This protocol will be reported according to meta-analysis of observational studies in epidemiology guidelines (MOOSE) and preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P) 2015 (15).
Eligibility Criteria of Primary Studies
Inclusion and exclusion criteria
Study type
This systematic review will include prospective and retrospective observational studies that they evaluate the clinical course of ulcerative colitis or/and Crohn’s disease after liver transplantation. No restriction on sample size and language will be applied for primary studies to be included.
Type of participants
All patients with ulcerative colitis or/and Crohn’s disease with any age group, including Adult or pediatrics and either gender, who underwent liver transplantation during the course of their disease, will be included in this study.
Search strategy and literature sources
Search strategy components
We will search PubMed/ MEDLINE, Scopus, WoS (Clarivate Analytics), Embase (Embase.com), from 01.01.1970 to 30.03.2020. In order to extract the near all relevant studies, search component include the diseases (Inflammatory Bowel Disease, Ulcerative Colitis, Crohn’s Disease, Primary Sclerosing Cholangitis and their synonyms) and the intervention (Liver Transplantation), as shown in Table1.
To find the synonyms of search components, thesaurus systems, including Emtree and MeSH, the free text method, the views of experts and also related articles and abstracts will be used.
The other methods used to find relevant studies are manually search in Grey literature (thesis, conference papers, and organizational reports), and contacting the experts to find relevant their unpublished studies and introducing related conferences.
The results of all searches carried out in the various databases and other resources will be collected in Endnote software.
Table 1
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The search strategy used in PubMed/MEDLINE from 01.01.1970 to 30.03.2020
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Number
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Search terms
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1
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((“Idiopathic Proctocolitis”[tiab] OR “Ulcerative Colitis”[tiab] OR “Colitis Gravis”[tiab] OR (“Inflammatory Bowel Disease”[tiab] AND “Ulcerative Colitis Type”[tiab])OR“chronic ulcerative colitis”[tiab] OR “colitis ulcerative”[tiab] OR “colitis ulcerosa”[tiab] OR “colitis ulcerosa chronic”[tiab] OR (colitis[tiab] AND ulcerative[tiab]) OR (Colitis[tiab] AND mucosal[tiab]) OR (colitis[tiab] AND ulcerous[tiab]) OR (Colon[tiab] AND “chronic ulceration”[tiab]) OR “histiocytic ulcerative colitis”[tiab] OR “mucosal colitis”[tiab] OR “ulcerative colorectitis”[tiab] OR “ulcerative procto colitis”[tiab] OR “ulcerative proctocolitis”[tiab] OR “ulcerous colitis”[tiab])
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2
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(“Crohn's Enteritis”[tiab] OR “Regional Enteritis”[tiab] OR “Crohn's Disease”[tiab] OR “Crohns Disease”[tiab] OR “Inflammatory Bowel Disease”[tiab] OR “Granulomatous Enteritis”[tiab] OR Ileocolitis[tiab] OR “Granulomatous Colitis”[tiab] OR “Terminal Ileitis”[tiab] OR “Regional Ileitides”[tiab] OR “Regional Ileitis”[tiab] OR “cleron disease”[tiab] OR “Crohn's disease”[tiab] OR “Crohns disease”[tiab] OR “enteritis regionalis”[tiab] OR (“intestinal tract”[tiab] AND “regional enteritis”[tiab]) OR “morbuscrohn”[tiab] OR “regional enterocolitis”[tiab])
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3
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(“Inflammatory Bowel Disease”[tiab] OR (“Bowel Diseases”[tiab] AND Inflammatory[tiab]) OR “Indeterminate colitis”[tiab] OR “undetermined colitis”[tiab])
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4
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(Cholangitides[tiab] AND Sclerosing[tiab]) OR “SclerosingCholangitides”[tiab] OR “Sclerosing Cholangitis”[tiab] OR (Cholangiitis[tiab] AND Sclerosing[tiab]) OR (Cholangiitides[tiab] AND Sclerosing[tiab])OR“SclerosingCholangiitides”[tiab]OR “SclerosingCholangiitis”[tiab] OR “Primary Sclerosing Cholangitis”[tiab] OR (Cholangitides[tiab] AND “Primary Sclerosing”[tiab]) OR “Primary SclerosingCholangitides”[tiab] OR “Primary SclerosingCholangitides”[tiab] OR (“Sclerosing Cholangitis”[tiab] AND Primary[tiab]) OR (Cholangitis[tiab] AND “Primary Sclerosing”[tiab])
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5
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1 OR 2 OR 3 OR 4
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6
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(liver[tiab] AND transplantation[tiab])OR “Liver Transplantations”[tiab])
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7
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1990/01/01:2019/12/31[dp]
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8
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5 AND 6 AND 7
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Screening and Selection
After the searching process and in the screening stage, two authors (ARS and MM) will review the title and abstract of the studies according to the inclusion and exclusion criteria and will find and extract the relevant studies. The studies with insufficient data in one or more aspects of the inclusion criteria will be excluded and a final decision will be made according to their full text in the subsequent stage.
