the placebo diet, tion, it is important to document the participant ’ s usual dietary particularly if a dietary intervention is widely known (e.g., a intake and past history of dietary therapies when controlling for gluten-free or high-fi ber diet). In these cases, provision of all baseline intake. For example, many patients with irritable bowel food is required to minimize the eff ect of knowledge and pre- syndrome may have already self-excluded suspected trig- conceptions. Another less satisfactory though practical solution ger food from their baseline diet, and this may contribute to a is to use the representative of a typical diet of the study popula- reduced magnitude or lack of benefi t for an elimination diet ( 21 ). tion to mimic normal eating situations (24 – 26 ). Th erefore, the incorporation of a defi ned run-in period before randomizing participants to a dietary intervention will not only Recommendations adjust for prior dietary habits but will also allow for physical • Choose a placebo that is nonbioactive and preferably has been adaptations to changes in diet. well tolerated in other studies • If utilizing a placebo in the form of a food item, it is desirable (a) to attain taste, texture, aroma, and appearance as close to Recommendations identical to the test food item, and (b) to ensure these diff er in • Usual dietary intake, past history of dietary therapies, whether only one component, i.e., the substance being tested self-implemented or advised by a health professional, and the • If utilizing a placebo in the form of an entire diet, it is prefer- use of supplements need to be documented and considered, to able to supply all the food. It is essential to ensure that the ROLE OF FOOD IN FUNCTIONAL GASTROINTESTINAL DISORDERS ROLE OF FOOD IN FUNCTIONAL GASTROINTESTINAL DISORDERS control for baseline intake number and groups of food changed between the two diets • Intake of the nutrient or food component of interest, should be as closely matched as possible, to achieve similar particularly in the placebo group should be quantifi ed before nutritional profi les and during implementation of the dietary intervention

Challenges with the design and delivery of the placebo diet . Challenges with blinding in dietary intervention trials . A s In dietary studies, the following forms of placebo are commonly alluded to above, successful blinding of interventions are rarely employed. achieved in dietary studies, except in those testing effi cacy of single dietary components. For example, with strict elimination di- • Placebo pill: Th is may be relatively easy to prepare and can be ets, it is diffi cult to blind patients to what they are eliminating, and identical in appearance to the active compound. However, as it is also diffi cult to provide control substitutes for the food they

