Appendix A. Cumulative Incidence of Second Intestinal Resection in Crohn S Disease: A

Appendix A. Cumulative incidence of second intestinal resection in Crohn’s disease: a systematic review and meta-analysis of population-based studies

Background:

Crohn’s disease is a chronic, incurable condition of the gastrointestinal tract commonly diagnosed in adolescents and young adults. Over the past decades, the incidence and prevalence have increased and are continuing to rise worldwide1. Due in part to its incurable nature, Crohn’s disease places a considerable emotional and financial burden on patients, their families, and society2,3.

Crohn’s disease is characterized by its remitting and relapsing behavior. Although medical

management may induce and maintain remission, it is not always effective. A recent systematic review and meta-analysis demonstrated that the 10-year risk of surgery was 46.64. Further, the risk of first surgery in Crohn’s disease was shown to be decreasing over time4. While this is promising news, over half of patients will relapse following an operation within 2 years5,6. Additionally, standardized regimens to prevent postoperative recurrence have changed over time. Immunomodulators and more recently anti-

TNF therapies have become more widely used as medical prophylaxis of postoperative Crohn’s disease recurrence5,7. However, the impact of these treatments on second surgery is not well characterized.

A number of population-based studies have explored the occurrence of second surgery in Crohn’s disease8-10. However, these studies have not been systematically assessed nor summarized to identify the occurrence of second surgery in Crohn’s disease. Therefore, we conducted a systematic review and meta-analysis of population-based studies to define the risk of second surgery among Crohn’s disease patients.

1.0 Focused Question:

Primary

1. What is the risk of second surgery in persons with Crohn’s disease (CD) who have already undergone a first surgery? Secondary

1. Has the risk of second surgery in persons with CD changed over time?

2.0 Search Strategy:

The online databases to be searched are Medline (between 1940-2014) and Embase (Excerpta

Medica Database) between 1980 and 2014, and PubMed 2014. Two independent reviewers (AF and DL) will search abstracts from the American Gastroenterological Association, American College of

Gastroenterology, United European Gastroenterology Week, and European Crohn’s and Colitis

Organisation between 2009 to 2012 will be reviewed. Additionally, the two independent reviewers will search the bibliographies of all included studies. An expert in the field (GK) will be consulted for information on potential ongoing or unpublished studies.

The search of online databases will include all languages and publishing dates. Animal studies will be included initially in order to avoid misclassification of study type by Medline and/or EMBASE.

These searches will be completed in accordance with search strategy recommended by Egger for systematic reviews for observational studies.

1. A Boolean search to identify relevant articles on inflammatory bowel diseases using the term “OR” to explode (search by subject heading) and map (search by keyword) the following MeSH headings and text (identified by .tw): a. MEDLINE “Inflammatory Bowel Diseases,” inflammatory bowel disease*.tw,” “ulcerative colitis.tw,” “crohn*.tw,” b. EMBASE “ulcerative colitis,” “crohn disease,” “inflammatory bowel disease.tw,” “ulcerative colitis.tw,” “crohn disease.tw” c. PUBMED “Inflammatory bowel disease,” “Crohn’s disease,” “ulcerative colitis” 2. A second Boolean search to identify relevant articles on the outcome of surgery, was done using the term “OR” to explode the following MeSH headings and text: a. MEDLINE “Colorectal Surgery,” “General Surgery,” “surgery.tw,” “surgical.tw,” “resecti*.tw” b. EMBASE “abdominal surgery,” “elective surgery,” “emergency surgery,” “general surgery,” “major surgery,” “minimally invasive surgery,” “surgery.tw,” “surgical.tw,” “resecti*.tw” c. PUBMED “colectomy,” “surgery,” “abdominal surgery” 3. A third Boolean search using the term “OR” was done to identify relevant population-based studies, using the following MeSH headings and text: a. MEDLINE “Epidemiologic Methods,” “Epidemiology,” “Population,” “prevalence.tw,” “incidence.tw,” “epidemiolog*.tw,” “population.tw,” “community.tw” b. EMBASE “epidemiological data,” “epidemiology,” “population and population related phenomena,” “prevalence.tw,” “incidence.tw,” “epidemiolog*,” “population.tw,” “community.tw” c. PUBMED “epidemiology,” “incidence,” “prevalence”

3.0 Initial Screen of Abstracts:

Two individuals will conduct an initial screen of identified abstracts with AF representing one reviewer and DL representing the second reviewer. Articles will be considered for further review if:

1. They report on original data from an original study (e.g. no reviews, comment, editorials, etc.) 2. They report a population-based estimate of second surgery in persons with CD using an observational study design.

