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Abstract
Background and aims We aimed to determine the predictors and risk for death among persons with either Crohn's disease (CD) or UC compared with the general population.
Methods We used the population-based University of Manitoba IBD Epidemiology Database to calculate HRs and their 95% CIs for cases relative to controls using stratified multivariable Cox proportional hazards regression models, controlling for socioeconomic status and comorbidities.
Results There were 10 788 prevalent cases of CD and UC and 101 860 matched controls. The HR for all-cause mortality in prevalent CD cases was 1.26 (95% CI 1.16 to 1.38) and in prevalent UC cases was 1.04 (95% CI 0.96 to 1.12). Compared with matched controls, CD cases were more likely to die of colorectal cancer, non-Hodgkin's lymphoma, digestive diseases, pulmonary embolism and sepsis and UC cases were more likely to die from colorectal cancer, digestive diseases and respiratory diseases. For incident cases, there were significant effects on mortality by socioeconomic status, comorbidity score and surgery. The greatest risk for death in both CD and UC was within the first 30 days following GI surgery. The first year from diagnosis was associated with increased risk of death in both CD and UC, but persisted after the 1st year only in CD.
Conclusions There is a significantly increased risk of mortality in CD compared with controls while in UC an increased risk for death was only evident in the first year from diagnosis. Surgery poses an increased risk for death in both CD and UC lasting up to 1 year.
- INFLAMMATORY BOWEL DISEASE
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Significance of this study
What is already known on this subject?
Compared with the general population, there is an increased mortality rate in Crohn's disease (CD) with conflicting data as to the relative mortality rates in UC. There is little information regarding predictors of mortality in IBD.
What are the new findings?
The first year from diagnosis was associated with an increased mortality rate in both CD and UC but beyond the first year from diagnosis the increased mortality only persisted in CD.
The top causes of death in descending order for both CD and UC were cancer, circulatory disease and digestive disease.
In terms of cause-specific mortality compared with population controls, prevalent CD cases were more likely to die of colorectal cancer, non-Hodgkin's lymphoma, digestive diseases, pulmonary embolism and sepsis than matched controls and prevalent UC cases were more likely to die from colorectal cancer, digestive diseases and respiratory diseases.
GI surgery had a strong impact on mortality rates. While the impact was greatest in the first 30 days from surgery, the increased mortality rate persisted in both CD and UC beyond 1 year from surgery.
How might it impact on clinical practice in the foreseeable future?
That surgery, especially among the elderly, had a significant impact on mortality should give clinicians pause both with regard to their reluctance to using immunomodulatory medications in both CD and UC and in considering surgery too late when the disease may be more advanced and the surgical risks higher.
Venous thromboembolism and sepsis in CD and colorectal cancer in both CD and UC are associated with mortality more than in the general population underscoring the importance of thromboembolism prophylaxis when indicated and the need for ongoing colorectal cancer surveillance in IBD.
Introduction
As the prevalence of IBD increases worldwide,1 it is important to determine if outcomes for individuals with IBD are comparable from different jurisdictions. This might provide some insight if the disease in different jurisdictions is the same disease and/or whether the diversity of management in different jurisdictions differentially impacts on important clinical outcomes. A key outcome is mortality and defining predictors of mortality may point to aspects of care that can potentially be enhanced or may identify associated comorbidity that warrants attention. While several other studies have reported on mortality rates in IBD, few have examined predictors of mortality. Further, as IBD is often diagnosed in young persons, even small increases in mortality rates may be impactful on productive years of life lost.
There has been a considerable literature written to date on mortality in IBD including four meta-analyses.2–5 In these studies, having Crohn's disease (CD) has been associated with an increased risk of mortality2–5 while results as to whether UC is associated with increased mortality rate are equivocal.4 ,5 Moreover, there are limited data on IBD associated mortality from North America and the results for CD have been conflicting.6 ,7 Furthermore, it is unclear whether the mortality risk among persons with IBD is influenced primarily by the underlying disease process, its surgical and medical treatments, or concomitant medical conditions which are associated with IBD.