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eliminate. Furthermore, many studies do not actually report the anxiety levels and negative responses to the intervention, or vice success of dietary blinding, which makes it diffi cult to assess the versa ( 14 ). Th is may be of relevance to the FGID population where strength of the fi ndings ( 27 ). increased stress and anxiety levels can have a major impact on Inadequate blinding can still occur when maximum eff orts are symptom outcomes (36 ). Th is approach may be less suitable in taken to conceal study nutrients in packages or by its appearance. participants who have serious self-perceived food-sensitivity reac- For example, two types of fi ber (insoluble bran and soluble tions. Th e need to monitor psychological well being in such dietary psyllium) and the placebo (rice fl our) were supplied in identical studies may also be warranted. containers to be mixed into yoghurts in a fi ber intervention study As an alternative to providing all food throughout the study, the in patients with irritable bowel syndrome (28 ). Not surprisingly, use of education-based dietary interventions, usually administered 75% of the participants were able to correctly guess the treatment by a dietician (37 ), or a partly controlled diet (i.e., the supply of they received. some food(s) containing the test nutrient) ( 38) can be applied. Several factors can reduce the success of blinding. Th ese might Th is yields a lower quality of evidence, but is easier to implement. include participants accessing information from the internet, For instance, in a fi ber intervention trial, participants might be media, or other health professionals, or having prior nutritional counseled on strategies of how to achieve a high-fi ber intake, or knowledge. Th e behavior of an unblinded investigator must also be fi ber might be hidden in the food and consumed as part of nor- considered, as subjects can be infl uenced by behavioral cues, such mal diet ( 28,39 ). Participants are more likely to achieve the target as the body language of the practitioner, and form beliefs about intake of fi ber in the latter study protocol, but both these types of whether the diet is credible. interventions are limited by the ability of the participant to follow dietary guidelines. Th ey are also limited by large interindividual Recommendations variations in the participant’ s usual intake of the study nutrient • Th e success of dietary blinding should be reported and, therefore, have less control over the exposure to other nutri- • An unblinded practitioner teaching the diets should not tional variables (40 ). evaluate the end points • Specialized teaching skills for the study investigator are Recommendations required to minimize the infl uence of behavioral cues from the investigator on subject’s perception of the sham diet • Closely monitor participants by reviewing food diaries at regular intervals during the intervention, to assess adherence and, if required, arrange for additional consultation with the dietician or research assistant • Where a study involves the participant being provided instruc- Challenges with adherence to the chosen experimental diet tions on how to follow the experimental diet, supportive aids and protocol. Although the choice of delivery of an experimen- may be provided to optimize adherence. Th ese may include tal diet is dependent on the cost and resources available, adher- emphasis on suitable food alternatives rather than purely re- ence to the dietary intervention is the biggest determinant of its moving food from the diet, and the use of pictorials or written eff ectiveness. A controlled feeding trial can be considered the gold information to reinforce understanding • In both feeding- or instruction-based trials, report details standard for producing high-quality evidence, as it not only max- of control and experimental diets, including similarities and imizes participant adherence to the intervention but also mini- diff erences in menu plans and nutritional analyses, for subse- mizes other confounding dietary habits ( 27,29 ). In such trials, all quent studies to reproduce their protocol or at least allow for or most of the background diet is provided and controlled for the reasonable comparison of results entire duration of the study. Th is is particularly suitable for assessing diffi cult-to-implement diets, such as “ a very low-carbohydrate diet ” (26,30 ) or strict elimination diets ( 31,32). When designing Challenges of assessment of dietary adherence . To o l s u s e d controlled feeding trials of more than 2 weeks’ duration, it may to measure dietary adherence, such as subjective reporting and be important to provide food that meets the estimated energy nutritional analysis, can be prone to error. Subjective reports of needs in all participants, as weight changes can impact on other food intake are strongly infl uenced by response bias; subjects may physiological markers ( 33). Previous studies have addressed this provide responses that are considered desirable for the interven- ROLE OF FOOD IN FUNCTIONAL GASTROINTESTINAL DISORDERS by allocating subjects to standard diets varying in energy content tion goals or to obtain perceived approval. For example, partici- (e.g., 8, 10, or 12 MJ / day) according to their requirements ( 34,35 ). pants may give perceived “ healthy ” responses, such as overreport- In addition, discretionary food intake may occur, although most ing fi ber intake or underestimating fat intake ( 41 ). Women and studies do not permit consumption of food not provided by the individuals with a higher body mass index are also more likely intervention (25,26 ). Reducing the likelihood of participants con- to underreport nutritional intake, particularly energy, which un- suming discretionary food items may be reduced by providing a derestimates the intake of dietary component assessed (42 ). Th e list of approved food (with specifi ed amounts / quantities as appro- burden of recording food intake may cause actual changes in eat- priate) for use when eating out ( 35). ing behaviors or normal food consumption ( 43 ). When analyz- Th e only potential limitation to such a study design where all food ing nutritional data, any diff erences in computerized nutritional is provided is that it may diff er substantially from a participant ’ s composition programs need to be considered, as food composi- usual dietary habits, with consequent increase in the participant’ s tion tables may vary according to geographical locations (44 );

