Low FODMAP Diet in the Treatment of Irritable Bowel Syndrome: A Systematic Review and Meta-Analysis

s identified during literature search were screened and potentially eligible articles 127 were read in full to determine whether they met eligibility criteria. 128 129 Data extraction and management 130 Data on patients (e.g. age, diagnosis), methods (e.g. randomization, allocation concealment), 131 interventions (e.g. duration, administration of diet, dietary adherence), control interventions 132 (e.g. type, co-interventions, outcomes (e.g. outcome measures, assessment time points) and 133 results were extracted independently by two authors using an a-priori developed data 134 M AN US CR IP T AC CE PT ED ACCEPTED MANUSCRIPT 5 extraction form. Discrepancies were discussed with a third review author until consensus 135 was reached. If necessary, the study authors were contacted for additional information. 136 137 Risk of bias in individual studies 138 Two authors independently assessed risk of bias using the risk of bias tool proposed by the 139 Cochrane Collaboration [7]. This tool assesses risk of bias on the following domains: 140 selection bias, performance bias, attrition bias, reporting bias, and detection bias using 12 141 criteria. Risk of bias was assessed for each criterion as 1) low risk of bias, 2) unclear, 3) high 142 risk of bias. Discrepancies were discussed with a third review author until consensus was 143 reached. 144 145 Data analysis 146 Assessment of effect size 147 If at least 2 studies assessing a specific outcome were available, meta-analyses were 148 conducted using Review Manager 5 software (Version 5.1, The Nordic Cochrane Centre, 149 Copenhagen) by a random effects model [10] using the generic inverse variance method. For 150 continuous outcomes, standardized mean differences (SMDs) with 95% confidence intervals 151 (CIs) were calculated as the difference in means between groups divided by the pooled 152 standard deviation (SD). SMDs were calculated as Hedge’s g using a standardized Excel 153 spreadsheet. For dependent samples (ie, crossover trials), the calculation was adapted for 154 intercorrelations between groups. Where no correlation was reported, it was estimated as 155 0.7. Where no SDs were available, they were calculated from standard errors, CIs, or t156 values, or attempts were made to obtain the missing data from the trial authors by e-mail. A 157 negative SMD was defined to indicate beneficial effects of the low FODMAP diet compared 158 with the control intervention for all outcomes (eg, decreased gastrointestinal symptoms) 159 except for quality of life where a positive SMD was defined to indicate beneficial effects (ie, 160 increased quality of life). Cohen’s categories were used to evaluate the magnitude of the 161 overall effect size as follows: SMD of 0.2 to 0.5, small; SMD of 0.5 to 0.8, medium; and SMD 162 greater than 0.8, large effect sizes. 163 164 Assessment of heterogeneity 165 The I statistics, a measure of how much variance between studies can be attributed to 166 differences between studies rather than chance, was used to analyze statistical 167 heterogeneity between studies. The magnitude of heterogeneity was categorized as I=0168 25%: low heterogeneity; I=26-50%: moderate heterogeneity; I=51-75%: substantial 169 heterogeneity; and I=76-100%: considerable heterogeneity. [7, 13] The Chi test was used to 170 assess whether differences in results were compatible with chance alone. Given the low 171 M AN US CR IP T AC CE PT ED ACCEPTED MANUSCRIPT 6 power of this test when only few studies or studies with low sample size are included in a 172 meta-analysis, a P-value ≤ 0.10 was regarded to indicate significant heterogeneity [7]. 173 174 Sensitivity analyses 175 To test the robustness of significant results, sensitivity analyses were conducted for studies 176 with high versus low risk of bias at the following domains: selection bias (random sequence 177 generation and allocation concealment), detection bias (blinding of outcome assessment), 178 and attrition bias (incomplete outcome data). If present in the respective meta-analysis, 179 subgroup and sensitivity analyses were also used to explore possible reasons for statistical 180 heterogeneity. 181 182 RESULTS 183 Literature search 184 The literature search retrieved 179 records, of which 113 non-duplicate records were 185 screened and 105 records were excluded because they did not use a RCT design and/or low 186 FODMAP diet was not an intervention. One further RCT was excluded as it used the low 187 FODMAP diet only to wash-out symptoms in the initial stage of the investigation on the 188 effects of diets high or low in gluten [14]. Nine full-text articles (RCTs) with a total of 596 189 subjects were finally included for qualitative analysis [15-23]. One randomized cross-over 190 trial was excluded from quantitative synthesis as data was not displayed as mean and SD 191 and further information from the authors could not be retrieved [24]. Of those, 561 patients 192 matched the intervention criteria and were included in the meta-analysis (Figure 1). 193 194 Study characteristics 195 Characteristics of the sample, interventions, outcome assessment and results are shown in 196