The aim of our study was to compare the all-cause mortality in CD and UC with that in a matched group of persons without IBD in Manitoba, Canada, using our population-based University of Manitoba IBD Epidemiology Database (UMIBDED). Further, we aimed to estimate the mortality rate for cases relative to a matched population due to specific conditions known to be more prevalent in IBD (such as colorectal cancer and venous thromboembolic disease as well as GI surgery) as well as other causes that are not specifically related to IBD (e.g., non-GI cancers, cardiovascular disease and suicide). We also aimed to evaluate the effects of socioeconomic status, medical comorbidity, time from diagnosis and time from GI surgery on overall mortality in IBD.
Methods
Data sources
Cases and controls were identified from the population-based UMIBDED, which was established in 1995 and is described in detail elsewhere.8 Manitoba is a central Canadian province with a population of 1.25 million in 2010; its population has experienced relatively little in- or out-migration over the past several decades. Briefly, the UMIBDED contains administrative data for IBD cases, ascertained using a validated case definition and matched controls. It includes individuals who had health coverage between 1 April 1984 and 31 March 2010 as identified from the administrative health databases, which include the registry of all enrolled residents in the province, hospital discharge records and physician billing claims of Manitoba Health (MH). MH is the single provincial health insurance provider for all Manitoba residents.
Residents of Manitoba who resided in the province for at least 2 years were identified as IBD cases if they had at least five unique physician contacts (either hospitalisation and/or outpatient physician billing claims) associated with International Classification of Disease (ICD)-9-CM codes 555 (CD) or 556 (UC) recorded as a diagnosis, or ICD-10-CA codes K50 and K51. ICD-10-CA codes have been used to report diagnoses in hospitalisation records since 2004. Persons residing in Manitoba for less than 2 years were included in the UMIBDED as IBD cases if they had at least three separate diagnoses with these ICD codes in the administrative health databases. The sensitivity and specificity of this case definition are both over 90% when compared with self-report data and chart-reviewed diagnosis.8 Specificity is closer to 100% in the entire population. We defined each IBD case as being prevalent or incident. Prevalent IBD cases included all individuals identified with IBD between 1 April 1984 and 31 March 2010. Incident IBD cases were those individuals who had at least 3 years of registration with MH prior to their initial IBD related encounter. The diagnosis date for incident cases was taken to be the date of the initial IBD related healthcare contact. Up to 10 controls were randomly matched to each IBD case, based on sex, region of residence (based on first three letters or numbers of the case's 6-digit postal code) and year of birth. A matched control was assigned the same index date as the respective IBD case (date of first IBD related encounter).
Deaths (and cause of deaths) were identified from the Vital Statistics Registry for the Province of Manitoba, which was linked to the UMIBDED. While date of death was available up to 31 March 2010, cause of death was available only to 31 December 2009. For prevalent cases through 31 December 2009, we identified all-cause and cause-specific deaths; for incident cases, only all-cause deaths were identified.
Within the UMIBDED, 76% of cases and 71% of controls were alive and in the study at the end date. Overall, 11% of cases and 10% of controls died during the study, and 13% of cases and 19% of controls lost MH coverage (likely meaning they moved from the province). These last subjects were censored at the time they lost MH coverage.