e.g., fructose content in food diff er between the nutrient databases Elimination and food challenge studies of Food Standards Australia New Zealand (45 ) and United States Th e principles . A food challenge study comprises the determina- Department of Agriculture ( 46 ). tion of a specifi c induction of symptoms or a surrogate marker An important fi rst step to measure adherence is to defi ne an of a food reaction, such as elevation of a biomarker, by food or accepted defi nition or a classifi cation schedule of adherence, a by food component. Th is is oft en applied to situations where either one that has been validated or is appropriately justifi ed. For symptoms are intermittent with wellness in between attacks. An example, most studies consider adherence as the consumption exception of this is the use of food challenge studies for the assess- of 90– 95 % or more of the provided diet (47,48 ), but this may be ment of post-prandial symptomatology, where a short duration of lower in instruction-based interventions. Th e choice of measure- fasting is incorporated to eliminate symptom triggers before chal- ment tools may also be infl uenced by whether the data collection lenging, such as the assessment of a high-fat meal on symptoms of is retrospective or prospective, and by the frequency of meas- functional dyspepsia ( 54 ). Issues associated with challenge studies uring adherence, such as daily records or a single snapshot of are addressed in the “ rechallenge ” section below. food intake. In general, the symptomatology of FGID is, by defi nition, Consideration must be taken when designing dietary inter- chronic. Th is necessitates an initial “ dechallenge ” phase by the ventions as to the type of measurement tool(s) that will be used. use of an “ elimination diet ” to minimize or alleviate pre-existing Examples of subjective tools are adherence questionnaires (49 ), symptoms, followed by the food challenge, better described as food records, 24-h dietary recall, and dietary histories ( 50 ). Adher- “ rechallenge, ” with the expectation that symptoms will redevelop ence diaries with check boxes of food consumed aft er assessment specifi cally in association with food or with food components to of returned portions have oft en been used in controlled feeding which the subject is intolerant. Th e results of the food challenges trials (19,26 ). Table 2 summarizes the strengths and limitations will ultimately determine the long-term therapeutic diet for the of these subjective tools. Conversely, nutritional biomarkers (such management of the symptoms. Additional studies (if available or as biochemical or serological changes) are not prone to bias from possible) would then be required to determine the pathogenesis of subjective reporting and are useful to correlate reported intake the specifi c reaction (an allergy, hypersensitivity, pharmacological with temporal changes in nutritional status. However, these mark- reaction, or intolerance). Table 3 summarizes some of the factors ers can be infl uenced by physiological factors, such as variations for consideration in the three stages of the elimination – rechallenge in absorption and metabolic pathways. In some instances, such as intervention. the measurement of the tissue content of fatty acids, dietary assessment questionnaires may be more appropriate ( 6 ). Design of the elimination diet phase . As previously described, When collection of dietary data relies heavily on the participant’ s the purpose of an elimination diet is to minimize or abolish the ability to report and recall accurately, clear instructions should patient ’ s symptoms. If the diet does not achieve this, then the pu- be provided with the reporting of food consumed, explaining the tative off ending food is still present, the duration of elimination is reasons for collecting dietary intake and motivating subjects to insuffi cient or the symptoms have little to do with specifi c food. be honest ( 51 ). Food models or photographs may be incorporated Hence, the two major issues in this phase are the design of the diet into questionnaires to reduce recall errors in portion sizes (51 ). and its duration, as outlined in Table 3. Food triggers may be all- For example, the use of computer-administered questionnaires or-none in their eff ects (such as gluten) or dose-dependent (such may be able to incorporate this strategy, particularly for retro- as FODMAPs). Th us, elimination diets may fi t anywhere within spective assessment tools (52 ). Another strategy is to validate the spectrum of one completely devoid of food triggers (such as an self-reported data with measurement of nutritional biomarkers, elemental diet) to one that only reduces the dose of putative trig- where appropriate, as discussed above (33 ). Large variations in gers (such as the low FODMAP diet), through to one that restricts dietary intake data can be reduced by excluding participants with one component only (such as a gluten-free diet). Diets employing implausible nutrient or energy intake during the baseline period total exclusion of potential trigger food may be anticipated to have ( 53 ). Most importantly, the choice of dietary tool needs to be well- a higher rate of symptom resolution. However, issues with diet matched with the aims and design of the nutritional intervention palatability and large drop-out rates are to be anticipated. In ad- ROLE OF FOOD IN FUNCTIONAL GASTROINTESTINAL DISORDERS ROLE OF FOOD IN FUNCTIONAL GASTROINTESTINAL DISORDERS (see Table 2) . dition, the optimal or minimal duration of following the elimination diet is important, as diff erent triggers appear to have diff erent Recommendations “ washout ” periods, as described in Table 3 . • D e fi ne an accepted defi nition or a classifi cation schedule of adherence Recommendations • Th e assessor measuring dietary data should have appropriate • A full defi nition of the structure and duration of the diet is skills in administering dietary assessment tools, to minimize needed interviewer-associated errors, to improve participant’s com- prehension of the questionnaire, and to assist in better recall • Th e drop-out rate during this phase should be reported of dietary information • Nutritional biomarkers may be more useful than dietary assessment tools to determine adherence in some circum- Design of the food challenge phase. In the challenge/ rechallenge stances phase, the goals can be twofold: fi rst, to identify the type of dietary