Articles will not be considered for further review if:

1. They do not include IBD patients 2. They do not include information on IBD surgery 3. There is no indication that the study is population-based (e.g. case series, case report)

The initial screen is intentionally broad in an attempt to capture any relevant literature. We will include both CD and ulcerative colitis in the first screen to ensure that we do not miss any CD patients.

In order to provide a comprehensive systematic review, we will not limit to a specific geographic region

(eg. Europe), time period (eg after 1990), but will include all original literature reporting on surgical risk in IBD, even if surgery type and IBD diagnosis method are not indicated. Agreement between reviewers will be quantified. Any disagreement will be resolved by consensus. The Boolean “OR” term will be used to decide which articles to consider for further review (if AF or MN indicate that further review is needed).

4.0 Second Screen of Articles Identified for Eligibility: Two individuals (AF, DL) will scan full-text articles for eligibility based on the following criteria:

Participants:

Include:

a. All human patients with CD a.i. All ages included a.ii. All clinical settings included Exposure/Comparison:

1. Second surgery following a first surgery 2. Year of CD diagnosis (before versus after 1980) a. Where year is defined by calendar year Outcome:

Include:

1. Report either: a. Risk of second surgery for the overall study period, 5, or 10 years after first CD surgery b. Report proportion of CD patients who underwent second surgery for the overall study period, 5, or 10 years after having had a first CD surgery. Exclude:

1. Second surgery for the overall study period, 5, or 10 years after first surgery not reported. 2. No description of how surgery was defined.

Design:

Include:

1. Observational studies a. Cohort (both prospective and retrospective) b. Cross-Sectional 2. Population-based studies a. Population-based is defined by use of probability sampling; study of entire population in defined area; or study of only centre serving a certain population of known size. Exclude:

1. Non-original research a. Review articles b. Randomized-controlled trials (RCTs) c. Quasi-RCTs 2. Case-control studies

This screen is designed to capture studies identifying second surgical risk among persons with

CD who had already undergone a first surgery for potential meta-analysis. The agreement between reviewers (AF and DL) for articles will be quantified. Any disagreement will be resolved by consensus.

5.0 Data Extraction:

A standard electronic data form has been developed and will be used to extract relevant information from articles. Two individuals will independently extract the data (AF and DL).

The following bullet points highlight the main categories presented in the form:

 Reference information (e.g. author, journal, year of publication)  Study population (e.g. location of study, year(s) of study, age, sex, sample size)  Condition information (e.g. diagnostic criteria, number of surgeries, data sources)  Breakdown of incidence/prevalence by socio-demographic factors (e.g. drug information, surgery information, subgroup incidence/prevalence – subgroups will be by age and sex)  Quality assessment (e.g. sample representativeness, assessment methods, statistical methods)

Selected studies will undergo an assessment of quality by each reviewer, and will be descriptively reported in a table. The elements of this assessment will be based on MOOSE standards for reporting of meta-analyses11. The use of MOOSE standards will allow for assessment of the amount of systematic error in the individual studies.

The quality assessment was adapted previously published literature on assessing the quality of prevalence studies12.

6.0 Data Synthesis/Analysis:

We will present data on the number and characteristics of articles identified for systematic review, and the number and characteristics of studies identified for meta-analysis. The number of studies identified and excluded (including reason for exclusion) will be summarized using the flow chart method identified by Egger13. The primary objective is to identify risk of second surgery in patients with CD for the overall study period, 5, and 10 years after diagnosis. The secondary objective is to assess changes in the risk of second surgery in CD before and after 1980.

When sufficient information is available, we will perform subgroup analyses by potential sources of heterogeneity such as population age, geographic location, method of data collection. These analyses will be quantified using the Cochran Q for subgroup analysis.

We will assess heterogeneity within study years using the Q statistic. If there is significant heterogeneity, we will use a random effects model to combine the studies. Because we suspect there to be significant heterogeneity, we will undertake a stratified analysis by continent of study. We will also consider performing meta-regression to explore clinical and methodological factors that might contribute to this heterogeneity. If sufficient information is available, we will explore the interaction of time with population age, geographic location, and method of data collection. The amount of heterogeneity will be quantified using I2.