Predictors of mortality and statistical analysis
Socioeconomic status was assessed by the Socioeconomic Factor Index (SEFI) which is a score derived from the application of exploratory factor analysis techniques to Statistics Canada Census 2006 data and includes several neighbourhood level social determinants of wealth, including age dependency ratio, rate of single parent households, rate of female single parent households, female labour force participation rate, unemployment rate and high school education rate. The SEFI has been validated in Manitoba and is described in detail elsewhere.9 To calculate the Charlson Comorbidity Index (CCI) score,10 comorbidities were identified from all diagnoses recorded in the administrative health data for the time period between 6 and 18 months prior to an individual's end of follow-up (i.e., date of death or emigration or 31 March 2010, whichever occurred earlier). If persons had an end date prior to 1 October 1985 (i.e., they did not have 18 months of data to assess for comorbidities) or did not have MH coverage for the period of time 18 months prior to the end date, CCI was assigned a missing value. The CCI was categorised as 0, 1, 2 or ≥3 with the reference category being 0.10
The data were descriptively analysed using means, SDs, frequencies and percentages. HRs and 95% CIs were estimated for IBD cases relative to controls using stratified multivariable Cox proportional hazards regression models; the covariates were the SEFI and CCI scores. Separate models were defined for CD and UC cases and their respective controls. For incident IBD cases only, separate models were fit to the data for deaths within 1 year of diagnosis and to the data for all deaths following IBD diagnosis and also by history of GI surgery (defined as small or large bowel resection, repair, stricture surgery or stoma creation). GI surgery was a time-dependent variable: no/presurgery, 0–29 days postsurgery, 30–365 days postsurgery and 366+ days postsurgery. Analyses were conducted for all ages (at the index/IBD diagnosis date), as well as for the following current age groups: <50 years, 50–69 years and 70+ years. We also undertook a multivariate analysis of incident cases with IBD who never had surgery (excluding those who did have GI surgery) compared with controls. Further, we assessed incident cases who had GI surgery and only included the controls who were alive on the day of the IBD cases’ initial GI surgery, and left censored all the person-time prior to GI surgery.
To determine the predictors of mortality within the cohort of individuals with IBD, separate analyses were conducted for incident IBD cases only; the model included sex, age, year of IBD diagnosis, SEFI, CCI and history of GI surgery as a time dependent variable. Again, only in IBD cases, but this time in prevalent cases who had surgery, we undertook a multivariate analysis assessing for impact of sex, age at surgery, SEFI, CCI and era of GI surgery (prior to 2000 vs 2000 and after).
The analysis was performed using SAS Institute V.9.3 (Cary, North Carolina, USA). The study was approved by the University of Manitoba Research Ethics Board and the Manitoba Health Information Privacy Committee.
Results
Characteristics of cases and controls
The characteristics of cases and controls are described in table 1. A total of 10 788 prevalent cases of CD and UC and 101 860 matched controls were included. Among prevalent cases of CD (n=5286), the mean duration of follow-up was 12.7 (±8.0 SD) person-years compared with 11.7 (±8.0 SD) person-years for controls. Among prevalent cases of UC (n=5502), the mean duration of follow-up was 11.7 (±7.8 SD) person-years compared with 10.8 (±7.6 SD) person-years for controls. There were a total of 8486 incident cases of CD and UC, with 81 200 matched controls. Follow-up time was similar for incident cases and controls (table 1).
Description of incident and prevalent cases and controls
All-cause and cause-specific mortality
Among prevalent CD cases, there were 634 deaths, including 31% from cancer, 26% from circulatory disease and 14% from digestive disease (table 2). The HR for all-cause mortality in prevalent CD cases was 1.26 (95% CI 1.16 to 1.38). Among prevalent UC cases, there were 802 deaths including 27% from cancer, 29% from circulatory disease and 11% from digestive disease (table 2). The HR for all-cause mortality in prevalent UC cases was 1.04 (95% CI 0.96 to 1.12). In terms of cause-specific mortality, prevalent CD cases were more likely to die of colorectal cancer, non-Hodgkin's lymphoma, digestive diseases, pulmonary embolism and sepsis than matched controls (table 2). Among prevalent UC cases, there was excess mortality associated with colorectal cancer, digestive diseases and respiratory diseases; however, cases were significantly less likely to die of lung cancer.