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Table 2 . Summary of measurement tools for dietary intake and considerations of their strengths and limitations

Method Methodology Advantages Disadvantages

Prospective Direct Consumption observed with known quantities Enables qualitative and quantitative as- Expensive observation of food provided. Quantity of remaining food sessment of nutrients consumed May not refl ect usual intake accounted for to determine fi nal consump- Validates recent reported intake from May induce behavior change tion data other methods Weighed or Written and verbal instructions are given on Requires training of participants Time consuming estimated food how to weigh and record all food and drink Short term intake assessed Burdensome to maintain records consumed for a specifi ed time period — Considered “ gold standard” for Diffi cult to measure food eaten away from 7 days ideal, but 3 days including 1 weekend dietary assessment home accurately day considered representative Food diary Participants trained to record in a prepared Not interviewer-dependent Trained staff required for data analysis diary all food and drink consumed for time Not subject to recall errors Information biased to motivated volunteers period specifi ed (usually 3 – 7 days). Recorded Omission of food may be minimal when May induce behavior change as weight/ volume or household measures conducted properly Requires diligent recording— may be or food models (diagrams pre-provided affected by motivation, literacy describing serving sizes for comparison). Reliability may decrease over time as Reporting must occur at time of consumption. respondent fatigues Interviewer clarifi es entries at end of assessment period Retropsective 24-h diet recall Participants recall all food and drink con- Quantitative assessment of recent Requires specialized nutritional assess- sumed on previous day. Interviewer asks spe- nutrient intake ment skills for interview cifi c questions regarding recipe ingredients, Short-term memory required May not refl ect usual intake food preparation, brand names of commercial Not subject to behavior change bias Less frequently eaten food may not be products. Interview conducted in person or Personal contact for data clarifi cation identifi ed over the telephone (49 ) No literacy requirement of respondent Portion sizes may be diffi cult to ascertain Useful for characterizing the average Does not account for seasonal variations in intake of a group or population, or for nutrient intake classifying individuals into quartiles of Needs repeated measures over period of nutrient intake time to increase accuracy Food frequency Participants asked to record (usually in a Self-administered Requires careful validation questionnaire tick / check box) how frequently individual food Inexpensive and quick May not be applicable to study population (FFQ) items or food groups are consumed. Quanti- Useful for large cohort studies Number of food items ties consumed usually also recorded (49 ) Long-term intake assessed – determines comprehensiveness Captures habitual intake over a longer – too many items may cause confusion period (from 1 month to 1 year) – too few options may cause high Can be used to target or quantify specifi c aggregation of data nutrients or aspects of food intake Quantitative analysis diffi cult Not open-ended Long-term memory required Tendency to overestimate nutrients due to overestimation of frequency of ingestion of a food

component and / or food that provokes gut symptoms and, second, method used for blinding, route of challenge, as well as the design to determine the threshold for symptom induction. of challenge or placebo ingredients ( Table 3), have been poorly ROLE OF FOOD IN FUNCTIONAL GASTROINTESTINAL DISORDERS Th e process of rechallenging an eliminated food or food sub- documented in many food challenge studies, reducing the qual- stance should be done slowly in a step-wise process and in gradual ity of evidence. Open challenges are of poor diagnostic value if doses if the goal is to assess tolerance. A washout period should be they are used on their own to confi rm reactions to food, but can implemented to attain symptom control with the continued elimi- be useful as negative predictors to liberalize long-term dietary nation diet before the next challenge (55 ). Evidence regarding the restrictions (55 ). Special attention should also be given to control ideal frequency of challenges and the period between each chal- for factors that can adversely interact with challenges, such as con- lenge remains obscure. Frequency of challenges must be consid- current medication use, alcohol intake, and physical activity levels ered to minimize the cumulative eff ect of food or food substance ( 58 ). Ultimately, the challenge protocol designed should also be ( 32,56,57 ). practical to implement in a clinical setting. Double-blinded, placebo-controlled food challenges are the A major issue with the measurement of subjective endpoints preferred method to identify food reactions ( 58). However, the of adverse symptoms in patients with FGID is the nocebo eff ect,