References:

1. Molodecky NA, Soon IS, Rabi DM, et al. Increasing incidence and prevalence of the inflammatory bowel diseases with time, based on systematic review. Gastroenterology. Jan 2012;142(1):46-54 e42; quiz e30. 2. Muller KR, Prosser R, Bampton P, Mountifield R, Andrews JM. Female gender and surgery impair relationships, body image, and sexuality in inflammatory bowel disease: patient perceptions. Inflammatory bowel diseases. Apr 2010;16(4):657-663. 3. Alves A, Panis Y, Mathieu P, Mantion G, Kwiatkowski F, Slim K. Postoperative mortality and morbidity in French patients undergoing colorectal surgery: results of a prospective multicenter study. Arch Surg. Mar 2005;140(3):278-283, discussion 284. 4. Frolkis AD, Dykeman J, Negron ME, et al. Risk of Surgery for Inflammatory Bowel Diseases Has Decreased Over Time: A Systematic Review and Meta-analysis of Population-Based Studies. Gastroenterology. Nov 2013;145(5):996-1006. 5. Peyrin-Biroulet L, Deltenre P, Ardizzone S, et al. Azathioprine and 6-mercaptopurine for the prevention of postoperative recurrence in Crohn's disease: a meta-analysis. The American journal of gastroenterology. Aug 2009;104(8):2089-2096. 6. Bernell O, Lapidus A, Hellers G. Risk factors for surgery and postoperative recurrence in Crohn's disease. Annals of surgery. Jan 2000;231(1):38-45. 7. Regueiro MD. Management and prevention of postoperative Crohn's disease. Gastroenterology & Hepatology. 2011;7(3):170-172. 8. Ramadas AV, Gunesh S, Thomas GA, Williams GT, Hawthorne AB. Natural history of Crohn's disease in a population-based cohort from Cardiff (1986-2003): a study of changes in medical treatment and surgical resection rates. Gut. Sep 2010;59(9):1200-1206. 9. Solberg IC, Vatn MH, Hoie O, et al. Clinical course in Crohn's disease: results of a Norwegian population-based ten-year follow-up study. Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association. Dec 2007;5(12):1430-1438. 10. Peyrin-Biroulet L, Harmsen WS, Tremaine WJ, Zinsmeister AR, Sandborn WJ, Loftus EV, Jr. Surgery in a population-based cohort of Crohn's disease from Olmsted County, Minnesota (1970- 2004). The American journal of gastroenterology. Nov 2012;107(11):1693-1701. 11. Stroup DF, Berlin JA, Morton SC, et al. Meta-analysis of observational studies in epidemiology: a proposal for reporting. Meta-analysis Of Observational Studies in Epidemiology (MOOSE) group. JAMA : the journal of the American Medical Association. Apr 19 2000;283(15):2008- 2012. 12. Boyle MH. Guidelines for evaluating prevalence studies. Evid Based Mental Health. 1998;1:37- 39. 13. Egger E, Smith GD, Altman DG. Systematic reviews in health care: meta-analysis in context. London: BMJ Publishing Group; 2001. Appendix B PRISMA Checklist