HRs and CIs for mortality in prevalent cases of Crohn's disease (CD) and UC compared with matched controls*
Among incident cases of CD there were 379 deaths. The HR for all-cause mortality was 1.21 (95% CI 1.08 to 1.36). Among incident cases of UC, there were 536 deaths and the HR for all-cause mortality was 1.05 (95% CI 0.96 to 1.15). The Kaplan–Meier survival curves for CD and UC and their respective controls are shown in figure 1. Within the first year of CD diagnosis, the HR for all-cause mortality was 1.47 (95% CI 1.03 to 2.09) and for UC the corresponding HR was 1.69 (95% CI 1.30 to 2.20) (table 3). After the first year from diagnosis among incident cases of CD, the HR for all-cause mortality was 1.19 (95% CI 1.05 to 1.34) and for UC the corresponding HR was 0.99 (95% CI 0.90 to 1.10) (table 3). Survival rates at 1, 5, 10, 15 and 20 years postdiagnosis and postsurgery are higher at each milestone for CD than UC which likely reflect the younger age on average of persons with CD (see online supplementary table S1).
Number of deaths, HR and 95% CI* for incident cases of all-cause mortality for Crohn's disease (CD) and UC compared with controls stratified by current age group*
Kaplan–Meier survival curve for Crohn's disease (CD) and UC separately compared with controls.
Predictors of mortality
For all-cause mortality in both CD and UC for all ages, the HR was similar among men and women (data not shown). For CD, those less than age 50 currently tended to have an increased HR for death compared with controls (2.15, 95% CI 0.91 to 5.04) within 1 year from diagnosis and had a significantly increased HR for death beyond 1 year from diagnosis (1.35, 95% CI 1.07 to 1.79). In those less than age 50, persons of ages 30–49 had significantly increased HR for death while the HR for death was not statistically significant for those under age 30 (table 3). For persons currently 70 years of age or older, there was no increased HR for mortality compared with controls. For UC, there was an increased HR for mortality within the first year from diagnosis; however, beyond 1 year from diagnosis there was no increased HR for mortality among any current age group (table 3).
Comparing incident cases with controls, GI surgery had a comparable impact on mortality in CD and UC. Controlling for SEFI and CCI, within 30 days from GI surgery, the HR for mortality in CD was 17.5 (95% CI 9.35 to 32.8) and in UC 21.0 (95% CI 13.27 to 33.3); 30–365 days from GI surgery, the HR for mortality in CD was 3.66 (95% CI 2.81 to 4.78) and in UC 3.07 (95% CI 2.52 to 3.75); and for beyond 365 days from GI surgery in CD was 1.56 (95% CI 1.34 to 1.81) and in UC 1.21 (95% CI 1.07 to 1.38). Table 4 shows the results of an analysis including only those persons with IBD who underwent GI surgery compared with controls who were alive on the day of the IBD patients’ initial GI surgery, and left censoring all the person-time prior to GI surgery. This analysis also shows a comparably increased HR for mortality in cases with CD and in UC who come to GI surgery. The greatest HR for death in this analysis was among those less than age 50 at time of GI surgery (CD, HR 1.9 (95% CI 1.45 to 2.5) and UC HR 2.3 (95% CI 1.53 to 3.45)). For incident cases compared with controls in both CD and UC, there was a higher HR for death among women vs men (table 4). Table 5 shows the results for persons who never underwent GI surgery. This shows that there remains a modest increased HR for mortality in CD and no increase in UC. The HR for death among persons who never underwent GI surgery was similar for men as for women (data not shown).
Analysis among incident cases with Crohn's disease (CD) and UC who came to GI surgery compared with their matched controls who were alive at the time of the initial GI surgery of the CD or UC case
HRs and 95% CIs* for mortality among incident IBD cases vs their controls including only those persons who never had GI surgery
Analysis among IBD cases only: Since GI surgery had an impact on HR for death among cases compared with controls, we undertook an analysis to assess the impact of GI surgery on the adjusted HR for death among those with CD and UC, respectively, compared with persons with CD or UC who never had GI surgery (table 6). In this model, GI surgery was significantly associated with mortality and time from GI surgery also had a significant impact. The greatest risk for death in both CD and UC cases was within the first 30 days following GI surgery. In this model of assessing those with IBD undergoing GI surgery vs those who did not, the HR for death at the different time points postoperatively waned with increasing age (data not shown). The only cause of death that was associated with a statistically significantly increased risk within 30 days of GI surgery was digestive disease (data not shown). Male sex and older age at diagnosis, as well as increasing comorbidities also significantly impacted on mortality in both CD and UC. Lower socioeconomic status was a statistically significant predictor of mortality in UC cases only.