Table 3 . The three phases of elimination diet-rechallenge studies

Components of study phase Design considerations Examples Situations used, success, and deﬁ cits in literature

Elimination diet phase Structure and Complete exclusion of large Oligo-antigenic diet Investigation of food allergy or hypersensitivity or defi nition of number of suspect food “ Few foods diet” (dietary staples where a large number of food triggers are suspected diet allowed — meat, rice, fruit (usually ( 54,59,62,63 ) pears), spring water) Defi cits: inconsistencies in food eliminated observed even within the same type of elimination diet (59,63 ) Complete exclusion of whole Elemental or polymeric diet Indicated when symptoms fail to improve with other forms of food. Liquid formula of fully Hydrolysed (usually amino acid) formula elimination, but dietary triggers are suspected or partially digested energy replacing intact or allergenic protein sources Restriction of suspected Low allergenic diet Food with high content of putative triggers (e.g., food food triggers to intake below Low FODMAP diet chemicals, FODMAPs, gluten) substituted with low content threshold likely to cause alternatives symptoms Duration for Determined by: ≥ 1 week Success: low FODMAP diet— greatest symptom control elimination Extent of food exclusion attained after 1 week (65 ) Severity of baseline symptoms ≥ in study population (64 ) 2 – 6 weeks Success: gluten-free diet — 70 % report symptom reduction Previous evidence for optimal after 2 weeks (66,67 ) symptom control 4 – 6 weeks Success: restricted chemical diet— 77 % reported ≥ 50 % improvement ( 55 ) Dietary Validated measures for IBS-severity scale using visual analog Majority of elimination studies in FGID used validated meas- endpoints symptom assessment scales ± adequate relief of global IBS ures ( 21,69 – 71 ) symptoms (68 ) Where possible, incorpo- Rectal sensory threshold (barostat Symptom improvement on IgG4-exclusion diet correlated with rate objective markers for studies) greater tolerance of rectal distension (72 ) improvement Breath hydrogen measurements Reduced breath hydrogen correlated with symptom improvement after low vs. high FODMAP diet (24 ) Objective or arbitrarily pre- 50 % Symptom reduction acceptable as ≥ 50 – 80 % reduction in both global and/ or individual symptoms defi ned criteria specifi ed clinical response ( 68 ) from baseline symptoms (55,69,70,73 ) Defi cits: most dietary trials defi ne improvement as “ asymptomatic” ( 54,74 ) Rechallenge phase Rechallenge Identifi cation of suspect food Open food challenges followed by Success: challenges fi rstly done openly in food groups with aims and double-blinded placebo-controlled food similar “ antigen ” content, then double-blinded placebo-control protocol challenges of food in food groups with positive reactions to reduce burden design Placebo and test food administered at of challenge (54 ) random and on separate days Random challenges of test / placebo on separate days minimized placebo reactions (5% patients had positive reactions to placebo in the study using this protocol) (55 ) Single food challenges in specifi ed order Defi cits: specifi c details of amount of food challenged often not reported (59,75 ) Assessment of threshold Stepwise and gradual reintroduction of 2-week FODMAP challenge— starting dose of 1/ 3 “ average ” → → ROLE OF FOOD IN FUNCTIONAL GASTROINTESTINAL DISORDERS ROLE OF FOOD IN FUNCTIONAL GASTROINTESTINAL DISORDERS for symptom provocation or single food / food component at varying dietary intake for 3 days increased to 2/ 3 for 3 days fi nal tolerance quantities total dose of estimated “ average ” dietary intake for remaining period ( 32 ) Route of challenges Oral Preferred method for evaluation as food is normally ingested arriving in stomach Nasogastric / tube feeding Prevents unblinding due to taste, texture, aroma (57 ) Allows examination of local physiological responses (76 ) Direct methods of administration into Allows objective identifi cation of gastrointestinal food allergy mucosal (e.g., colonic provocation test) reactions ( 77 )