Eventually, in the next step, two of the authors (ARS and AAK) will review the full text of the studies in order to determine the final studies, independently.
Any discordance in these steps will be resolved by consensus, and if the disagreement is not resolved, the opinion of a third expert (GS) will be used to resolve the case.
Risk of bias assessment in included studies
We will use the Newcastle Ottawa Scale (NOS) for observational studies (for cross-sectional, retrospective and cohort studies) to assess the quality of final included studies. This scale has eight items including parts of selection, comparability and outcome (16).
To investigate the likelihood of a relationship between the quality of the preliminary studies and their results, the methodological quality of the included studies will be independently assessed by three independent authors (ARS, AK and HA). Any inconsistencies will be resolved by consensus, and if no agreement is reached yet again, the case will be resolved by seeking the views of a third expert (GS).
Data extraction
For final included studies, three authors (ARS and GS and HA) will independently extract the following summary data: first author name, study design, country, sample size, demographic variables of the participants, and duration of disease before liver transplantation, follow-up duration after the operation, cytomegalovirus infection, steroid consumption, smoking status, frequency (%) of patients with improvement and frequency (%) of patients with worsening of the course of disease, and use of tacrolimus or cyclosporine medication.
We will provide a summary of data in a table. In the absence of the required statistical data in the original studies, the authors will attempt to contact with their authors to obtain the appropriate data. The study will be eliminated if the author fails to respond to us for three times.
Strategy for data synthesis
The clinical course of the IBD would be evaluated both before and after liver transplantation. Accordingly, the frequency (%) of patients with quiescent disease activity, improvement, or aggravation in disease severity would be assessed based on the data of studies. A battery of scoring systems have been applied in studies to assess the clinical course of IBD including Mayo score (disease activity index), simple clinical colitis activity index, need for hospitalization, need for escalation in medical therapy and Crohn’s disease activity index, specifically for those with CD (3, 10, 12). Considering the lack of mean value and standard deviation of the scores in all relevant studies, and diversity of use of different score base instruments, we would include the frequency (%) of the patients in remission or exacerbation after LT.
The result of the final original studies will be appeared concisely in a table encompassing the first author’s name, year of publication, study design and the sample size and demographic data of the participants.
Statistical analysis
The pooled frequency (%) for improved and exacerbated patients after transplantation, as a key measure, will be calculated in this study. The combination method will be based on methodological similarities in the included studies by the Fixed Effect Model or the Random Effect Model. If meta-analysis is not possible due to sever methodological heterogeneity, a narrative qualitative discussion based on findings from individual studies will be presented. Forest plots will be plotted for all the studies to show the separated and pooled frequency and their corresponding 95% CIs. The software used in the present study will be Stata V.14.1 (Stata Corp, college station, TX, USA).
Assessment of heterogeneity
The Q-statistic test and I2 statistics and their corresponding 95% CIs will be used to assess the statistical heterogeneity of the frequency (%) values in the included studies. The following references according to Cochrane Handbook will be used as the bases for determining the degree of heterogeneity. Heterogeneity values of 0%–40% will be taken as ‘perhaps not important’; Heterogeneity values of 30%–60% as ‘moderate heterogeneity’; Heterogeneity values of 50%–90% as “substantial heterogeneity” and Heterogeneity values of 75%–100% as ‘considerable heterogeneity’ (17). The level of statistical significance will be set at p< 0.05 for the Q-test.
Sub group analysis
Sub group analysis or meta-regression, if sufficient data are available, will be used appropriately to investigate the effect of statistical heterogeneity. In this study, variables such as age, sex, smoking, type of medication, and severity of IBD before transplantation are the variables that will be used in sub group analysis.
Sensitivity analysis
The one-out remove method will also be used for sensitivity analysis. If one of the combinations (K-1) of the studies shows a different result to the others, we will carefully consider the features of that study.
Quality analysis
Quality analysis will be performed if there is a statistically significant difference between the results of high-quality and low-quality studies.
Assessment of publication bias
If there are sufficient studies of more than 10, both Funnel Plot and Begg's and Egger's statistical tests will be used to evaluate publication bias. If the previously mentioned methods show evidence of the bias, the Fill & Trim method will be used to correct the publication bias effect.
Patient and public involvement
No patients will be involved in this study