HRs and 95% CIs for death among incident cases of CD and UC who had GI surgery compared with those who did not
We then undertook an analysis among prevalent cases and controls to assess the impact of age at surgery and era of GI surgery (2000 and after vs prior to 2000) controlling for SEFI and CCI. Persons coming to GI surgery who were older had significantly increased HR for death than those under age 50. Era of surgery did not impact on HR for death (see online supplementary table S2).
Discussion
Our study found that CD was associated with a significantly increased all-cause mortality rate compared with the general population and that UC was not associated with an overall increased all-cause mortality rate. We also determined that all-cause mortality was increased in the first year following diagnosis for both CD and UC, but remained elevated following 1 year from diagnosis only for CD. An increased burden of medical comorbidity and lower socioeconomic status were significant determinants of IBD associated mortality. Surgery had a particularly important impact on mortality with the highest HR for mortality evident within the first 30 days from surgery but there was an evident impact on HR for death even out to 1 year postoperatively. Further, for persons with IBD who underwent surgery compared with controls still alive at the time of the surgery, the HR for death was comparably increased in CD and UC with the greatest impact in those less than 50 at the time of surgery. Females may be at higher risk for death after surgery for their IBD than their non-IBD (control) female counterparts than males.
Assessing current age, older persons with CD and UC (other than in that first year from diagnosis in UC) were not at increased risk of death compared with population controls. The main increased HR for death was evident among those currently younger than 50 years of age compared with population controls, including for persons with UC within 1 year from diagnosis. These data were mostly accrued among those ages 30–49 years (as opposed to those younger than 30). However, within the IBD cohort alone, persons 50–69 years and more so those at least 70 years of age who underwent surgery had a significantly higher HR compared with those younger than 50. The elderly in general have higher absolute risks for death postoperatively.11–13 We have previously shown that the elderly who are newly diagnosed with UC have an increased risk of early colectomy but once they survive the first year they have a reduced rate of colectomy suggesting a more aggressive early course of disease and a milder course of disease over the long term than younger patients.14 The impact of age and surgery on mortality may have implications for how newly diagnosed and, in particular, active UC is managed in the elderly. While there are concerns for the use of immunomodulatory agents in the elderly with reports of higher withdrawal rates from antitumour necrosis factor (anti-TNF) agents and even occasional deaths in anti-TNF users,15 ,16 balancing the risks of surgery with immunomodulatory drugs is even more challenging in the elderly. It will be of interest to reassess mortality rates in the elderly with IBD over time as there are increasingly more persons who are elderly remaining on immunomodulatory drugs.
Undergoing GI surgery is an important driver of mortality in IBD, with there being a particularly high risk for death within 30 days of GI surgery, which was particularly pronounced among persons with UC. The high risk of postoperative mortality is likely due to a combination of direct postsurgical complications, but may also relate to the pre-existing preoperative risk factors. Patients who require surgery for IBD have often exhausted most of the options for medical management, and may be underweight and or malnourished. These persons may have also undergone a rapid intensification of medical therapy in a final bid to avoid surgery, and therefore may be even further immunosuppressed. The impact of preoperative anti-TNF therapy has been studied and two meta-analyses have suggested an increased risk for postoperative complications, particularly infections in CD patients who used anti-TNF preoperatively.17 ,18 The first month postoperatively is a time of particularly higher risk for death than at other times. Perioperative sepsis and the increased risk for venous thromboembolic disease may play a role in these mortality rates. If it is indeed postsurgical status which is a major driver of overall mortality in IBD, the decreasing surgery rates in CD and UC in Manitoba and in much of the world14 ,19–21 are reassuring. It will be of interest to determine if mortality rates also decrease over time.