Table 3 continued on following page

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Table 3 . Continued

Components of study phase Design considerations Examples Situations used, success, and deﬁ cits in literature

Food Upper limit or lower limit of 16 g daily intake of gluten challenge for Symptoms induced in 68 % patients with IBS (37 ) challenge normal dietary intake 6 weeks (37 ) amount and frequency Same dose for each challenge “ Allergens ” or hypersensitive reactions The positive diagnostic yield was 6% in one study using this regardless of food type challenge method ( 74 ) Defi cits: this method does not take into account that different foods are consumed in different quantities Washout period for symptoms Short washout period, e.g., ≥ 3 Food chemical challenges ( 55 ) to normalize before next “ symptom-free ” days challenge Longer washout periods, Challenges with food components implicated in immunologic e.g., 1 – 3 weeks or unclear pathways of symptom induction (37,69 ) Control of Form and physical structure Freeze-dried food in capsules Defi cits: does not detect oropharyngeal reactions (78 ) blinding and of food challenge Encapsulation reduces absorption rate and can delay placebo symptoms response Food extracts hidden in food vehicles Good choice of food vehicles, e.g., soups (79), , elemental formula drinks (78) , or gluten or whey in muffi ns ( 37 ) Design of placebo— inert and Potato starch Positive reactions to potato starch occurred in 13% well-tolerated Sucrose subjects (55 ) Glucose Positive reactions to sucrose occurred in 17% participants ( 55 ) Xylose 15 – 63 % subjects reacted to glucose in three studies (54,74 ) No reactions from xylose reported in two studies (69,70 ) Endpoint Validated symptom See above See above assessment measurements or objective endpoint if possible Duration for symptom Observation period for symptoms ranged Gastrointestinal symptoms persisted for median 3 (range 1– 8) assessment after antigen from few hours to few days ( 80 ) days after milk and wheat challenges (11,69,70 ) exposure Modifi ed long-term diet Long-term Complete exclusion of food Food with positive challenges avoided Success rate in three studies: 98– 100 % participants reported protocol with positive reactions. and retested 2 – 3 months later (75 ) symptom improvement (69,71,75 ) Challenges can be repeated Few (n = 2) studies repeated challenges to confi rm positive to eliminate nocebo or reactions ( 59,75 ) confi rm positive challenge Follow-up duration Range of follow-up duration between Adherence to diet decreases with duration of elimination, 4 – 24 months (69,70,75,80 ) but not many report adherence rate ( 71,75)

Design factors for considerations with evidence of success and limitations. a phenomenon defi ned as the worsening of symptoms as a result generation window and, therefore, the optimal duration for end- of negative expectations of being challenged and not from the point assessment. In comparative studies, assessments in healthy content of the placebo food (Table 3). Th is can perhaps explain controls must be taken at the same time points as in the FGID ROLE OF FOOD IN FUNCTIONAL GASTROINTESTINAL DISORDERS some of the inconsistencies in the literature. Lessons from p o p u l a t i o n . studies in food allergy have demonstrated the importance of objective endpoints, such as the measurement of a wheal-size in Recommendations a skin-prick test. • A double-blinded, placebo-controlled challenge protocol is An important consideration is the duration aft er exposure to ideal for identifying adverse food reactions the challenged food for the measurement of endpoints (Table • Th e rechallenging process should be executed in a step-wise 3). Th is will vary depending on what the challenge substance is, process and in gradual amounts dose, patient phenotype, and type of symptom response expected. • An adequate washout period should be implemented to attain symptom control Conducting a pilot study before embarking upon a defi nitive • Frequency of challenges should be designed to minimize the study may be helpful to determine the expected symptom cumulative eff ect of challenge dose