Reported Section/topic # Checklist item on page # TITLE Title 1 Identify the report as a systematic review, meta-analysis, or both. 1 ABSTRACT Structured summary 2 Provide a structured summary including, as applicable: background; objectives; data sources; study eligibility criteria, participants, and interventions; study appraisal and synthesis methods; results; limitations; conclusions and implications of key findings; systematic review registration number. 3 INTRODUCTION Rationale 3 Describe the rationale for the review in the context of what is already known. 6 Objectives 4 Provide an explicit statement of questions being addressed with reference to participants, interventions, comparisons, outcomes, and study design (PICOS). 6, 7 METHODS Protocol and registration 5 Indicate if a review protocol exists, if and where it can be accessed (e.g., Web address), and, if available, provide registration information including registration number. 7 (Appendix A) Eligibility criteria 6 Specify study characteristics (e.g., PICOS, length of follow‐up) and report characteristics (e.g., years considered, language, publication status) used as criteria for eligibility, giving rationale. 7 Information sources 7 Describe all information sources (e.g., databases with dates of coverage, contact with study authors to identify additional studies) in the search and date last searched. 7 Search 8 Present full electronic search strategy for at least one database, including any limits used, such that it could be 7 repeated. (Appendix C) Study selection 9 State the process for selecting studies (i.e., screening, eligibility, included in systematic review, and, if applicable, included in the meta‐analysis). 7 Data collection process 10 Describe method of data extraction from reports (e.g., piloted forms, independently, in duplicate) and any processes for obtaining and confirming data from investigators. 7, 8 Data items 11 List and define all variables for which data were sought (e.g., PICOS, funding sources) and any assumptions and simplifications made. 7, 8 Risk of bias in 12 Describe methods used for assessing risk of bias of individual studies (including specification of whether this was individual studies done at the study or outcome level), and how this information is to be used in any data synthesis. 7, 8 Summary measures 13 State the principal summary measures (e.g., risk ratio, difference in means). 7, 8 Synthesis of results 14 Describe the methods of handling data and combining results of studies, if done, including measures of consistency (e.g.,7, 8 Risk of bias across studies 15 SpecifyI2 for each any meta-analysis) assessment of risk of bias that may affect the cumulative evidence (e.g., publication bias, selective reporting7, 8 within studies). Additional analyses 16 Describe methods of additional analyses (e.g., sensitivity or subgroup analyses, meta-regression), if done, indicating 7, 8 which were pre‐specified. RESULTS Study selection 17 Give numbers of studies screened, assessed for eligibility, and included in the review, with reasons for exclusions at 9 (Figure 1) each stage, ideally with a flow diagram. Study characteristics 18 For each study, present characteristics for which data were extracted (e.g., study size, PICOS, follow-up period) and 9, 10 provide the citations. Risk of bias within studies 19 Present data on risk of bias of each study and, if available, any outcome level assessment (see item 12). 10 (Appendix D) Results of individual 20 For all outcomes considered (benefits or harms), present, for each study: (a) simple summary data for each intervention 105 (Figure 2) studies group (b) effect estimates and confidence intervals, ideally with a forest plot. Synthesis of results 21 Present results of each meta-analysis done, including confidence intervals and measures of consistency. 10, 11

Risk of bias across studies 22 Present results of any assessment of risk of bias across studies (see Item 15). 11

Additional analysis 23 Give results of additional analyses, if done (e.g., sensitivity or subgroup analyses, meta-regression [see Item 16]). 10, 11

DISCUSSION Summary of evidence 24 Summarize the main findings including the strength of evidence for each main outcome; consider their relevance to key 11-14 groups (e.g., healthcare providers, users, and policy makers). Limitations 25 Discuss limitations at study and outcome level (e.g., risk of bias), and at review-level (e.g., incomplete retrieval of 13 identified research, reporting bias). Conclusions 26 Provide a general interpretation of the results in the context of other evidence, and implications for future research. 11-14 FUNDING Funding 27 Describe sources of funding for the systematic review and other support (e.g., supply of data); role of funders for the 17 systematic review. Appendix C Detailed Search Strategy for Medline, EMBASE, and Pubmed

Used validate d Probabilit Study Used criteria y sampling sample standardize for Describe Target or entire represents d data disease Patient s those Other population population the target collection diagnosi retentio lost to biase Study defined surveyed population methods s n > 70% follow-up sa Hellers et al, 1979 Yes Yes Yes Unclear Yes Yes NR No Binder et al, 1985 Yes Yes Yes Unclear Yes Yes Yes No O’Keefe et al, 1989 Yes Yes Yes Unclear Yes Yes Yes No Peyrin-Biroulet et al, 2012 Yes Yes Yes Yes Yes NR NR No Lakatos et al, 2012 Yes Yes Yes Yes Yes NR NR No Ramadas et al, 2010 Yes Yes Yes Unclear Yes Yes NR No Boualit et al, 2012 Yes Yes Yes Yes Yes NR NR No Nguyen et al, 2011 Yes Yes Yes Unclear Yes NR NR No Solberg et al, 2007 Yes Yes Yes Yes Yes Yes Yes No Benchimol et al, 2011 Yes Yes Yes Unclear Yes NR NR No Nguyen et al, 2012 Yes Yes Yes Unclear Yes NR NR No Nguyen et al, 2014 Yes Yes Yes Unclear Yes NR NR No NR Not reported a Other biases assessed were selection and misclassification bias