Our results are generally in line with the some of the previously performed studies evaluating mortality in persons with IBD. However, there is some heterogeneity among the studies, which requires further discussion. In comparison with other North American data sources, our data on overall mortality risk differ from the Olmsted County report that suggested no increased risk of death in CD6 while our results were similar to the report from the Northern California Kaiser Permanente.7 The data from within Europe vary and hence it may be that mortality outcomes cannot be generalised for all of IBD but rather may be region-specific. The meta-analysis by Jess and colleagues in UC underscored the importance of jurisdictional differences.5 The five Scandinavian studies reported higher mortality rates (pooled standardised mortality rate (SMR) 1.2, 95% CI 1.1 to 1.4, p=0.001) than did the non-Scandinavian countries (pooled SMR 0.8, 95% CI 0.7 to 0.9, p=0.001). Correspondingly, the European Cohort study of Inflammatory Bowel Disease (EC-IBD) did not show regional variation in mortality from northern to southern regions.22 In the meta-analysis by Jess and coworkers in UC,5 there was a fair amount of heterogeneity between studies with excess mortality observed in Scandinavian countries and reduced mortality observed in Italy, New Zealand, the UK and the USA. In terms of our finding a particularly increased HR for death within the first year from diagnosis, this was also reported in a 3-hospital study from the UK23 and also in a population-based study from Denmark.24
Considering the causes of death (there were increased rates of death from pulmonary embolism and sepsis in CD in our study) draws attention to venous thromboembolism prophylaxis, and meticulous care for balancing immunomodulatory therapy and infection risk both of which are critical in CD. In UC, the divergence between the increased risk of death from respiratory diseases and the decreased likelihood of lung cancer related death is not easily explained. An increased risk of death from respiratory diseases in UC was also seen in the multi-country EC-IBD study,22 driven mostly by data from Denmark and in a countrywide study from Denmark,24 and reduced risk of death from lung cancer was also reported in an Italian study.25 Patients with UC are less likely than the general population to be current smokers.26 Conversely, there also appears to be an increased risk of asthma and chronic bronchitis in persons with IBD27 and lung dysfunction in IBD.28–36 Therefore, it is possible that the higher rate of respiratory deaths associated with UC is not related to smoking.
The increased rates of death from colorectal cancer in both CD and UC and non-Hodgkin's lymphoma in CD are in line with a report from Manitoba over a decade ago.34 We have been among the only jurisdictions to report an increased risk of non-Hodgkin's lymphoma independent of thiopurine use.37 Thiopurines have been shown to increase the risk of non-Hodgkin's lymphoma in IBD.38 Considering that thiopurines are used more commonly in CD than in UC in Manitoba, the underlying risk for non-Hodgkin's lymphoma in CD and the risk posed by thiopurines may be driving the increased mortality evident from this cancer in CD and not in UC.
The increased risk of death from colorectal cancer is in keeping with data from Olmsted County, Minnesota, where there was an increased risk of intestinal cancer deaths in CD,6 and from the Kaiser Permanente Northern California IBD cohort in both CD and UC.39 Conversely, in Denmark, the risk of colorectal cancer in IBD has been declining in recent years as has the SMR from colorectal cancer (although the overall SMR from colorectal cancer for a 30-year period was significantly elevated).24 ,40 Similarly, in Sweden, while the overall relative risk of colorectal cancer diagnosis was increased in persons with IBD compared with controls, the recent relative risk has been lower than in years past. Further, the SMR in recent years has declined compared with the 1960s such that it was not significantly increased compared with the general population (2000–2004).41 Again, this emphasises that outcomes after IBD diagnosis may be different in North America than in Europe and hence population-based studies from North America are required to estimate risks in North America. Since North American studies suggest an increased risk of death from colorectal cancer, we should likely remain vigilant in surveying for this potentially preventable cause of death.