Table 4 . Supplementary checklist for design of dietary intervention trials

Participants 1. Describe baseline characteristics of active treatment and control groups, specifi cally any history of food reactions or perceived intolerances and body weight. Experimental protocol 1. Dietary trial should be registered. 2. Clearly provide rationale for dietary intervention. 3. Describe how pre-intervention dietary intake (of food, nutrient, or other dietary component) was measured. Is a run-in period incorporated to allow for dietary adaptation? 4. Describe steps taken to randomize and ensure blinding of participants and/ or investigators, where possible. 5.Defi ne participant adherence to intervention. a. Describe strategies used to improve adherence. b. Describe the dietary assessment tool(s) used, with justifi cation. State the nutritional program used to analyze data. c. Report on participant compliance rate. d. Are measures taken to exclude data or subjects who are non-adherent? 6. Provide details on controlling confounding factors, such as medication interactions, physical activity. 7. Describe sources of funding and other support (such as supply of food). Experimental diets 1. Defi ne whether all, most or part of the diet is provided to patients. 2. If all or most food provided, give details of types of food (meal plans) and nutritional profi le. a. Give details on how energy balance and nutritional adequacy are ensured. b. Describe the setting in which food was prepared or consumed. c. Is consumption of food not supplied allowed? Provide steps taken to control for discretionary food intake. 3. If no food is provided in the interventional study, explain how diet will be controlled for. a. Give details on similarities and differences of dietary education between intervention and control groups. b. Document qualifi cations of clinical investigators and their roles in relation to intervention. Is there a dietician in the team? c. Who administered the intervention? 4. If intervention involves nutrients or whole food, is the test food physically matched with placebo and how are these consumed? 5. If intervention involves a whole diet, is there a control/ sham diet? a. If not, describe measures to control for placebo responses. b. Apart from dietary component tested, are the test and control diets similar in nutritional content? Discussion of fi ndings 1. Consider issues of multicollinearity with other nutrients, participant expectancies and discuss limitations of tools used. 2. Discuss applicability of research fi ndings to formulating “ real-world ” dietary recommendations.

• Factors that can adversely interact with challenges such as Safety issues concurrent medication use, alcohol intake, and physical activ- Although diet has less of a potential to elicit fatal side eff ects with ity patterns should be considered the exception of food anaphylactic reactions, safety considerations • Measure endpoints in an appropriate time frame aft er exposure still need to be incorporated. For example, in light of restricting • Th e adequacy of blinding, design of the food ingredient and large amounts of food, care should be taken to ensure nutritional its route for challenging, as well as how other confounding adequacy is maintained, particularly for those in the early life infl uences were controlled should be described cycle or with specifi c nutritional needs (33,62 ). Th is is more likely to assist in adherence to the dietary therapy as well as to mimic conditions as in the “ real world, ” to improve application of fi nd- Follow-up phase . Once response to food triggers and / or the tol- ings. Reporting of adverse events in dietary studies should have erance threshold has been established, the next step is to deter- the rigor of that in pharmacological trials, but seldom does. mine the long-term therapeutic diet ( “ modifi ed elimination diet” ) for the management of gastrointestinal symptoms (Table 3 ). Recommendation Th ere is a paucity of long-term data, as several studies do not • Adverse events should be sought and reported report on follow-up data or cease further investigations in pa- ROLE OF FOOD IN FUNCTIONAL GASTROINTESTINAL DISORDERS ROLE OF FOOD IN FUNCTIONAL GASTROINTESTINAL DISORDERS tients whom dietary triggers have been identifi ed (21,59,60 ). Adherence to such diets in the long run is an issue, particularly as signifi cant changes to dietary habits can impact on life- CONCLUSION style and other aspects of well being (61 ). Th e true benefi t of Th e design of dietary studies in patients with FGID has many chal- the elimination diet approach should be judged by its long-term lenges, which have seldom been met in published data. One way effi cacy ( Table 3 ) . to improve such performance is to provide guidelines for the opti- mization of study design, interpretation, and reporting. Suggested guidelines are shown in Table 4. Inadequacies of the design and Recommendations reporting of such trials largely stem from diffi culties in manipu- • Longer-term outcomes should be reported lating the diet, food or their components, blinding, and adher- • Indications of the duration of the need for such dietary restrictions are desirable ence to modifi cation of dietary habits. Translation of nutritional research into practice can also be hindered by the interpretation

The American Journal of GASTROENTEROLOGY VOLUME 108 | MAY 2013 www.amjgastro.com Functional Gastrointestinal Disorders 757

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