There are some limitations to our study. With the administrative data of the UMIBDED and the Vital Statistics Registry, we could not access charts to directly confirm the causes of death. Also, we could not ascertain IBD-specific factors such as disease phenotype, disease severity or other behavioural issues like exercise, tobacco use, alcohol consumption or obesity which may have effects on the likelihood of death. Further, the administrative definition of IBD required persons to have 5 individual contacts with the healthcare system before they could be deemed to be a case of IBD. It is possible that some persons with IBD die before they have 5 individual contacts with the healthcare system (die before they are deemed to be a true case of IBD within our UMIBDED). With this in mind, it is possible that we have underestimated the risk for death among persons with IBD. Nonetheless, the comprehensive nature of our administrative databases and that we have persons with over 25 years of postdisease follow-up is a unique strength of the study.
In summary, we are reporting a statistically significant increased risk of mortality in CD compared with controls and a smaller but not statistically significant increase in mortality rate in UC. Pulmonary embolism and sepsis are important causes of death in CD while respiratory disease is an important cause of death in UC. Colorectal cancer remains an increased cause of death in both CD and UC, hence ongoing colonoscopic surveillance remains of value despite recent reports from Europe of no increased risk of colorectal cancer diagnosis or deaths in IBD. The first year after diagnosis and also after surgery in both CD and UC is a time when patients are at increased risk of death. The first 30 days from surgery, in particular, is associated with relatively very high mortality rates in both CD and UC. Not surprisingly, the elderly who come to GI surgery have a higher risk for death than those younger than 50 who come to GI surgery. Clinicians, therefore, should be more open to the use of immunomodulatory therapy in the elderly to reduce the risk of requiring surgical management. It also seems that for persons who do not have GI surgery, mortality rates in CD are still elevated suggesting some intrinsic risk for death posed by CD that is independent of GI surgery. Most patients with IBD have a comparable lifespan to the general population but, as therapy of these diseases becomes more complex, our data showing certain associations with mortality are a reminder that IBD should still be cared for in a multispecialty fashion.
References
Supplementary materials
Supplementary Data
This web only file has been produced by the BMJ Publishing Group from an electronic file supplied by the author(s) and has not been edited for content.
Files in this Data Supplement:
- Data supplement 1 - Online table 1
- Data supplement 2 - Online table 2
Footnotes
Contributors CNB: study concept and design; acquisition of data; analysis and interpretation of data; drafting of the manuscript; critical revision of the manuscript for important intellectual content; statistical analysis; study supervision. ZN: study concept and design; analysis and interpretation of data; critical revision of the manuscript for important intellectual content; statistical analysis; technical, or material support. LET, HS and LML: study concept and design; analysis and interpretation of data; critical revision of the manuscript for important intellectual content; statistical analysis.
Funding The authors declare that there were no financial conflicts for any of the authors with any third party in conducting this research. This research study was not funded by any third party.
Competing interests CNB is supported in part by the Bingham Chair in Gastroenterology. CNB has provided consultation to Abbvie Canada, Janssen Canada, Forest Canada, Takeda Canada, Bristol Myers Squibb, Vertex Pharmaceuticals, Hospira and Pfizer. He has received research grants from Abbvie Canada and unrestricted educational grant from Aptalis Pharmaceuticals Takeda Canada, Shire Canada and Abbvie Canada. LET is supported by the CIHR New Investigator Award in Gastroenterology, and has received Research Support from Abbvie Canada and Pfizer Canada. She has also participated on Advisory Boards for Abbvie Canada, Takeda Canada and Janssen Canada, and served on Speaker's Panels for Pfizer Canada and Takeda Canada. HS has provided consultation to Medial Cancer Screening, Israel. LML is supported by a Manitoba Research Chair. The results and conclusions presented are those of the authors.
Ethics approval University of Manitoba Health Research Ethics Board.
Provenance and peer review Not commissioned; externally peer reviewed.
Data sharing statement All data that are available have been included in the paper or in the supplementary files.